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G. Mostbeck

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    SC01 - Staging Before and After Induction Therapy for N2 Disease (ID 325)

    • Event: WCLC 2016
    • Type: Science Session
    • Track: Radiology/Staging/Screening
    • Presentations: 6
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      SC01.01 - The Importance of Mediastinal Down-Staging During Induction Therapy of N2 Disease (ID 6598)

      P. De Leyn, H. Decaluwe, C. Dooms, J.F. Vansteenkiste

      • Abstract
      • Slides

      Abstract:
      The importance of mediastinal downstaging during induction therapy of N2 disease P. De Leyn*, H. Decaluwe*, C. Dooms** and J. Vansteenkiste**. Department of Thoracic Surgery*, Department of Pneumology**, University Hospitals Leuven, Belgium Patients with preoperative pathological proven N2 disease have a dismal prognosis after surgery. Neoadjuvant chemotherapy or chemoradiotherapy is a therapeutic option that is used in patients with baseline resectable stage IIIA-N2 non-small cell lung cancer. Mediastinal downstaging is an important prognostic factor for long term survival. Different restaging techniques are available. The mediastinum can be restaged by CT scan, remediastinoscopy, VATS, PET-CT and EBUS-EUS fine needle aspiration. In primary staging, CT scan has proved to have a low accuracy. It is not surprising that the accuracy of CT scan in restaging the mediastinum is also low. In a Spanish study of 24 patients who underwent neoadjuvant chemotherapy for N2 non-small cell lung cancer, staging was performed by CT scan and remediastinoscopy (1). CT scan had a sensitivity of 41%, a specificity of 75% and an accuracy of 58%. In a prospective study of 93 patients who were restaged by integrated PET-CT after induction chemoradiotherapy, repeat PET-CT was found to be more accurate than CT alone for pathological stages. However, there were 20 false negative and 25 % false positive cases. So, in case of suspicion of residual mediastinal disease, nodal biopsies are still required (2). We evaluated in a prospective single center study repeat mediastinoscopy and PET-CT after induction chemotherapy for N2 disease. PET-CT had a sensitivity of 77% and a specificity of 88% (3). Repeat mediastinoscopy, technically much more difficult than the first procedure, offers the advantage of providing histological evidence of response after induction therapy. Although some centers obtain good results (4), most surgeons will accept that remediastinoscopy is technically difficult and often incomplete. We performed a prospective study to evaluate the accuracy of remediastinoscopy and PET-CT in restaging the mediastinum after mediastinoscopy proven N2 disease (3). The first mediastinoscopy was thoroughly performed with a mean lymph node level of 3.6 per patient biopsied. In our experience, remediastinoscopy was technically feasible, but inaccurate due to severe adhesions and fibrosis. The sensitivity to detect residual mediastinal lymph nodes was only 28,6% with an accuracy of 58,3%. Minimally invasive endoscopic technique EUS and EBUS also obtain histological diagnosis. Their accuracy is very good in baseline mediastinal staging. In the study Herth et al (5) EBUS-FNA was performed for restaging after induction chemotherapy or chemoradiotherapy for N2 disease in 124 patients. The sensitivity was 76% but the negative predictive value was as low as 20%. The largest series in the literature is reported by Szlubowski (6). They combined EBUS-EUS FNA for restaging N2 disease in 106 