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    MTE 01 - Management of Small Nodules Detected by CT Screening (Sign Up Required)

    • Type: Meet the Expert
    • Track: Radiology/Staging/Screening
    • Moderators:
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      MTE 01.01 - Management of Small Nodules Detected by CT Screening; A Surgeon's Perspective

      07:00 - 08:00  |  Presenting Author(s): Jun Nakajima

      • Abstract

      Abstract:
      Along with the prevalence of screening with computed tomography (CT), small pulmonary ground-glass density nodules (GGN) have been detected more frequently. A GGN is a round area of increased pulmonary opacity with intact bronchial and vascular structures. GGNs showing no or slow growth during follow-up period are most likely to be “early” adenocarcinomas showing lepidic pattern pathologically. There are three problems in diagnostics and therapeutics of GGNs. First, should they be treated or not? They might not change for years. We might take a risk of postoperative comorbidity for a harmless disease. Some large prospective observational studies on these pulmonary small GGNs have been performed: From clinical practice performed in these clinical trials, We found that 5-30% of GGN were resected during the observation period, because of the increased size or appearance of solid part in the GGN. Almost all of the pathologies of the resected GGN were adenocarcinomas. Part-solid GGNs were more likely to be diagnosed as invasive adenocarcinomas than pure GGNs. That is, we can correctly diagnose small pulmonary GGNs as adenocarcinomas when their CT images are changed. However, it is still unclear whether surgical intervention will contribute to increased survival from lung cancer. Second, how to detect pulmonary GGOs at surgery, if they are located deep in lung parenchyma? GGNs are difficult to identify even by bimanual palpation through open thoracotomy, because they are as soft as lung parenchyma if they show pure GGN appearance. Preoperative marking of these GGN is mandatory to ensure a definite resection. Many methods for detecting small pulmonary nodules have been developed: Preoperative hookwire placement under CT observation has been most widely performed. The punctured hook wire with thread can easily be identified that excisional biopsy may be done through thoracoscopy. However, arterial air embolism is reported to be occasionally associated with the placement of hookwire which can cause lethal results. Instead, dye marking, or fiducial placement through bronchoscopy has been revived to replace the hookwire method. We have recently developed Virtual-assisted lung mapping (VAL-MAP), a relatively brand-new lung marking technique using dye multiple dye markings through bronchoscope. Before bronchoscopy, we create a virtual 3-D bronchoscope map with CT and plan where to mark. Multiple dye markings enable us to determine the extent of resection with safe margin from the tumor. Actually safer margin from the tumor was shown to be secured by this method. Third, how to determine the extent of pulmonary resection for these small GGNs? Still there is no evidence other than lobectomy and lymph node dissection for early non-small cell lung cancer (NSCLC), clinical trials have been performed to prove feasibility and no-inferiority of sublobar resections (wedge resection and segmentectomy) for small NSCLC, especially those ≤2cm in diameter. In Japan and USA, prospective randomized studies are on the way to obtain more reliable evidence. In conclusion, management of small pulmonary nodules suspected of an early carcinoma includes the determination of operative indication, detection technique of the tumor, aiming to safer and effective treatment of these tumors.

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    MTE 02 - Appropriate and Optimized Handling of Specimens (Sign Up Required)

    • 07:00 - 08:00
    • 10/16/2017
    • Location: Room 316
    • Type: Meet the Expert
    • Track: Biology/Pathology
    • Moderators:
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      MTE 02.01 - Appropriate and Optimized Handling of Surgically Resected Specimens

      07:00 - 07:30  |  Presenting Author(s): Erik Thunnissen

      • Abstract

      Abstract:
      Erik Thunnissen[1], Chris Dickhoff[2,3], Rutger Lely[4], MA (Rick) Paul[3] Departments of [1]Pathology, [2]Surgery, [3]Cardiothoracic Surgery and [4]Radiology, VU University Medical Center, Amsterdam, the Netherlands. Guidelines for gross handling are to our knowledge not formulated in the literature. However, the College of American Physicians (CAP) formulates "required elements" for synoptic reporting regarding gross handling of pulmonary resection specimen, mainly focusing at pathology staging, but does not include grossing requirements[1]. The current practice of handling resection specimen in Amsterdam involves interaction with surgeons for submission of specimen. This includes i) Information about pretreatment, type of surgery (including pneumonectomy, (sleeve) lobectomy, segmentectomy, and wedge resection), site of specimen, number of tumors; ii) eventual frozen section for diagnosis and/or resection margin; iii) eventual additional information of specimen e.g. adhesion from parietal pleura, additional wedge from adjacent lobe adhesion; iv) agreement on marking the ‘cold’ side from bronchial resection slice [see note A]; For the pathologist, the order of handling the fresh specimen is i) to maintain the 3 dimensional orientation of the resection specimen along the axial, coronal and sagital planes; ii) to describe outer surface of specimen; iii) to photograph overview from medial and lateral side; iv) to cut slice of bronchial resection margin; v) to cut tumor, preferably in axial plane for sampling of normal lung tissue and tumor for research (culture, freezing) [see notes B and C]; vi) to perform perfusion fixation of peripheral lung; vii) and to immerse whole specimen in large volume neutral buffered formalin. After 24 hours, fixation the specimen is handled in the following way: i) Intrapulmonary lymph nodes are separately embedded ii) the specimen is further cut in slices along the same plane as done for the fresh specimen; iii) the slices are positioned in order of cutting, numbered and photographs taken; iv) description of specimen with tumor characteristics: focality (size; vital, necrosis, fibrosis), distance from tumor to margins recorded (to bronchial resection, pleura). If tumor is present in sequential slices, cumulative tumor thickness is measured; v) other characteristics are described (mucus in dilated bronchi; post-obstruction pneumonia; emphysema etc.) vi) sample representative blocks from tumor, normal tissue, resection margin arteria pulmonalis, and nearest point(s) to pleura for embedding in paraffin; vii) annotate the location of sampled blocks on a copy of the gross slices. After a few days during first microscopy, the 3 dimensional orientation can be reconstructed and the pTNM parameters extracted from the gross and microscopic information. If needed, additional samples can be taken [see note C]. Classification is performed for most parts according to the WHO[2], except for not reproducible categories and immature concepts. Pathology reporting contains pTNMR [see note D]. The pathology report is usually made within 9 working days, except if bony structures are included, then the process will contain an additional week. If postoperative radiotherapy is indicated, the 3 dimensional approach also supports determination of the position(s) for radiation, especially if clips were not placed during surgery. Note A As for frozen section, the cold side of the bronchial resection margin [i.e. the side distant from the patient] is placed downwards on the frozen template, the first cut frozen section sections [representing the nearest to the patient tissue margins (warm side)] are sequentially placed on the microscope slide. In case of uneven surface maximally 6 sections, until complete circumference is achieved, are placed on two microscopic slides, and stained for H&E The bronchial resection margin is considered tumour-free, if the complete circumferential margin does not contain tumor. If needed, in this judgement sequential complementarity of the 6 sections may be taken into account. The sleeve lobectomy has two resection margins: one on the cold side and the other on the warm side (larger bronchial diameter). These are separately examined. If only tumor cells are found in lymph vessels (but no direct tumor spread), this will be reported, but not considered necessary for indication of additional bronchial margin, as lymphangitic distribution is associated with N2 disease[3,4]. Note B As it has been proven that loose tissue fragments are caused by gross cutting[5,6], the knife is rinsed and quickly wiped after each slice that happens to contain tumor. STAS is considered to be an artifact and in contrast to CAP and WHO classification, is not considered as part of the tumor. Note C In Pancoast tumor, the ‘en-bloc resection’ incorporates extrapulmonary structures directly invaded by tumor, usually ribs. During the fresh handling, the thoracic wall is cut from the lung. Subsequently, both cut surfaces are coloured to denote the artifical edges. Bone requires after fixation extra time for decalcification, extending reporting with one week. Note D The R = defined as follows: R0 = free resection margins; R1 = microscopic margins not free; R2 = margins not free during gross examination/surgery;. Peripheral wedge resections contain a parenchymal margin, which is represented by the tissue at the staple line(s). The staples are cut from the specimen, but not further examined. Adjacent tissue is sampled for microscopic examination. If this section does not contain tumor, the margin is free (R0). However, if this contains tumor, an educated guess is reasonable, encompassing the amount of tumor compared to the other sections, and the estimation of the staple thickness (±2mm). 1. College of American Pathologists. Cancer Protocol Templates. Lung cancer vs4. http://www.cap.org/web/oracle/webcenter/portalapp/pagehierarchy/cancer_protocol_templates.jspx?_afrLoop=445529225217710#!%40%40%3F_afrLoop%3D445529225217710%26_adf.ctrl-state%3Dxmm1doio_4. 2. Travis W., Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. (Travis W., Brambilla E, Burke AP, Marx A, Nicholson AG, eds.). Lyon: IARC; 2015. 3. Thunnissen FBJM, den Bakker MA. Implications of frozen section analyses from bronchial resection margins in NSCLC. Histopathology. 2005;47(6):638-640. doi:10.1111/j.1365-2559.2005.02263.x. 4. Vallières E, Van Houtte P, Travis WD, Rami-Porta R, Goldstraw P. Carcinoma in situ at the bronchial resection margin: a review. J Thorac Oncol. 2011;6(10):1617-1623. doi:10.1097/JTO.0b013e31822ae082. 5. Blaauwgeers H, Flieder D, Warth A, et al. A Prospective Study of Loose Tissue Fragments in Non–Small Cell Lung Cancer Resection Specimens. Am J Surg Pathol. June 2017:1. doi:10.1097/PAS.0000000000000889. 6. Thunnissen E, Blaauwgeers HJLG, de Cuba EM V, et al. Ex Vivo Artifacts and Histopathologic Pitfalls in the Lung. Arch Pathol Lab Med. 2016;140(3):212-220. doi:10.5858/arpa.2015-0292-OA.

