Virtual Library

Abstract:
The clinical stage is the clinician’s best and final estimate of the extent of the disease prior to the initiation of definitive therapy. As such, the clinical stage creates the foundation for all cancer treatment recommendations. Patients with lung cancer and metastasis to the ipsilateral mediastinal and/or subcarinal lymph node(s) (LN) have a nodal descriptor of N2. Such N2 metastasis reflects a biologically advanced disease with spread beyond the primary tumor in the lung itself. In the forthcoming eighth addition of the TNM classification for lung cancer, the current (7th edition) nodal descriptors and location for both clinical and pathological nodal status (N0 to N3) adequately predict prognosis. Although for lung cancer, nodal status is based on the anatomic location of the involved node, and not on the number of metastatic lymph nodes, future staging models could assess the number of involved nodes and location.(1) Determination of metastases to mediastinal lymph nodes constitutes a critical point in staging and treatment recommendations. Computed tomography and FDG-PET + CT scans are helpful to guide treatment decisions; invasive staging is still recommended to confirm mediastinal nodal involvement. (2) (3) (4) Invasive staging for diagnosis of N2 LN includes cervical mediastinoscopy (CME) or mediastinotomy (Chamberlain’s procedure), endoscopic bronchial ultrasound (EBUS), or esophageal ultrasound (EUS). The use of CME regardless of radiographic evidence of nodal involvement (“routine mediastinoscopy”) is not a cost effective approach, and adds little to the accuracy of staging in patients with an adequate noninvasive preoperative evaluation. (5) Endobronchial ultrasound combined with mediastinoscopy (2;4) can be effective. VATS techniques can evaluate enlarged level 5 or 6 lymph nodes, and as well, enlarged level 8 or 9 or low level 7 lymph nodes. Esophageal ultrasound (EUS) guided aspiration can be used for level 7 and AP window LN Patients with clinically early stage NSCLC (cStage I or II), who have complete resection (R0) and subsequently identified microscopic or occult N2 metastases, represent a biologically favorable subset with improved survival following adjuvant therapy. Surgery alone for cStage IIIA (N2) lung cancer is infrequently performed however, selected patients may benefit from a multidisciplinary approach to treatment which include local and systemic components. (6). Definitive concurrent chemoradiotherapy is commonly recommended for N2 disease given the identifiable locally advanced NSCLC and likely occult systemic metastases. . Induction chemoradiotherapy has been evaluated for treatment of clinical stage IIIA (N2) NSCLC. (7;8) In these two phase III trials, surgery did not provide an overall survival benefit; however, in an exploratory analysis, induction therapy followed by lobectomy had improved survival. Multidisciplinary team discussions for individual patients are essential to optimize benefits of treatment. In selected resectable IIIA NSCLC patients, induction chemoradiotherapy followed by resection is an alternative treatment to chemoradiotherapy alone. (6) The Society of Thoracic Surgery National General Thoracic Surgery Database evaluated identified only 3319 patient with cStage IIIA (N2) NSCLC who underwent resection between 2002 and 2012. (9) Patients were >65 years of age and only 46% were treated with induction therapy. 93% had FDG PET scans, and 51% were coded as having undergone invasive mediastinal staging. Nodal over-staging occurred in 43% of patients. Lobectomy was the most common procedure (69%). The unadjusted 5 year survival following induction therapy was 35%. Selection of patients for resection may depend on the number of ipsilateral LN stations involved, and the ability of induction therapy to create a clinical post-induction yN0 nodal status. Endobronchial ultrasound (EBUS) is used initially to diagnosis ipsilateral LN metastasis and exclude contralateral metastasis. Following induction therapy, repeat EBUS may confirm yN0 status of the previously involved LN, and be validated by cervical mediastinoscopy. The surgeon must answer this question for each patient with N2 disease: When does resection following induction therapy consistently provide better survival than definitive C+RT? Large pragmatic clinical trials may facilitate new knowledge in this area. Regardless of approach (open or minimally invasive techniques), a mediastinal lymph node dissection is recommended. A recent study utilizing the National Cancer Database from the American College of Surgeons Commission on Cancer, demonstrated that with Stage I NSCLC better survival was associated with resecting 10 or more lymph nodes to optimally confirm stage I status.(10) Although this is not a therapeutic intervention, it emphasizes the need for mediastinal lymph node dissection to ensure accuracy by decreasing variability in the mediastinal dissection, and optimizing the accuracy of the pathologic staging. Reference List (1) Asamura H, Chansky K, Crowley J, Goldstraw P, Rusch VW, Vansteenkiste JF, et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revision of the N Descriptors in the Forthcoming 8th Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2015 Dec;10(12):1675-84. (2) Silvestri GA, Gonzalez AV, Jantz MA, Margolis ML, Gould MK, Tanoue LT, et al. Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013 May;143(5:Suppl):211S-50S. (3) Stamatis G. Staging of lung cancer: the role of noninvasive, minimally invasive and invasive techniques. European Respiratory Journal 2015 Aug;46(2):521-31. (4) Detterbeck FC, Postmus PE, Tanoue LT. The stage classification of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013 May;143(5:Suppl):191S-210S. (5) Fernandez FG, Kozower BD, Crabtree TD, Force SD, Lau C, Pickens A, et al. Utility of mediastinoscopy in clinical stage I lung cancers at risk for occult mediastinal nodal metastases. J Thorac Cardiovasc Surg 2015;149(1):35-41. (6) Ramnath N, Dilling TJ, Harris LJ, Kim AW, Michaud GC, Balekian AA, et al. Treatment of stage III non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013 May;143(5:Suppl):314S-40S. (7) Albain KS, Swann RS, Rusch VW, Turrisi AT, III, Shepherd FA, Smith C, 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 Aug 1;374(9687):379-86. (8) van Meerbeeck JP, Kramer GW, Van Schil PE, Legrand C, Smit EF, Schramel F, 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 Mar 21;99(6):442-50. (9) Boffa D, Fernandez FG, Kim S, Kosinski A, Onaitis MW, Cowper P, et al. Surgically Managed Clinical Stage IIIA-Clinical N2 Lung Cancer in The Society of Thoracic Surgeons Database. Ann Thorac Surg 2017 Aug;104(2):395-403. (10) Samayoa AX, Pezzi TA, Pezzi CM, Greer GE, Asai M, Kulkarni N, et al. Rationale for a Minimum Number of Lymph Nodes Removed with Non-Small Cell Lung Cancer Resection: Correlating the Number of Nodes Removed with Survival in 98,970 Patients. Annals of Surgical Oncology , 2016 23, Suppl 5:1005-1011.

Abstract:
The unique location of Pancoast tumors makes complete resection challenging and usually includes the upper lobe, involved chest wall with or without the subclavian vessels, portions of the vertebral column and T1 nerve root, and dorsal sympathetic chain. Several approaches are used depending on tumor location. Posterior Approach The patient is positioned in the lateral decubitus position, rotated slightly anteriorly to expose the paravertebral region. The chest is explored via a posterolateral thoracotomy in the 5[th] intercostal space. If the tumor appears resectable, the incision is extended to the base of the neck posteriorly and around the anterior border of the scapula anteriorly. The scapula is elevated with an internal mammary retractor. The scalene muscles are detached from the first and second ribs. Involved ribs are divided anteriorly. Dissection is carried along the superior border of the first rib in the subperiosteal plane. The erector spinae muscles are retracted off the thoracic spine to expose the costovertebral gutter. The transverse processes and rib heads are resected en-bloc at the lateral border of the facet joint. The chest wall is retracted anteriorly, and the intercostal nerves ligated before division to prevent cerebrospinal fluid leak. Thoracic nerve roots below T1 are transected without neurologic sequelae. Since the T1 nerve root provides motor innervation to the hand, it is ligated only in cases of tumor invasion. Division of the C8 nerve root will result in permanent arm/hand paralysis. The detached chest wall is allowed to fall into the chest cavity and an upper lobectomy and lymph node dissection is completed. Reconstruction of the chest wall is necessary when the defect is larger than the first three ribs and can be performed with a 2 mm thick PTFE patch. Tumors Involving the Vertebral Bodies and Epidural Region Vertebral body invasion by Pancoast tumors no longer a contraindication to surgical resection because of contemporary spine instrumentation. With multimodality therapy, T4 lesions with vertebral body or epidural extension can be resected with curative intent. We use spine MRI to divide tumors into four classes, A-D, based on the degree of spinal column and neural tube involvement. Class A and B tumors are T3 lesions amenable to complete R0 resection. Class C and D tumors are T4 lesions not amenable to en-bloc resection but can still be completely resected. Class C tumors extend into the neural foramina with limited or no vertebral body involvement but have unilateral epidural compression. Class D tumors involve the vertebral column, either the vertebral body and/or lamina with or without epidural compression. Class A, B and some class C tumors are approached through a posterolateral thoracotomy. A high-speed drill is used to remove involved vertebral bodies. The posterior longitudinal ligament is removed and provides a margin on the anterior dura. The disc spaces adjacent to the tumor are exenterated in order to aid in spinal fixation. Anterior reconstruction alone is sufficient for resections of 1-2 vertebral bodies. Autologous bone from the iliac crest or non-diseased rib, allograft fibula, methymethacrylate with Steinman pins, or corpectomy