patients. Sensitivity was 67% with a negative predictive value of 73%. Some recent smaller studies showed better results for EBUS-EUS to prove persistent nodal disease. Most of the new lesions that appear after induction chemotherapy on PET-CT are not malignant (7). We know that some patients with minimal persistent N2 disease (mainly single level) can have a good prognosis after surgical resection (8). In a study published by Dooms et al (9) patients with less than 10% viable tumor cells in mediastinal lymph node sampled at mediastinoscopy and s with more than 60% decrease of SUV~max~ of primary tumor had a five year survival of over 60%. Therefore, we believe that a new staging algorithm could be used to select patients for radical therapy after induction chemotherapy for N2 disease. At baseline staging, pathological N2 disease should be proved by EBUS-EUS fine needle aspiration. PET-CT should be done to exclude distant metastasis and to evaluate SUV~max~ of the primary tumor. At restaging, mediastinoscopy with nodal dissection should be performed. Also repeat PET-CT should be done. In patients with major pathological response in lymph nodes and a major SUV drop of the primary tumor, surgery can be performed with good outcome. References (1)Mateu-Navarro M, Rami-Porta R, Bastus-Oiulats R, Cirera-Noqueras L, Gonzalez-Pont G. Remediastinoscopy after induction chemotherapy in non-small cell lung cancer. Ann Thorac Surg 2000;70:391-5. (2)Cerfolio R, Bryant A, Ojha B. Restaging patients with N2 (stage IIIa) non-small cell lung cancer after neoadjuvant chemoradiotherapy: a prospective study. J Thorac Cardiovasc Surg 2006;131(6):1229-1235. (3)De Leyn P, Stoobants S, Vansteenkiste J, Dewever W, Lerut A.. Prospective study of accuracy of redo videomediastinoscopy and PET-CT in detecting residual mediastinal disease after induction chemotherapy for NSCLC. Lung Cancer 2005;49 Suppl 2 : S3. (4)Rami-Porta R, Call S. Invasive staging of mediastinal lymph nodes: mediastinoscopy and remediastinoscopy. Thorac Surg Clin 2012: 22:177-89. (5)Herth F, Annema J, Eberhardt R, Yasufuku K, Ernst A, Krasnik M, Rintoul R. Endobronchial ultrasound with transbronchial needle aspiration for restaging the mediastinum in lung cancer. J Clin Oncol 2008;26(20):3346-3350. (6)Szlubowski A, Zielinski M, Soja J, Filarecka A, Orzechowski S, Pankowski J, Obrochta A, Jakubiak M, Wegrzyn J, Cmiel A. Accurate and safe mediastinal restaging by combined endobronchial and endoscopic ultrasound-guided needle aspiration performed by single ultrasound bronchoscope. Eur J Cardiothor Surg 2014;46:262-266. (7)Collaud S, Lardinois D, Tischler V, Steinert H, Stahel R, Weder W. Significance of a new fluorodeoxyglucose-positive lesion on restaging positron emission tomography/computed tomography after induction therapy for non-small-cell lung cancer. Eur J Cardiothorac Surg 2012;41:612-616. (8)H. Decaluwé, P. De Leyn, J. Vansteenkiste, C. Dooms, D. Van Raemdonck, P. Nafteux, W. Coosemans, T. Lerut. Surgical multimodality treatment for baseline resectable stage IIIA-N2 non-small cell lung cancer. Degree of mediastinal lymph node involvement and impact on survival. Eur J Cardiothoracic Surg 2009 ;36 :433-9. (9)Dooms C, Verbeken E, Stroobants S, Nackaerts K, De Leyn P, Vansteenkiste J. Prognostic stratification of stage IIIA-N2 non-small-cell lung cancer after induction chemotherapy: a model based on the combination of morphometric-pathologic response in mediastinal nodes and primary tumor response on serial 18-fluoro-2-deoxy-glucose positron emission tomography. J Clin Oncol 2008;26(7):1128-1134.