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      MTE 02.02 - Appropriate and Optimized Handling of Biopsy or Cytology Specimens

      07:30 - 08:00  |  Presenting Author(s): Mari Mino-Kenudson

      • Abstract

      Abstract:
      The recent advance in personalized medicine along with minimally invasive endoscopic techniques in the field of lung cancer has brought significant complexities to handling of tissue samples. Due to the histology-directed therapy, additional stains are frequently required to achieve accurate histologic subtyping on small biopsy and cytology samples. It is recommended that epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and ROS1 testing be performed for patients with advanced non-squamous small cell lung cancer (NSCLC) in a reflex manner. In addition, multiplex assays, including next generation sequencing (NGS), are increasingly being used for detection of the molecular targets. Furthermore, immunohistochemistry (IHC) for programmed death ligand-1 (PD-L1) is now routinely performed in NSCLCs with wild type EGFR and ALK to determine eligibility for PD-1/PD-L1 blockade.(1) In most advanced NSCLC patients, a small biopsy or cytology specimen is often the only sample available for the diagnosis and biomarker analyses. Thus, appropriate tissue acquisition, processing and management for multiple tests are crucial and are best achieved by the interaction of all physicians involved in the patient care.(2, 3) Tissue acquisition All the necessary work-up is usually performed on a small biopsy or cytology specimen taken from a patient with advanced disease, tissue sampling should be aimed at obtaining the largest yield of tumor in the safest and least invasive manner.(4) Tissue processing Appropriate pre-analytic tissue handling is one of the keys to successful implementation of IHC-based and molecular assays in general.(3, 5) An ischemia time from tissue procurement to the initiation of fixation should be short (as short as possible), and biopsies should immediately be immersed in fixative for 6-48 hours. Of note, multiple tissue fragments in a biopsy sample (obtained from one lesion) may be submitted in a few tissue cassettes to avoid tissue exhaustion that is not infrequently seen when the single available tissue block is cut and used for multiple purposes. Neutral buffered formalin is historically the preferred and most common fixative used in the practice of histopathology.(6) Consequently, the majority of pathology laboratories typically perform the initial validation of IHC and molecular protocols on FFPE tissue. Decalcifying solutions used for bony specimens vary in their effects on retention and integrity of nucleic acids and proteins. Thus, results of IHC on decalcified specimens are unpredictable because of wide variations in specimen types and sizes, fixation time, and the particular solution(s) used.(7) Similarly, alcohol fixation used for cytology specimens, including alcohol-fixed cell blocks, decreases IHC accuracy by causing loss or decrease of immunogenicity when IHC protocols optimized with FFPE tissue samples are used.(8) For molecular assays, samples fixed with acidic solutions (including decalcifying salutations) and heavy metal fixatives are not recommended due to further degradation of nuclear acid and heavy metals hampering PCR reaction, respectively.(9) Thus, tissue sampling of a bone metastasis for this purpose should be avoided, if possible. In case the bone metastasis is the only accessible lesion for sampling, the pathologist may try to separate a soft tissue component submitted in the formalin. Up to 40% of advanced NSCLC patients are diagnosed by cytology alone. Cytology smears, cytospins and liquid-based cytology (LBC), processed from fine needle aspiration (FNA) or other modalities, are typically treated with alcohol-based solution or sprays devoid of exposure to formalin that leads to fragmentation of nuclear acids, thus often contain tumor cells with intact nucleic acid ideal for molecular testing. However, formalin-fixed paraffin-embedded (FFPE) cell blocks processed from the residual material from FNA or LBC or body fluid are the preferred samples for ancillary testing in many laboratories, since they can be handled in the same way as biopsy/resection specimens.(2) Tissue management To maximize small samples, the number of times when the tissue block needs to be cut for diagnosis, IHC and molecular testing should be minimized. It is because a decent amount of tissue is cut and wasted for trimming of the block at each round of sectioning. Thus, extra sections may be cut up front at the first cutting for diagnostic histology sections. Many pathology laboratories already have protocols in place per local requirements under close supervision by pathologists. It is also important that the pathologist is in close communication with oncologists and proceduralists to ensure that relevant clinical information is provided before sectioning is done. Diagnostic work-up between the lesion with high probability of a lung primary and a possible metastasis, and that between primary diagnosis and progression/recurrence after targeted therapy are often different, thus lack of the critical information may lead to unnecessary IHC. Last, but not least, the pathologist needs to evaluate tissue adequacy (tumor cellularity, the presence or absence of necrosis and tissue quality, etc.) before submitting samples for molecular testing. References: 1. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 8.2017 – July 14, 2017. 2. Bubendorf L, Lantuejoul S, de Langen AJ, et al. Nonsmall cell lung carcinoma: diagnostic difficulties in small biopsies and cytological specimens: Number 2 in the Series "Pathology for the clinician" Edited by Peter Dorfmuller and Alberto Cavazza. Eur Respir Rev. 2017;26(144). 3. Tsao MS, Hirsch FR, Yatabe Y. IASLC atlas of ALK and ROS1 testing in lung cancer. 2nd ed. Colorado: Editorial Rx Press; 2016. 4. Thunnissen E, Kerr KM, Herth FJ, et al. The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach of a working group. Lung Cancer. 2012;76(1):1-18. 5. Mino-Kenudson M. Programmed death-ligand 1 immunohistochemistry testing for non-small cell lung cancer in practice. Cancer. 2017;125(7):521-8. 6. Thavarajah R, Mudimbaimannar VK, Elizabeth J, et al. Chemical and physical basics of routine formaldehyde fixation. J Oral Maxillofac Pathol. 2012;16(3):400-5. 7. Fitzgibbons PL, Bradley LA, Fatheree LA, et al. Principles of analytic validation of immunohistochemical assays: Guideline from the College of American Pathologists Pathology and Laboratory Quality Center. Arch Pathol Lab Med. 2014;138(11):1432-43. 8. Zhou F, Moreira AL. Lung Carcinoma Predictive Biomarker Testing by Immunoperoxidase Stains in Cytology and Small Biopsy Specimens: Advantages and Limitations. Arch Pathol Lab Med. 2016;140(12):1331-7. 9. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med. 2013;137(6):828-60.