cages can all be used for reconstruction. Patients requiring any degree of epidural decompression in the upper thoracic spine undergo combined posterior and anterior approach. Long segment posterolateral spinal instrumentation and fusion avoids the development of debilitating deformity. Class D tumors involving the posterior elements (spinous process, laminae, and pedicles) are also resected through a combined posterior/anterior approach. Patients are first positioned prone and a posterior midline incision made. The involved areas of the spinous process, laminae, and pedicles are resected. Epidural tumor is dissected off the dura and a multilevel resection of affected nerve roots done. Posterior fixation is accomplished in order to maintain coronal and sagittal stability. Muscle flap rotation by a plastic surgeon can be done to reduce the risk of skin breakdown and infection of the spine hardware. The incision is then closed, the patient turned to the lateral decubitus position, a posterolateral thoracotomy performed, and the lung and chest wall resection completed. Anterior Approaches Pancoast tumors involving the subclavian vessels are best approached anteriorly, using the anterior transcervical approach originally described by Dartevelle and modified by others. The patient is positioned supine with the neck hyperextended and the head turned to the opposite side of the lesion. An inverted L-shaped incision is carried down the anterior border of the sternocleidomastoid muscle and extended below the clavicle to the level of the second intercostal space, then turned horizontally following a parallel line below the clavicle to the deltopectoral groove. The sternal attachment of the sternocleidomastoid is divided along with the insertion of the pectoralis major. The scalene fat pad and lymph nodes are excised. If the tumor is resectable, the upper part of the manubrium is divided and the incision carried into the second intercostal space via an L-shaped incision. The involved section of the subclavian vein is resected but not reconstructed. The anterior scalene muscle is divided at its insertion onto the first rib. The phrenic nerve is preserved. The subclavian artery is resected and reconstructed with a 8 or 10 mm PTFE graft. The middle scalene muscle is detached from the first rib to expose the C8 and T1 nerve roots. The ipsilateral prevertebral muscles and paravertebral sympathetic chain and stellate ganglion are resected off the anterior aspect of the vertebral bodies of C7 and T1. TheT1 nerve root is commonly divided just lateral to the T1 intervertebral foramen. The anterolateral arch of the first rib is divided at the costochondral junction and the second rib is divided at its midpoint. The third rib is dissected on its superior border in a posterior direction toward the costovertebral angle and the first two through three ribs are disarticulated from the transverse processes. From this cavity, an upper lobectomy is completed. If exposure for the lobectomy and chest wall resection is inadequate, the anterior incision is closed, the patient turned into the lateral decubitus position and the rest of the resection performed via a posterolateral thoracotomy

Abstract:
In recent years, the number of early stage lung cancers has enormously increased mainly due to frequent use of chest CT in routine practice or screening purpose. Both curability and non-inavasiveness are required especially for such early disease. Increased number of VATS lobectomy and sublobar resection for selected patients is the international trend in such situation. Diagnosis: Retrospective data revealed that the sensitivity of conventional bronchoscopic examination for peripheral cancer < 2cm is only 34%. The combination of Virtual bronchoscopic navigation and EBUS guide-sheath has demonstrated the improved sensitivity, thus this new combination strategy should be necessary for differential diagnosis of small cancers detected by chest CT[1)]. Surgical procedure: A total of 38000 lung cancers were resected in Japan in 2013 and 70% of surgeries were video-assisted[2)]. Segmentectomy has been performed intentionally mainly for lung cancer 2cm or less in diameter. Several comparative studies between lobectomy and segmentectomy for tumors < 2cm showed no significant difference in survival[3)]. Recently, segmentectomy is selected based on the size and high resolution CT (HRCT) findings of the tumor. The proportion of consolidation diameter to tumor diameter correlates with biological malignancy and the establishment of robust image criteria predicting non-invasive cancer is desirable to find candidates for segmentectomy. The Japan Clinical Oncology Group (JCOG) conducted a prospective study to recognize the relationship between HRCT finding and pathological non-invasiveness in clicical stage IA cancer (JCOG0201)[4)]. This study revealed that adenocarcinoma <2.0 cm with <0.25 consolidation to the maximum tumor diameter showed pathological non-invasiveness in 98.7% and this criterion could be used to predict early lung cancer preoperatively[5)]. Based on the result of JCOG0201, two prospective