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      SC01.02 - PET-CT for Response Assessment During Induction Therapy of N2 NSCLC (ID 6599)

      C. Pöttgen, M. Stuschke

      • Abstract
      • Slides

      Abstract:
      Approximately 30% of patients with non-small cell lung cancer (NSCLC) are found to have locally advanced stage III tumours at initial diagnosis. For these patients the curative therapeutic options include definitive high-dose radiotherapy with concurrent chemotherapy or, alternatively, induction treatment followed by surgery. Preoperative chemotherapy or combined radiochemotherapy protocols followed by resection result in cure rates of 25-35 percent at 3 years for locally advanced NSCLC. However, surgical resection in patients with stage IIIa N2 remains an issue of controversy depending on the extent of lymph node involvement. Neoadjuvant chemo- or radiochemotherapy is being used to reduce disease burden in the mediastinum before surgery since patients who are downstaged via neoadjuvant therapy and then undergo resection experience a significantly longer 5-year survival of 40% to 50% than those who are found to have residual N2 disease at the time of surgery. Thus, identification of patients who are N2 negative after completion of their neoadjuvant therapy is a critical component for patient selection for thoracotomy. However, clinical restaging in these patients often is challenging. Endoscopic ultrasound guided biopsies (EUS/EBUS-FNA) have increasingly become available and are currently preferred procedures for staging and restaging before surgery due to their high diagnostic accuracy.(1) Serial PET-CT imaging captures anatomical changes and additionally offers semiquantitative information about morphometric and metabolic tissue changes during induction treatment. Issues of PET-CT performance and quality assurance concerning standardization have been clarified during recent years and the validity of repeated measurements has been approved.(2) Successful induction treatment regimes have been frequently found to reduce 18F-FDG uptake and thus PET-CT allows to assess the therapeutic response. Reduction in FDG-uptake of mediastinal lymph nodes after induction therapy has been shown to correlate well with histopathologic response (3), while postinduction PET avidity taken alone was not consistently found to be associated with pathological N2 involvement (4). In the direct comparison of EUS-FNA with PET-CT for restaging after induction chemoradiotherapy, concordance between findings of restaging EUS-FNA and metabolic response of lymph node metastases was observed in 63% patients treated within a prospective study but the diagnostic accuracy of PET-CT was limited.(5) Nevertheless, serial FDG-uptake measurements seem to provide prognostic information during induction therapy. Data collected in prospective trials suggest that a decrease in SUV~max~ between 45% to 60% optimally separates between responders and non-responders (6-9). In a recent large retrospective analysis, a decrease in SUV~max~ greater than 60% in the involved mediastinal nodes was the best predictor of overall survival, better than changes seen in the primary tumour site. (10) An analysis of a randomized trial in potentially resectable stage III NSCLC of induction treatment (including a hyperfractionated accelerated radiotherapy phase) and definitive radiochemotherapy compared with induction treatment followed by surgery confirmed that as early as after two cycles of cisplatin-based induction chemotherapy percentage of SUV~max~ remaining represents a significant prognostic parameter.(9) PET-response was of higher importance than all other clinical factors. Cut-off levels between 0.45 and 0.55 were predictive for freedom from extracerebral progression in all randomized patients. No important differences in the predictive value were observed comparing resection versus definitive radiochemotherapy. PET-response was closely related to extracerebral distant metastases but not to local recurrences, independent of treatment. One might conclude that less PET-responsive tumors are successfully controlled by intensified hyperfractionated accelerated radiochemotherapy or neoadjuvant radiochemotherapy and resection at loco-regional sites so that the highest risk of relapse remains at extracerebral distant sites. Therefore, a selection or intensification of the local therapy according to SUV-decrease is not warranted by these data. Functional imaging has not yet been fully established for treatment guidance but prospective evaluation is underway. In the group of poor-responding patients, treatment intensification by independent systemic options such as targeted therapy or immunomodulating therapy may become emerging new treatment options within clinical trials. References: 1) De Leyn EJCTS 2014, 2) Young, EJC 1999, 3) Pöttgen CCR 2006, 4) Ripley JTCS 2016, 5) Stigt, Lung Cancer 2009, 6) Hoekstra, JCO 2005, 7) Eschmann, Lung Cancer 2007, 8) Dooms, JCO 2008, 9) Pöttgen, JCO 2016, 10) Barnett ATS 2016

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      SC01.03 - EBUS/EUS for Staging During Induction Therapy of N2 NSCLC (ID 6600)

      F. Stanzel

      • Abstract
      • Slides

      Abstract not provided

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      SC01.04 - The Role of Mediastinoscopy in Induction Therapy of N2 NCSLC (ID 6601)