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    MTE 03 - Surgery for T4 Lung Cancer (Sign Up Required)

    • Type: Meet the Expert
    • Track: Surgery
    • Moderators:
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      MTE 03.01 - Do Extended Resections Improve T4 Lung Cancer Outcomes?

      07:00 - 08:00  |  Presenting Author(s): Dominique H Grunenwald

      • Abstract

      Abstract:
      T4 lung cancers invading neighboring structures comprise a heterogenous group of locally invasive tumors. In a small subset of these localized tumors whose extrapulmonary invasion preceded any lymphatic extension, an adequate excisional procedure can achieve surprising long term survivals. The indications for such procedures and the anticipated outcomes should be weighed on a case by case basis, in terms of potential perioperative complications and expertise of the surgical team. Advanced surgical techniques are now being applied for T4 lesions due to improvements in surgery and anesthesiology and progress in combined treatment modalities. In the present staging, T4 tumors without mediastinal nodal metastasis are now considered to be potentially curable if complete resection is possible. A summary of the literature, under the light of personal experience allows a critical point of view, knowing that a surgical procedure which would not be reproducible in other centers would never be recognized as an option for practice. Therefore among the published series it is important to distinguish the real progress given by innovative techniques or procedures that could be applied throughout the world, even only in selected centers, from the simple reports of individual performances or exploits. Proximal tumors from the lower lobe may involve the atrial wall of the heart. In some cases a left atrial resection can be performed, followed by direct closure, or replacement of the atrial wall. Fukuse reported a series of 42 patients, from which left atrium was resected in 14 patients, Mortality rate was low (2.4%), regarding complexity of the procedures [1]. Low stages in nodal status were associated with increased survival (p = 0.0013). More recently was reported a series of 19 patients who underwent extended lung resection involving the left atrium without cardiopulmonary bypass [2]. An interatrial septum dissection is performed, thus increasing the length of the atrial cuff. R0 resections were observed in 89% of the patients. Ninety-day mortality rate was 16%. Five-year survival rate is 44%, and 3 patients (16%) are alive more than 6 years after surgery. Other reports advocate the use of cardiopulmonary bypass in these occasional situations [3-5]. Invasion of the superior vena cava (SVC) by a T4 non small cell lung c ancer (NSCLC) led surgical teams to attempt lobectomies or pneumonectomies extended to the vena cava [6]. Actually direct extension to the vessel by the tumor mass itself is a rare situation. SVC involvement generally results from a bulky disease, in which the nodal disease is the greatest component. The rationale of resecting SVC in N2 disease remains questionable, in view of the high potential of metastatic spread and the poor prognosis. Nevertheless, different techniques were proposed, including lateral clamping of SVC, partial, or total reconstruction. These procedures are associated with high morbidity rates. A multicentric international review of prosthetic replacement after SVC resection for nsclc in 28 patients (N2 involvement in 50%) showed morbidity and mortality rates of 39% and 14%, respectively. Overall 5-year survival rate was 15% [7]. Despite some reports who claim better survival rates, close to 50% at five years, the latter seems more realistic, and this warrants a thorough evaluation with the aim to preclude these patients from surgery in case of N2 involvement. A bronchial carcinoma extended to the tracheal bifurcation can be resected in selected patients [8]. A high rate of post-operative morbidity (10 to 30%), including bronchial dehiscences, jeopardizes the outcome, but long-term survivals have been observed in 15 to 23% of the cases. A meticulous mediastinal assessment is mandatory to eliminate invasion of the airway by a bulky disease. Only patients with T-invasion will be offered surgical resection. NNSCLC invading the thoracic inlet can easily penetrate spinal structures because of their particular anatomic situation. The best local control for resectable tumors is achieved by surgical operation, provided the resection is complete and respecting oncologic principles. Direct invasion of the vertebral body became an option following the first report in 1996 of a successful en bloc total vertebrectomy for lung cancer invading the spine [9]. Reported experiences from Europe, North-America and Asia demonstrate feasability and encouraging results of these challenging procedures, . Recently a comprehensive literature search, on a total of 1,001 abstracts and 93 articles found overall 5-year survival rates ranging from 37% to 59% and the mortality rate ranged from 0% to 6.9% [10]. Undoubtly enbloc resection for lung cancer invading the spine is reaching the stage of current practice in expert centers. This is probably due to a particular biology of these tumors which are peripheral and whose noisy symptoms lead to a relatively early diagnosis, thus permitting a high rate of complete resections. Evidence suggests that triple modality therapy with complete resection of locally advanced Pancoast tumors with involvement of the spine offers an advantage over other therapeutic modalities. Despite the absence of such an evidence in other T4 lung cancers, recent advances in patient's care and surgical techniques allowed surgeons to become more aggressive, and to propose occasionally extended resections with encouraging long-term survival rates to patients suffering from tumors invading the tracheal bifurcation, the left atrium, or the great vessels. The 8[th] edition of TNM classifies,T4N0-1 tumors in a "surgical" category, stage IIIA. 1. Fukuse T, et al. Extended operation for nsclc invading great vessels and left atrium. Eur J Cardiothorac Surg 1997;11:664–9 2. Galvaing G, et al. Left atrial resection for T4 lung cancer without cardiopulmonary bypass: technical aspects and outcomes.Ann Thorac Surg 2014;97:1708-13 3. Klepetko W, et al. T4 lung tumors with infiltration of the thoracic aorta: is an operation reasonable? Ann Thorac Surg 1999;67:340–4 4. De Perrot M, et al. Resection of locally advanced (T4) nsclc with cardiopulmonary bypass. Ann Thorac Surg 2005; 79:1691–6 5. Langer NB, et al. Outcomes after resection of T4 nsclc using cardiopulmonary bypass. Ann Thorac Surg 2016;102:902-10 6. Grunenwald DH. Resection of lung carcinomas invading the mediastinum, including the superior vena cava. Thorac Surg Clin 2004;14:255–63 7. Spaggiari L, et al. Superior vena cava resection with prosthetic replacement for nsclc: long term results of a multicentric study. Eur J Cardiothorac Surg 2002;21:1080–6 8. Mathisen DJ, Grillo HC. Carinal resection for bronchogenic carcinoma. J Thorac Cardiovasc Surg 1991;102:16−23 9. Grunenwald D, et al. Total vertebrectomy for en bloc resection of lung cancer invading the spine. Ann Thorac Surg 1996;61:723–6 10. Setzer M, et al. Management of locally advanced pancoast (superior sulcus) tumors with spine involvement. Cancer Control 2014;21:158-67