studies were performed and finished recruitment, phase II trial of wide wedge resection for radiological non-invasive adenocarcinoma (tumor diameter 2cm or less and consolidationratio<0.25) (JCOG0804) and randomised phase III trial for radiological invasive adenocarcinoma (tumor diameter 2cm or less and consolidation ratio>0.25) to evaluate non-inferiority in OS of segmentectomy compared to lobectomy (JCOG0802)[6)]. The indication of segmentectomy will be demonstrated by the results of these studies. Clinical research: PET-CT has been routinely used for clinical staging and the standardized uptake value (SUV) of the main tumor is recognized to be as a predictor of the clinicopathological characteristics and prognosis. Analyses of 610 resected stage IA adecocarcinoma showed that maxSUV and GGO ratio cutoffs to predict recurrence were 2.9 and 25%, respectively. They were also related to nodal metastasis, histological tumor invasiveness and recurrence. The 5-year RFS of cases with maxSUV <2.9 (n=456) was 95%, while cases with maxSUV>2.9 (n=154), 72% (p<0.001)[7)]. Our result showed that maxSUV cutoff of possibility for recurrence was 2.6 in adenocarcinoma, which was also related to nodal metastasis and histological tumor invasiveness. The 3-year relapse-free survival was 99%/78% (maxSUV lower/higher than 2.6) and following multivariate analysis, pathological nodal status and SUVmax were found to be independent predictive factors for relapse-free survival. Surgical management of early stage lung cancer should be selected based on the tumor size and consolidation ratio on HRCT. The results of RCTs will demonstrate the indication of sublobar resection in near future. Further analysis is encouraged for the evaluation of biological aggressiveness in each case[8)]. References Asano F, Shinagawa N, Ishida T, et al. Virtual bronchoscopic navigation combined with ultrathin bronchoscopy. A randomized clinical trial. Am J Respir Crit Care Med 2013; 188:327-333 Committee for Scientific Affairs The Japanese Association for Thoracic Surgery, Thoracic and cardiovascular surgery in Japan during 2013 : Annual report by the Japanese Association for Thoracic Surgery. Gen Thorac Cardiovasc Surg.2015;63:670-701. Okada M, Koike T, Higashiyama M, et al. Radical sublobar resection for small-sized non-small cell lung cancer: a multicenter study. J Thorac Cardiovasc Surg. 2006; 132: 769-775 Suzuki K, Koike T, Asakawa T, et al.: A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan Clinical Oncology Group 0201). J Thorac Oncol 2011;6:751-756 Asamura H, Hishida T, Suzuki K, et al. Radiographically determined noninvasive adenocarcinoma of the lung: Survival outcomes of Japan Clinical Oncology Group 0201 J Thorac Cardiovasc Surg 2013;146:24-30 Nakamura K, Saji H, Nakajima R, et.al. A Phase III Randomized Trial of Lobectomy Versus Limited Resection for Small-sized Peripheral Non-small Cell Lung Cancer (JCOG0802/WJOG4607L) Jpn J Clin Oncol 2010;40:271–274 Uehara H, Tsutani Y, Okumura S, et al. Prognostic Role of Positron Emission Tomographyand High-Resolution Computed Tomography in Clinical Stage IA Lung Adenocarcinoma Ann Thorac Surg 2013;96:1958–1965 Tsutani Y, Miyata Y, Nakayama H,et al.. Sublobar resection for lung adenocarcinoma meeting node-negative criteria on preoperative imaging. The Annals of thoracic surgery. 2014;97:1701-1707

Abstract:
During the last two-three decades the surgical approach for the treatment of lung cancer had significantly changed. Compared to the traditional posterolateral thoracothomy the introduction and diffusion of a more conservative muscle sparing lateral thoracothomy has shown a first change to lesser trauma for patients, but only with the advent of mininvasive surgery we have witnessed the real change in terms of improving the quality of life and reducing perioperative pain (1). According to some review articles (2) not only perioperative outcome was improved with MIS compared to thoracotomy but also advantages in terms of oncological outcome have been reported even if it is possible that some selection bias could have played a role in the review results. Many studies have confirmed the benefits for the patients treated with MIS compared to open including reduced pain, complications, blood trasfusions and postoperative stay, and improved quality of life, ahestetic and functional results (3). Different technique have been described with different number of small incisions but all have in common that no rib spreading is performed and the dissection is done looking at the monitor. The most common videothoracoscopic techniques are: a. the Cophenaghen approach with an anterior incision of 4-6 cm in the IV intercostal space and 2 more trocars is characterised by an anterior to posterior approach to the mediastinum. This technique has been described by Heine Hansen and by Mc Kenna (4); b. the posterior approach of the Edinburgh school has been described by William Walker and reproduces the posterior approach to the hylum similar to that of the posterolateral thoracothomy (5). In this technique the utility incision is posterior, in the auscultatory