      S. Call

      • Abstract
      • Slides

      Abstract:
      Rationale for restaging after induction therapy Persistent mediastinal nodal involvement after induction therapy is an independent prognostic factor associated with poor prognosis [1]. Based on the results of two phase III clinical trials on multimodality treatment for pathologically proven N2 non-small cell lung cancer (NSCLC) [2,3], patients with persistent mediastinal involvement do not benefit from surgical resection in terms of survival. The assessment of an objective response after induction therapy continues to be a diagnostic challenge. For this reason, the use of ‘mediastinal downstaging’ as a criterium to select patients for surgery requires a reliable restaging method to predict pathologic stage before lung resection. Algorithm for mediastinal restaging The European Society of Thoracic Surgeons guidelines for preoperative lymph node staging for NSCLC recommend histological confirmation of objective response after induction therapy. This confirmation can be done with ultrasound-guided endoscopic techniques. However, the use of an invasive surgical technique is still recommended when the results of endoscopic procedures are negative [4]. The role of mediastinoscopy Mediastinoscopy in restaging can be performed in the following situations: 1) after induction therapy with no pretherapeutic invasive diagnosis; 2) after induction therapy with mediastinal histological confirmation by endoscopic techniques; 3) after induction therapy preceded by staging mediastinoscopy. In this case, mediastinoscopy is a reoperation: a remediastinoscopy. The use of first mediastinoscopy for restaging is addressed in a small series [5]. In this article, a negative predictive value (NPV) of 90% with a prevalence of ypN2 of 46% were reported. Theoretically, this approach could be a good strategy to perform an easier and safe mediastinoscopy due to the absence of adhesions in the mediastinum. Remediastinoscopy (reMS) is a technique that does not differ much from a conventional mediastinoscopy. However, reMS is technically more demanding because of peritracheal adhesions, resulting in a lower accuracy in comparison with the first procedure. The main goal of this procedure is to take new biopsies of those nodes that had been positive at first mediastinoscopy. Moreover, if it is technically feasible, other nodal stations should be reached to rule out subclinical progression of the disease. Although reMS is not a common procedure, several authors have reported its feasibility and consistent results (see table 1). In addition, its results do not seem to depend on the type of the induction therapy (chemotherapy or chemoradiation) or on the level of thoroughness of the initial mediastinoscopy [6]. Morbidity rate ranges from 0% to 4%, and complications are not specific of reMS because they can also occur at first mediastinoscopy [1,6-8]. Regarding mortality, only one death has been reported. Based on the four largest published series, this intraoperative death represents a mortality rate of 0.2% [1,6-8]. The role of transcervical lymphadenectomies During the last decade, two new surgical staging procedures were developed: videoassisted mediastinoscopic lymphadenectomy (VAMLA) and transcervical extended mediastinal lymphadenectomy (TEMLA). The main difference between these procedures is that VAMLA is an endoscopic technique performed through a videomediastinoscope, and TEMLA is an open procedure assisted by a videomediastinoscope or a videothoracoscope, depending on the nodal station dissected. Both techniques imply the removal of all the lymph nodes of the explored nodal stations, allowing the identification of minimal nodal disease that is not identified on computed tomography (CT) or positron emission tomography (PET). Therefore, after a properly performed transcervical lymphadenectomy, the restaging of the mediastinum is unnecessary because there is