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    MTE 04 - Radiotherapy for SCLC (Sign Up Required)

    • Type: Meet the Expert
    • Track: Radiotherapy
    • Moderators:
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      MTE 04.01 - Role of Radiotherapy in Multimodality Treatment for SCLC

      07:00 - 07:30  |  Presenting Author(s): Corinne Faivre-Finn

      • Abstract

      Abstract:
      Major advances in SCLC include improvements in RT techniques, the use of prophylactic cranial irradiation (PCI) for all stages of SCLC and the improved combination of chemotherapy and RT (Califano). The role of thoracic radiotherapy is well established in the management of stage I-III SCLC (Pignon). There is increasing evidence in the literature in favour of early concurrent chemo-radiotherapy, and a standard of care for patients with a good performance status is twice-daily thoracic radiotherapy (45 Gy in 3 weeks) with concurrent cisplatin and etoposide (Turrisi). Although current clinical trials are exploring the efficacy of new chemotherapeutic strategies, essential questions related to the optimisation of thoracic radiotherapy and the benefit of chemo-radiotherapy in sub-groups of patients remain unanswered, e.g. the elderly (Blackhall). The CONVERT trial (twice-daily (BD) versus once daily (OD) radiotherapy given concurrently with chemotherapy in stage I-III SCLC) was reported at ASCO 2016 (Faivre-Finn). OD RT did not result in a superior survival or worse toxicity than BD RT (two-year survival was 56% (95% CI 50-61) vs 51% (95% CI 45-57), p= 0.14). The survival for both regimens was higher than previously reported and using modern RT techniques radiation toxicities were lower than expected. In the stage IV setting the CREST trial as shown that the addition on thoracic RT to chemotherapy and PCI leads to a significant reduction in intrathoracic recurrence and, despite the lack of a significant benefit in overall survival at 1 year, there were significant improvements in overall survival at 2 years (Slotman). It is crucial that patients with SCLC are given the opportunity to participate in clinical research in order to continue to improve the survival of this disease. Molecular studies are ongoing aiming to gain improved insight into the molecular biology of SCLC, discover and/or validate candidate biomarkers for response, resistance to or toxicity of systemic treatment and radiation. It is expected that this understanding will lead to the development of targeted therapies that will not only prove efficacious but also less toxic than more conventional chemotherapy treatments. In combination with advanced RT techniques and better imaging, it is hoped that the rates of long term survivors will increase significantly in the future. We will address the following controversial questions • Should BDRT be considered standard of care in stage I-III SCLC? • Role of CTRT in stage I-II SCLC • Role of CTRT in elderly patients with LS-SCLC • Should thoracic RT be given to all patients with stage IV SCLC? References Califano R, et al. Management of small cell lung cancer: recent developments for optimal care. Drugs. 2012 5;72(4):471-90 Pignon JP, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992; 327:1618-1622. Turrisi AT, et al. Twice daily compared to once-daily thoracic radiotherapy in limited-stage small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999; 340: 265-271. Auperin A, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999;341(7):476-84. Blanchard P, et al. Prophylactic cranial irradiation in lung cancer. Curr Opin Oncol. 2010; 22(2):94-101 Blackhall F et al. Treatment of limited small cell lung cancer: an old or new challenge? Curr Opin Oncol. 2011; 23(2):158-62 Faivre-Finn C, et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol. 2017;18(8):1116-1125 Slotman BJ, et al.Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet. 2015 3;385(9962):36-42 Slotman BJ, et al. Which patients with ES-SCLC are most likely to benefit from more aggressive radiotherapy: A secondary analysis of the Phase III CREST trial. Lung Cancer. 2017; 108:150-153

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      MTE 04.02 - General Principles of PCI in the Treatment of SCLC