triangle and usually two or three additional ports are used; c. the single port described by Gaetano Rocco and Diego Gonzales Riva with a single incision of 4-8 cm usually in the V intercostal space through which the tools and the camera are inserted (6). More recently new approaches has been described including the microlobectomy and the subxhifoid approach. Both techniques are aimed to reduce the pain of the intercostal nerve injury by avoiding the utility incision in the intercostal space. Despite all these advantages for the patients the manual vats has been embraced by a minority of thoracic surgeons and the diffusion has been very slow mainly due to technical difficulties, like the limited visual information, limited freedom of movement, unstable camera platform and poor ergonomics, and doubts on oncological radicality. To overcome videothoracoscopic technical limitations, the micromechanic and robotic sophisticated technology has been introduced with the robotic surgical systems. Natural movements of the surgeon’s hands are translated into precise instrument movements inside the patient with tremor filtration. Three dimensional view offers a visual magnification that compensate the absence of haptic feedback. The robotic surgical system is the result of a long process of development aimed at producing a natural extension of the surgeon’s eyes and hands via the intermediation of a computer. In this way, the ease of movement obtained with open surgery is summated with the advantages of the minimally invasive technique. Since 2002, when the first robotic system for surgery was introduced, robot-assisted thoracic surgery (RATS) has been adopted by an increasing number of centres around the world, and today is used in ~10% of lobectomies in the US (7, 8). Two different techniques have been described in robotic thoracic surgery, the complete portal robotic lobectomy or segmentectomy (CPRL or CPRS) maynly used by surgeons of North American, characterised by 3-4 arms technique, CO2 insufflation, posterior to anterior hilar dissection and a specimen extraction incision at the end of the procedure (9); and the Robotic Assisted Thoracoscopic Surgery (RATS), characterized by a 4-arms approach, a utility incision since the beginning, no routine CO2 insufflation and anterior to posterior hilar dissection (10). To date, no randomized trials have reported comparative data on RATS vs. VATS or thoracotomy for lung cancer. Retrospective analysis comparing RATS vs. thoracotomy have revealed advantages for the RATS approach, especially shorter hospital stays and a lower complication rate but when compared to VATS, RATS produces similar or only slightly better results, the two being minimally invasive techniques with no need for rib separation. A few studies have reported RATS to be safer than VATS, with less conversions for bleeding, less complications and lengths of stay; in others, it was associated with lower postoperative consumption of pain killers and quicker return of patients to normal activity. In addition, lymph-node upstaging has been shown to be higher with RATS than with VATS, with a similar rate as thoracotomy. The main disadvantage of RATS is the higher costs of instrumentation and surgical kits. Nevertheless, the future will probably see reductions in the costs of robotics and improvements in the instrumentation, integration with 3D imaging to improve virtual reality, and more patients benefitting from minimally invasive procedures for lung malignancies. References 1. Demmy TL, Curtis JJ. Minimally invasive lobectomy directed toward frail and high-risk patients a case-control study. Ann Thorac Surg 1999;68:194-200. 2. Whitson BA, et al. Thoracoscopic versus thoracotomy approaches to lobectomy: differential impairment of cellular immunity. Ann Thorac Surg 2008;86:1735-44. 3. Bendixen M, et al. Postoperative pain and quality of life after lobectomy via video-assisted thoracoscopic surgery or anterolateral thoracotomy for early stage lung cancer: a randomised controlled trial. Lancet Oncol. 2016;17:836-44. 4. Hansen HJ, et al. Video-assisted thoracoscopic surgery (VATS) lobectomy using a standardized anterior approach. Surg Endosc. 2011;25:1263-9. 5. Walker WS, et al. Thoracoscopic pulmonary lobectomy. Early operative experience and preliminary clinical results. J Thorac Cardiovasc Surg. 1993;106:1111-7. 6. Gonzalez-Rivas D, et al. Uniportal video-assisted thoracoscopic bronchovascular, tracheal and carinal sleeve resections†. Eur J Cardiothorac Surg 2016;49 Suppl 1:i6-16. 7. Park BJ, et al. Robotic assistance for video-assisted thoracic surgical lobectomy: technique and initial results. J Thorac Cardiovasc Surg 2006;131:54-9. 8. Cerfolio RJ, et al. Initial consecutive experience of completely portal robotic pulmonary resection with 4 arms. J Thorac Cardiovasc Surg 2011;142:740-6. 9. Dylewski MR, et al. Pulmonary resection using a total endoscopic robotic video-assisted approach. Semin Thorac Cardiovasc Surg 2011;23:36-42. 10. Veronesi G, et al. Four-arm robotic lobectomy for the treatment of early-stage lung cancer. J Thorac Cardiovasc Surg 2010;140:19-25.