no material left for a new biopsy. Focusing on the use of these procedures for restaging after induction therapy, only TEMLA has been validated on two retrospective studies conducted in the same institution. In the first series with 63 patients, the diagnosis of N2-3 disease before induction treatment was confirmed with invasive techniques in 27 patients (20 with endosonography and 7 with mediastinoscopy), and with CT in 36. Sensitivity, specificity and accuracy of restaging TEMLA were 95.5%, 100% and 98.3%, respectively [9]. In the second series with 176 patients treated with chemo- or chemotherapy, the restaging values of endobronchial endosonography (EBUS) and/or esophageal ultrasonograpy (EUS) (88 patients) were compared with those of TEMLA (78 patients). There was a significant difference between EBUS/EUS and TEMLA for sensitivity (64.3% and 100%; p < 0.01) and NPV (82.1% and 100%; p < 0.01) in favor of TEMLA [10]. Regarding their use for primary staging, VAMLA and TEMLA represent a new paradigm. Firstly, transcervical lymphadenectomies could also be considered part of the induction treatment because the mediastinum is staged and downstaged by these operations. Secondly, due to the fact that nodal restaging is unnecessary, new parameters should be used to select patients for lung resection after induction such as the stability of the primary tumor and the absence of extrathoracic disease based on the results of postinduction CT or PET. Finally, intraoperative pathologic study of the remaining lymph nodes should confirm the absence of nodal involvement before proceeding with lung resection, especially if pneumonectomy is required. Conclusions In multimodality treatments for patients with stage IIIA(N2) tumors, pathologic restaging after induction therapy is essential to decide on subsequent treatment. ReMS is a useful procedure regardless of the induction treatment used or the intensity of the first mediastinoscopy. The role of transcervical lymphadenectomies in staging and restaging should be implemented in clinical practice and validated in future clinical trials. References 1. De Waele M, Serra-Mitjans M, Hendriks J, et al. Accuracy and survival of repeat mediastinoscopy after induction therapy for non-small cell lung cancer in a combined series of 104 patients. Eur J Cardiothorac Surg 2008;33:824-8. 2. Van Meerbeeck JP, Kramer GW, Van Schil PE, et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 2007;99:442-50. 3. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non- small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379-86. 4. De Leyn P, Dooms C, Kuzdzal J, et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg 2014;45:787–98. 5. Lardinois D, Schallberger A, Betticher D, et al. Postinduction video-mediastinoscopy is as accurate and safe as video-mediastinoscopy in patients without pretreatment for potentially operable non-small cell lung cancer. Ann Thorac Surg 2003;75:1102–6. 6. Call S, Rami-Porta R, Obiols C, et al. Repeat mediastinoscopy in all its indications: experience with 96 patients and 101 procedures. Eur J Cardiothorac Surg 2011; 39:1022-7. 7. Stamatis G, Fechner S, Hillejan L, et al. Repeat mediastinoscopy as a restaging procedure. Pneumologie 2005;59:862-6. 8. Marra A, Hillejan L, Fechner S, et al. Remediastinoscopy in restaging of lung cancer after induction therapy. J Thorac Cardiovasc Surg 2008;135:843-9.
 9. Zieliński M, Hauer L, Hauer J, et al. Non-small-cell lung cancer restaging with transcervical extended mediastinal lymphadenectomy. Eur J Cardiothorac Surg 2010;37:776–80. 10. Zielinski M, Szlubowski A, Kołodziej M, et al. Comparison of endobronchial ultrasound and/or endoesophageal ultrasound with transcervical extended mediastinal lymphadenectomy for staging and restaging of non-small-cell lung cancer. J Thorac Oncol 2013;8:630-6. Table 1. Staging values of the largest published series of remediastinoscopies for restaging after induction therapy.