      07:30 - 08:00  |  Presenting Author(s): David L Ball

      • Abstract

      Abstract:
      The brain is a well recognized sanctuary site for micrometastases in patients with small cell lung cancer (SCLC) treated with chemotherapy. The administration of prophylactic cranial irradiation (PCI) in patients responding to chemotherapy reduces the incidence of clinically detectable brain metastases in patients with both limited [1] and extensive disease [2, 3]. In patients with limited disease, this translated into a survival benefit in a meta-analysis of 987 complete responders , but in patients with extensive disease, one trial of 286 responders to chemotherapy showed a survival benefit [2], whilst in another of224 patients it did not [3]. The design of this latter trial suggested that regular surveillance with MRI and treatment at the time of metastasis detection might be an equally effective strategy. This could reduce the incidence of the most serious toxicity of PCI which is delayed neurotoxicity. Limiting the total dose is another possible means of reducing neurotoxicity. A randomized trial of three dose prescriptions restricted to patients with limited disease showed no difference in rate of brain metastases between 25 Gy in 10 fractions versus two higher dose schedules , but there was a higher mortality associated with the higher doses, due to an unexplained increase in disease progression [4]. In spite of this high level evidence there are still numerous uncertainties facing the clinician when deciding whether to recommend PCI. 1. Is the classification limited versus extensive disease still appropriate when selecting patients? 2. Are there subgroups of patients with metastatic disease more likely to benefit from PCI than others because their overall prognosis is better? [5] 3. Should there be an upper age limit? 4. Are pre-existing neurologic conditions or paraneoplastic syndromes contraindications? 5. In patients with extensive disease, is pretreatment MRI required? 6. Is MRI surveillance cost effective? 7. Is there a role for hippocampal sparing techniques or neuroprotective agents? 8. Is there a place for lower dose/shorter fractionation schedules? 9. In patients with extensive disease having consolidative chest irradiation, is there any difference between giving PCI simultaneously versus sequentially? 10. What will be the role of PCI in the era of immunotherapy? Question 7 is currently the subject of an actively recruiting randomized trial (NRG-CC003), but for the other questions, physician and patient discretion will be required for the forseeable future. References 1. Auperin, A., et al., Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med, 1999. 341: 476-84. 2. Slotman, B., et al., Prophylactic Cranial Irradiation in Extensive Small-Cell Lung Cancer N Engl J Med, 2007. 357: 664-672. 3. Takahashi, T., et al., Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol, 2017. 18: 663-671.. 4. Le Pechoux, C., et al., Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol, 2009. 10:467-74. 5. Eberhardt, W.E., et al., The IASLC Lung Cancer Staging Project: Proposals for the Revision of the M Descriptors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol, 2015. 10:1515-22.

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    MTE 05 - Neuroendocrine Tumors: Pathology and Genetic Update (Sign Up Required)

    • Type: Meet the Expert
    • Track: Biology/Pathology
    • Moderators:
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      MTE 05.01 - Neuroendocrine Tumors: Pathology and Genetic Update

      07:00 - 08:00  |  Presenting Author(s): Elisabeth Brambilla

      • Abstract

      Abstract:
      Pathology In the current WHO 2015 classification[1] neuroendocrine lung tumors are listed in the order of their frequency with SCLC first as it is the most common (15% of lung cancer). Despite the grouping of these tumors together, it is clear that the carcinoids have major clinical, epidemiologic, histologic and genetic differences compared to the high grade SCLC and LCNEC. SCLC and LCNEC have much higher mitotic rates (more than 11 per 2mm2), more necrosis than carcinoids and can show combinations with other lung cancer types including adenocarcinoma or squamous cell carcinoma, which testify of a common progenitor cell derivation, not shared by carcinoid which is never mixed with a non-neuroendocrine (NE) tumor type Immunohistochemistry (IH) / neuroendocrine markers can be very helpful in diagnosing pulmonary NE tumors especially in small biopsies with crushed artefact. Endocrine morphology and neuroendocrine IH markers are both required for the diagnosis of LCNEC. The cases with one missing (Endocrine morphology or NE markers) are considered as large cell carcinoma in the absence of other differentiation marker on resection specimens, and as non- small cell lung carcinoma on small samples. Genomic update Small cell lung carcinoma [2-3] The universal biallelic alteration of both TP53 and RB1 gene was remarkable (100% for P53 and 93% for RB1) by different alterations of each of the 4 alleles. Other significantly mutated genes are KIAA1211 and COL22A1 with unclear functions, as well as RGS7 and FPR1 involved in G-protein-coupled receptor signalling. Locally clustered mutations occurred on CREBBP (15%) and EP300 (13%) genes, inactivating their histone acetylase functions. Notch family genes were recurrently mutated (25%) whereas RNA transcriptome analysis revealed a rate of Notch inactivation of 77% associated with up regulation of neuroendocrine (NE) lineage genes (DLK1 a Notch inhibitor, CHGA (chromogranin A), ASCL1 a master regulator of NE lineage, and GRP (gastrin releasing protein)). Another Notch inhibitor DLL3 was reported to be upregulated in 65% of SCLC[3]. DLL3 is considered as a therapeutic target tested in several clinical trials[4]. The mouse model validated NOTCH as a tumor suppressor and master regulator of NE malignant differentiation in SCLC[ 3]~.