      Author Year N S NPV DA
      Stamatis et al. [7] 2005 160 0.74 0.86 0.92
      De Waele et al. [1] 2008 104 0.71 0.73 0.84
      Marra et al. [6] 2008 104 0.61 0.85 0.88
      Call et al. [8] 2011 84 0.74 0.79 0.87
      Abbreviations: N: number of patients; S: Sensitivity; NPV: Negative predictive value; DA: Diagnostic accuracy

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      SC01.05 - Video-Thoracoscopy for Staging of N2 NSCLC During Induction Therapy (ID 6602)

      T.A. D’Amico

      • Abstract
      • Slides

      Abstract:
      The optimal strategy for patients with stage III non-small cell lung cancer (NSCLC) is not well-established and significant variation in practice exists across the United States and Europe. In the U.S., the majority of National Comprehensive Cancer Network (NCCN) member institutions consider surgery to be indicated in stage IIIA patients with involvement of a single N2 lymph node station smaller than 3 cm who have undergone induction chemotherapy. However, there is no agreement among institutions regarding treatment for other manifestations of stage IIIA-N2 involvement (e.g., multi-station or bulky disease) and both NCCN and European Society of Medical Oncology (ESMO) guidelines recommend that the role of surgery be discussed in a multidisciplinary tumor board setting. The use of induction chemotherapy vs induction chemoradiotherapy is currently of great interest worldwide, and the use of the latter is still common despite the results of numerous clinical trials and meta-analysis. The lack of consensus regarding treatment strategies for stage III NSCLC is in part due to the relatively low number of randomized studies available to guide decision-making, as well as institutional biases despite evidence. One important issue is the role and methods of restaging after induction therapy for patients with potentially resectable Stage IIIA (N2) disease. While all would agree that pathologic confirmation of N2 disease prior to induction chemotherapy is mandatory, using EBUS or mediastinoscopy, not all surgeons believe that restaging after induction therapy to confirm response to chemotherapy is necessary, despite evidence that the overall and cancer-specific survival of non-responders is quite low. There are 2 dominant strategies for staging and restaging patients with N2 disease: EBUS prior to induction therapy and restaging with videomediastinoscopy or mediastinoscopy prior to induction therapy and restaging with thoracoscopy or repeat mediastinoscopy. There may be a role for each strategy depending on individual patient characteristics. Advantages of thoracoscopic restaging after induction therapy include the ability to resect all ipsilateral nodes to most accurately assess response and the resection of nodal tissue at thoracoscopy is the first step in thoracoscopic resection and thus greatly facilitates the procedure. The role of thoracoscopic restaging after induction therapy will be reviewed, and the technical aspects for successful restaging and thoracoscopic lobectomy after induction therapy are demonstrated in videos. References 1. Martins RG, D'Amico TA, Loo BW, Jr., et al. The management of patients with stage IIIA non-small cell lung cancer with N2 mediastinal node involvement. Journal of the National Comprehensive Cancer Network : JNCCN. 2012;10(5):599-613. 2. Vansteenkiste J, De Ruysscher, D, Eberhardt WEE, Lim E, Senan S, Felip E, Peters s. Early-Stage and Locally Advanced (non-metastatic) Non-Small-Cell Lung Cancer: ESMO Clinical Practice Guidelines. Annals of Oncology. 2013;24((suppl 6)):vi 89-98. 3. Ettinger DS, Wood DE, Akerley W, et al. Non-small cell lung cancer, version 6.2015. Journal of the National Comprehensive Cancer Network : JNCCN. 2015;13(5):515-524. 4. Weeks JC, Uno H, Taback N, et al. Interinstitutional variation in management decisions for treatment of 4 common types of cancer: A multi-institutional cohort study. Annals of internal medicine. 2014;161(1):20-30. 5. Pless M, Stupp R, Ris HB, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015;386(9998):1049-1056. 6. Katakami N, Tada H, Mitsudomi T, et al. A phase 3 study of induction treatment with concurrent chemoradiotherapy versus chemotherapy before surgery in patients with pathologically confirmed N2 stage IIIA nonsmall cell lung cancer (WJTOG9903). Cancer. 2012;118(24):6126-6135. 7. Girard N, Mornex F, Douillard JY, et al. Is neoadjuvant chemoradiotherapy a feasible strategy for stage IIIA-N2 non-small cell lung cancer? Mature results of the randomized IFCT-0101 phase II trial. Lung Cancer. 2010;69(1):86-93. 8 Jaklitsch MT, Gu L, Harpole DH, D'Amico TA, et al. Prospective phase II trial of pre-resection thoracoscopic restaging following neoadjuvant therapy for IIIA(N2) non-small cell lung cancer: Results of CALGB 39803. J Thorac Cardiovasc Surg 2013;146: 9-16 9. Yang CF, Gulack BC, Gu L, et al. Adding radiation to induction chemotherapy does not improve survival of patients with operable clinical N2 non-small cell lung cancer. The Journal of thoracic and cardiovascular surgery. 2015;150(6):1484-1492; discussion 1492-1483. 10. Shah AA, Berry MF, Tzao C, et al. Induction chemoradiation is not superior to induction chemotherapy alone in stage IIIA lung cancer. Ann Thorac Surg. 2012;93(6):1807-1812.

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      SC01.06 - Q&A (ID 6867)

      • Abstract

      Abstract not provided



Author of

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    WS03 - IASLC Meets ESTI: Imaging in Lung Cancer Staging and Diagnosis (ID 361)

    • Event: WCLC 2016
    • Type: Workshop
    • Track: Radiology/Staging/Screening
    • Presentations: 1
    • Now Available
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      WS03.04 - Ultrasound- and CT-Guided Biopsies for the Diagnosis of Lung Cancer (Now Available) (ID 6766)

      G. Mostbeck

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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