~ TP73 gene breaks inducing intragenic fusions and rearrangements, creates the N-terminally truncated transcripts variants lacking a fully competent transactivation domain and exerting dominant negative functions on both wild type p73 and p53. With additional mutations in TP73, 13% SCLC showed alteration in TP73 gene. Somatic copy number alterations (CNA) include focal events on 3p14.3-3p14.2 (FHIT gene) and 3p12.3-3p12.2 (ROBO1) with reduced expression of theses 2 genes. Homozygous deletion of the CDKN2A locus (chromosome 9p) and amplification of the MYC family genes (MYCL1, MYCN, MYC) as well as of FGFR1 (6%) and IRS2 (2%) were recurrent events. The remarkable largely mutually exclusive mutations in the five key genes: CREBBP, EP300, TP73, RBL1, RBL2 (equivalents of RB1 in the mouse model) and Notch suggest they may exert similar pro-tumorigenic functions in the development of SCLC and are candidate drivers[3]~.~ Large cell neuroendocrine carcinoma (LCNEC) TP53 was the most frequently inactivated gene (92%) followed by RB1 (42%) Biallelic inactivation of both TP53 and RB1 (the hallmark of SCLC) was seen in 40%.Mutations in STK11/ LKB1(30%, characteristic of ADC) and KEAP1 (22%, detected in both ADC and SCC but not in SCLC). The mutations were deleterious (nonsense, splice and frameshift mutations) or missense affecting important protein domain mutations in RB1 and STK11/KEAP1 which occurred in a mutually exclusive fashion (p<0.0001). Damaging mutations also occur in chromatin-remodelling genes ARID1A and MEN1/PSP1 in 10% and 7% of LCNEC respectively; Ras family alterations were found in 10% of cases. Overall RAS family, BRAF and NKX2-1 alterations were mutually exclusive with RB1 ( P=0.0049) suggesting again distinct genomic patterns in LCNEC . Analyses of CNA on 60 LCNEC reveals similarities to SCLC[3]. As mutations, the pattern of copy number alterations of LCNEC share characteristics with SCLC, ADC, or SCC. Overall from genomic profiles, while certain alterations (RB1 MYCL1) resemble thoses found in SCLC, others are typical of adenocarcinoma (STK11, NKX2-1, RAS, BRAF) or of squamous cell carcinoma( KEAP1, NFE2L2), showing the heterogeneity of LCNEC which can be divided into molecular subsets by similarities with other major lung cancers. At transcriptional level[5] an unsupervised consensus clustering showed a common cluster including both SCLC and LCNEC characterized by high expression of neuroendocrine lineage transcription factors, as well as high levels of cell cycle regulation and DNA damage response genes, and centrosomal functions. Although LCNEC shared characteristics with ADC and SCC, theses were dissimilar and strongest correlation was being found with SCLC. The transcriptional relationship of LCNEC and SCLC revealed 4 consensus clusters I-IV. Tumors in cluster I exclusively contained LCNECs with STK11 or KEAP1 alterations (type1-LCNEC) characterized by a high level-expression of chromogranin A and synaptophysin. The majority of LCNECS in cluster 2 enriched in cases with RB1 alterations exhibited reduced levels of NE markers and elevated Notch signalling, low expression of ASCL1 and DLL3 an inhibitor of NOTCH signalling pathway (type 2 LCNEC).. Whereas type1-LCNECs harbor STK11 or KEAP1 alterations but share NE expression profiles with SCLC , type2- LCNEC (40% of LCNEC) bear genetic resemblance with SCLC with RB1 alterations ,but profound transcriptional differences with SCLC. Carcinoid Tumors Molecular alterations underlying pathogenesis of this tumor were enlighted only recently[6] Genome/exome sequencing data from 44 tumor/normal pairs, allowed identification of MEN1, ARID1A, and EIF1AX as significantly mutated genes. MEN1, PSIP1(13%) and IRID1A play important roles in chromatin remodelling process showed mutually exclusive frameshifts and truncating mutations. Mutations in histone methyltransferases (SETD1B, SETDB1, NSD1) and demethylases (KDM4, PHF8) as well as members of the polycomb complex 1 and 2 (CBX6 and EZH1) mutations were accompanied with LOH. In total 40% of carcinoids carried mutually exclusive mutations in genes involved in covalent histone modification. Truncating and frameshift mutations occur in ARID1A (6,7%), and other mutations in this SWI/SNF chromatin remodelling complex in 22%. With sister chromatid cohesion affected by reccurrent mutations (COHESIN, STAG1, NIPBL, the microRNA processor DICER and ERCC6L), 51% of carcinoid carried mutations in chromatin remodelling genes. There was no genetic segregation between typical and atypical carcinoid, neither between the expression clusters generated from both subtypes. References Travis WD, Brambilla E, Burke A, Marx A, Nicholson A. WHO Classification of the Tumours of the Lung, Pleura, Thymus and Heart. 4th Edition. Lyon: IARC Press; 2015. Peifer M, Fernandez-Cuesta L, Sos ML, et al. Nat Genet 2012;44:1104-10. George J, Lim JS, Jang SJ, et al. Nature 2015;524:47-53. C.Rudin, M.C. Pietenza, M. Todd et al. Lancet Oncol 2017; 18: 42–51. Georges et al. Nature communication. In press 2017 Fernandez-Cuesta L, Peifer M, Lu X, et al. Nature communications 2014;5:3518.

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    MTE 06 - Lung Cancer Pathology Update (Sign Up Required)

    • 07:00 - 08:00
    • 10/16/2017
    • Location: Room 315
    • Type: Meet the Expert
    • Track: Biology/Pathology
    • Moderators:
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      MTE 06.01 - Lung Cancer Pathology Update

      07:00 - 08:00  |  Presenting Author(s): Andre L. Moreira, Prudence Russell

      • Abstract

      Abstract:
      This session will focus on some new definitions and concepts in the recently published 2015 WHO classification of lung tumors (1), some of which were showcased in the 2011 IASLC/ATS/ERS lung adenocarcinoma classification (2), while others are introduced for the first time. We will focus on resected lung adenocarcinoma as well resected squamous cell carcinoma, large cell carcinoma and the neuroendocrine tumor spectrum. Adenocarcinoma: In the 2015 WHO classification, the definition of adenocarcinoma has been expanded from a malignant epithelial tumor with glandular differentiation or mucin production to include tumors that also express pneumocyte immunomarkers (e.g. TTF1, Napsin A). This means that undifferentiated carcinomas formerly classified as large cell carcinoma that express pneumocyte immunomarkers, like undifferentiated carcinomas that show mucin expression, are now included in the solid adenocarcinoma category. Invasive adenocarcinomas account for >70% of all surgically resected cases and consist of a complex admixture of histologic subtypes. In an effort to represent this morphologic complexity, comprehensive histologic subtyping was introduced in the 2011 IASLC/ATS/ERS classification. A number of recent studies have demonstrated the utility of comprehensive histologic subtyping in identifying prognostically significant groups of tumors . Studies published both before and after the 2011 IASLC/ATS/ERS classification have highlighted the importance of the secondary patterns in addition to the predominant pattern in resected lung adenocarcinoma. Comprehensive histologic subtyping, its pitfalls and the emerging significance of secondary patterns in tumour recurrence and prognosis will be discussed further in this session. Grading: There is no well-established, internationally accepted grading system in resected lung adenocarcinoma. A simple grading system based on predominant histologic subtype has been proposed due to the prognostic significance of predominant histologic subtype. Other suggested grading schemes include different combinations of mitotic count, second predominant pattern and nuclear features with predominant histologic subtype. The emerging concept of an objective grading system for pulmonary adenocarcinomas will be briefly explored in this session. Another newly introduced concept in the 2015 WHO classification is that of tumour spread through alveolar spaces (STAS) which may occur with micropapillary clusters, solid nests or single cells. STAS was found to be associated with an increased recurrence rate in patients with stage I adenocarcinomas <2cm who underwent sublobar resections (3). Tumour size and staging: A recent study confirmed that in resected non-mucinous adenocarcinoma, the size of the invasive component, excluding the lepidic (equated with in situ) component of the tumor, correlates better with patient outcome than total tumour size (4). This finding has been supported by other studies and is expected to be included in the upcoming 8[th] edition TNM staging system for the T descriptor for pathologic staging in resected non-mucinous adenocarcinoma (5). Squamous cell carcinoma (SQCC) is the second most prevalent Non-small cell lung cancer (NSCLC), behind adenocarcinoma. Contrary to the latter where most changes in nomenclature, diagnosis and molecular pathology have occurred, SQCC has a strong association to smoking and remains a challenge for oncologists with few therapeutic advances. To reduce the risk of over diagnosing SQCC, the definition of SQCC became stricter in the 2015 WHO classification. For the diagnosis of this entity it is necessary to have evidence of keratinization and intercellular bridges. For non-keratinizing SQCC it is necessary to demonstrate evidence of squamous differentiation by immunohistochemical (IHC) stain (diffuse positivity for p40 or p63 and absence of adenocarcinoma markers such as TTF-1 and napsin-A). Non-keratinizing SQCC shares a solid pattern of growth with adenocarcinoma; in addition, solid type adenocarcinomas can have squamoid features such as glassy and abundant cytoplasm that can mimic SQCC (6), therefore it is recommended the use of IHC for any NSCLC with solid pattern of growth. Presence or absence of mucin is not a criterion for diagnosis of SQCC. Similar to adenocarcinoma, there is no grading system for SQCC. There is evidence that tumour budding is associated with worse prognosis (7). Basaloid carcinoma is now classified in the same group of SQCC and no longer part of large cell carcinoma. In contrast, Lymphoepithelioma-like carcinoma of the lung that share IHC profile with squamous cell carcinoma is grouped in the category of other undifferentiated tumours that also include NUT carcinoma. Large cell carcinoma: remains a separate category; however, the diagnosis of this entity is greatly reduced. Large cell carcinoma is an undifferentiated carcinoma (positive for cytokeratin markers), which lacks evidence of differentiation by morphology and lineage specific immunohistochemical profile (TTF-1/Napsin-A and p40 negative). This classification is supported by molecular profile (8). High Grade Neuroendocrine Carcinomas. This tumour category remains largely the same from previous classification with the exception that Large Cell Neuroendocrine Carcinoma (LCNC) is now grouped with neuroendocrine tumours. It is no longer part of a Large Cell Carcinoma category. Recent studies have suggested that LCNEC is a heterogeneous group ranging in the spectrum from NSCLC-like to small cell carcinoma-like tumours (9). LCNEC that resemble NSCLC have higher incidence of KRAS mutations, whereas those morphologically closer to small cell carcinoma have higher incidence of RB mutation. The significance of these findings for tumour classification and especially for therapeutic options are still unknown as more studies need to be done. There have been several studies on the genetic and epigenetic profile of small cell carcinoma that could lead to new therapeutic options (10). However, the diagnosis and classification of this tumour remains the same. Carcinoid Tumours: Typical and atypical carcinoid tumours maintained the same morphological criteria for diagnosis and classification. Recent molecular studies have showed however that these tumours have distinct molecular profiles from the high grade relatives (LCNC and small cell carcinoma) (10). References: Travis WD, Brambilla E, Nicholson A, Noguchi M, et al, (eds). (2015) WHO Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. 4[th] ed., Lyon: IARC. Travis WD, Brambilla E, Noguchi M, et al. (2011). International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 6: 244-85 Nitadori J, Bograd AJ, Kadota K, et al. (2013) Impact of micropapillary histologic subtype in selecting limited resection vs lobectomy for lung adenocarcinoma of 2cm of smaller. J Natl Cancer Inst. 105:1212-10. Yoshizawa A, Motoi N, Riely GJ, et al. (2011). Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Mod Pathol. 24: 653-64. Travis WD, Asamura H, BAnkier AA et al. (2016) The IASLC Lung cancer Staging Project: Proposal for coding T category for subsolid nodules and assessment of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol. 11:1204-23. Rekhtman N, Paik P, Arcila M, et al (2012). Clarifying the spectrum of driver oncogene mutations in pure, biomarker-verified squamous cell carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations. Clin Cancer Res. 18:1167-76. KAdota K, Nitadori J, woo KM et al. (2014). Comprehensive pathological analyses in lung squamous cell carcinoma:single cell invasion, nuclear diameter, and tumor budding are independent prognostic gfactors for worse outcomes. J Thorac Oncol. 9:1126-39 Rekhtman N, Tafe LJ, Chaft JE et al. (2013) Distinct profile of driver mutations and clinical features in immunomarker-defined subsets of pulmonary large cell carcinoma. Modern Pathol. 26:511-22. Rekhtman N, Pietanza MC, Hellman M, et al. (2016) Next-Generation Sequencing of Pulmonary Large cell neuroendocrine Carcinoma Reveals Small Cell Carcinoma-like and Non-Small Cell Carcinoma-like subsets. Clin Cancer Res. 22:3618-29. Bunn PA, Minna J, Augustyn A et al. (2016). Small cell Lung Cancer: can recent advacnes in biology and molecular biology be translated into improved outcomes? J Thorac Oncol. 11:453-74

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    MTE 07 - Molecular Biology: Minimum Requirement for Clinicians (Sign Up Required)

    • 07:00 - 08:00
    • 10/16/2017
    • Location: Room 501
    • Type: Meet the Expert
    • Track: Chemotherapy/Targeted Therapy
    • Moderators:
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      MTE 07.01 - Molecular Biology that Clinicians Should Know: From a Clinical Viewpoint

      07:00 - 07:30  |  Presenting Author(s): Prasad S. Adusumilli

      • Abstract

      Abstract:
      This presentation will summarize the basics of cancer molecular biology and its application in lung cancer. The optimal treatment for patients with EGFR mutations in 2017, the need for tissue rebiopsy and plasma detection, and semiquantification methods will be discussed. The role of next-generation tyrosine kinase inhibitors that are approved in different countries will be summarized. The evolution of new targeted therapies and their current status of investigation will be presented. Additionally, the current status of combination targeted therapies with immunotherapy will be reviewed. The role of quantitative proteomics, plasma circulating tumor DNA, and high-throughput sequencing in current clinical practice will be summarized. By the end of the session, the audience will be familiar with the current status of driver genes, approved targeted therapies, and emerging concepts of combination therapies.

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      MTE 07.02 - Molecular Biology that Clinicians Should Know: From a Basic Viewpoint

      07:30 - 08:00  |  Presenting Author(s): Martin Filipits

      • Abstract

      Abstract not provided

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    MTE 08 - Technical Details of EBUS and EUS (Sign Up Required)

    • 07:00 - 08:00
    • 10/16/2017
    • Location: Room 502
    • Type: Meet the Expert
    • Track: Pulmonology/Endoscopy
    • Moderators:
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      MTE 08.01 - Technical Aspects of EBUS-TBNA for Clinicians

      07:00 - 07:30  |  Presenting Author(s): Takahiro Nakajima

      • Abstract

      Abstract:
      Since the clinical introduction of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in 2004, EBUS-TBNA has become accepted worldwide due to its minimal invasiveness but high diagnostic ability. EBUS-TBNA is an image-guided procedure, and the instruments and devices used for endobronchial ultrasonography as well as transbronchial needle aspiration have continuously evolved. Furthermore, such device improvements have been accompanied by improvements in the techniques of ultrasound visualization, sampling with a dedicated needle, and specimen handling. Initially, the only indication of EBUS-TBNA was nodal staging of lung cancer; however, now its indications have expanded to not only malignant diseases but also benign diseases, such as sarcoidosis or tuberculosis. EBUS-TBNA has also recently been used for the important tasks of “core sampling” and “rebiopsy”. The advent of immune checkpoint inhibitors and novel tyrosine kinase inhibitors has resulted in additional applications of EBUS-TBNA in the era of precision medicine. In 2016, the American College of Chest Physicians published a guideline focusing on the technical aspects of EBUS-TBNA. This guideline described several techniques of EBUS-TBNA for which the evidence level had been thought too difficult to grade. The ungraded consensus-based statement managed this limitation well and thus became a useful technical guide for clinicians. The guideline also described sedation to be used when performing EBUS-TBNA. Since many patients who underwent EBUS-TBNA suffered from severe coughing during the procedure, the guideline recommended performing moderate or deep sedation in the first paragraph. In addition, performing the procedure in a more comfortable condition for clinicians was required, which would help them perform the procedure repeatedly following the necessary treatment course as mentioned above. The first report of an EBUS image analysis was the classification of B-mode features of benign and malignant lymph nodes by the first generation EBUS ultrasound processor with 7.5MHz radiofrequency. Owing to improvements in ultrasound processors and increased radiofrequency to 10MHz, EBUS image analyses are now being increasingly performed, including the use of various new Doppler features and image analysis technologies, such as gray scale texture analyses and fractal dimension analyses. The latest ultrasound processor equipped with elastography is capable of depicting the relative stiffness of the targeted tissue within the region of interest. However, whether or not a spectrum analysis of EBUS radiofrequency can provide precise information of the target histology is still being investigated. After all, EBUS-TBNA is a sampling modality, so “tissue is the issue” remains the point of focus. However, we often encounter cases with multiple nodes within the same nodal station. In addition, some metastatic lymph nodes are unable to be diagnosed due to the limited metastatic area within the lymph node (micrometastasis). Advances in EBUS image analyses may help reduce examination time and medical resource usage as well as allow for more precise TBNA needle control. The dedicated TBNA needle was originally developed from the needle used for endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). The handle of the needle was designed to be manipulated by the operator alone. The initial size of the needle was 21 and 22 gauge. Now, however, several types of dedicated needles are commercially available from different manufacturers; currently available needle sizes are 19, 21, 22, and 25 gauge, and each tip is designed for a specific purpose. The size (amount) of the biopsied material, the degree of blood contamination, and the quality of the histological structure (degree of tissue crushing) can all be affected by needle selection. Although the optimum needle type is still unclear, clinicians may need to select a needle depending on the character of the targeted lesion and the purpose of the biopsy. Specimen handling is another important issue. EBUS-TBNA is basically a needle biopsy procedure; therefore, the obtainable material is fundamentally cytological material. We can often obtain “core” specimens, even when using TBNA which is a cytological sampling procedure. We first introduced the “tissue coagulation clot” method for the EBUS-TBNA “core” specimen. The “core” usually consists of tumor tissue fragments floating in coagulation tissue. By modifying the specimen-processing protocol, a good quality cell block can be made and used for pathological evaluations, including immunohistochemistry and ancillary testing, such as fluorescence in situ hybridization. We now need to determine any genetic alterations in lung cancer prior to starting treatment. The rapid on-site evaluation of the obtained material during the procedure may play a crucial role in sample processing, despite the lack of any clear evidence that this improves the diagnosis rate so far. We still need to develop the optimum specimen handling protocol in order to maximize the utility of microsamples obtained by EBUS-TBNA. Finally, training for EBUS-TBNA is still important for both mentors and mentees. We recently described the utility of a biosimulator for advanced EBUS-TBNA training to encourage efficient sampling. Many training models, including low- and high-fidelity models, and courses were developed, and the trainees were evaluated by dedicated evaluators. Performing high-quality training is crucial to ensuring a safe procedure as well as a high diagnostic yield. EBUS-TBNA is a still-evolving technology, and we clinicians need to continue brushing up our skills and seeking better ways to examine and treat patients. More clinical studies are needed to address the issues still unresolved by the current technical guideline.

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      MTE 08.02 - Clinical Aspects of EUS(B)-FNA

      07:30 - 08:00  |  Presenting Author(s): Bin Hwangbo

      • Abstract

      Abstract:
      Endoscopic ultrasound guided fine needle aspiration (EUS-FNA) has been used for lung cancer staging and diagnosis since ‘90s. However, the usefulness of EUS-FNA has not been addressed in the lung cancer field due to the limited accessibility to mediastinal lymph nodes and the low availability of the technique by thoracic physicians. The development of endobronchial ultrasound guided-transbronchial needle aspiration (EBUS-TBNA) changed the staging process of lung cancer markedly. EBUS-TBNA, which can target mediastinal nodal stations accessible by cervical mediastinoscopy, has replaced standard cervical mediastinoscopy. In the era of EBUS-TBNA, the role of EUS-FNA in lung cancer staging is being re-estimated. Moreover, endoscopic ultrasound with bronchoscope guided fine needle aspiration (EUS-B-FNA) which uses an ultrasound bronchoscope for transesophageal sampling has increased the use of EUS procedure by bronchoscopists. EBUS-TBNA and EUS-(B)-FNA have different accessibility to the mediastinum, therefore the two approaches are considered to be complementary in lung cancer staging. Among mediastinal nodal stations, EBUS-TBNA can access stations 2R, 2L, 3P, 4R, 4L and 7. Some lymph nodes at station 1 and station 8 can be targeted by EBUS-TBNA. EUS-(B)-FNA has limited ability to target pre-tracheal lesions that are easily accessed by EBUS-TBNA. EBUS-TBNA has a higher accessibility to mediastinal nodal stations than EUS-(B)-FNA in the mediastinal staging of potentially operable lung cancer. However, EUS-(B)-FNA can access the inferior mediastinum (stations 8 & 9) and some areas of the aorto-pulmonary window (station 5). The additional benefit of combined EBUS/EUS staging over EBUS-TBNA has been studied. According to a recent meta-analysis by Korevaar et al that evaluated 10 studies that looked at the additional benefit of the combined approach, the pooled sensitivity improvement by adding EUS-(B)-FNA to EBUS-TBNA was 12% in mediastinal staging of lung cancer. It is clear that adding EUS-(B)-FNA following EBUS-TBNA is beneficial for lung cancer staging in some patients. More studies are needed to find indications for adding EUS-(B)-FNA to EBUS-TBNA. As well as for mediastinal staging, EUS-(B)-FNA is useful for lung cancer diagnosis and tissue acquisition when the target is accessible by EUS-(B). In general, EUS-(B) is a better tolerated procedure than EBUS-TBNA. EUS-B-FNA can be performed following bronchoscopic procedures in the same session when bronchoscopy is difficult due to dyspnea, cough, etc. EUS-FNA and EUS-B-FNA are safe procedures with low complication rates. There are still issues regarding adequate training and cost in applying EUS for lung cancer staging. More efforts are necessary to increase the availability of EUS-(B)-FNA in the staging and diagnosis of lung cancer.