Abstract:
High risk lung cancer patients represent a challenge in thoracic oncology, they are often related to heavy smoke habit with increased cardiovascular or respiratory diseases that prevents for getting optimal results in their lung cancer treatment. In the other hand it is widely accepted that lobectomy and lymphadenectomy is the standard treatment for younger patients with adequate cardiopulmonary function, specially in solid lung cancer patients (1). High risk patients with early stage lung cancer, often undergo sublobar resections, regardless of histology or tumor size, which increases the risk of local recurrence and may decrease long-term survival. However, a significant group of these patients have a good prognosis, either because their histology or tumor size are favorable, they present slow growing tumors or because they can undergo anatomical sublobar resections and a lymphadenectomy that provides an adequate disease control. In patients without respiratory or cardiovascular impairement it is accepted that sublobar resections have the same possibility of controlling the disease than lobectomy for ground glass opacity lesions, partially solid lesions (<50%) or with invasion area less than 5mm (2,3,4). The biggest problem appears in high-risk patients with solid lesions, in whom sublobar resections have not demonstrated the same oncological performance compared to lobectomy. This group will face the dilemma of decreasing operative morbimortality and the risk of postoperative respiratory disability versus decreased global and disease-free survival (5). Reports and our own expeience with the treatment of T1 and T2 patients with segmentectomies and wedge resections suggests that it is appropriate to try these patients with economical resections to improve the quality of life and survival in a group of patients whose survival curve does not depend only on cancer, but it is also important the competitive causes of mortality (ex. cardiovascular disease, pulmonary fibrosis, emphysema) (5). In our group, we evaluate cardiovascular risk with echocardiography and provocative test for myocardial ischemia, preferably exercise stress test. Respiratory risk is evaluated with spirometry, DLCO and cardiopulmonary exercise testing (peak VO2 and ventilatory equivalent VE/VCO2) (6,7). If ppoFEV1 <60%, ppoDLCO <60%, V02 <10-15ml/kg/min and/or CO2 equivalent >35, values that show that the patient is high-risk or inoperable, we incorporate the patient to an exercise training program. Our protocol considers 1-1.5 hours/day of training, with progressive load to improve muscular strength, cardiovascular and respiratory capacity, associated with full medical treatment (LABA/LAMA inhalers plus inhaled and eventually systemic corticosteroids). After completing the training period, the patient is reevaluated and the treatment plan is defined: 1.- If he leaves the high-risk group (VO2 >15ml/kg/min with VE/VCO2 <35), he will receive standard oncological surgery, according to tumor size and radiological/histological findings (TNM, GGO vs solid component, invasion). 2.- If the surgical contraindication persists (VO2 <10ml/kg/min with VE/VCO2 >35), we prefer non-surgical treatments (like SBRT). In our institution, less than 5% of patients that enter the training program remain inoperable. 3.- If the patient persists in the high or moderate-risk group (VO2 10-15ml/kg/min with VE/VCO2 <35), we prefer sublobar resections. In patients where the tumor is pure GGO or predominantly GGO (<50% solid) and measure less than 2 cms, we perform a VATS wide wedge resection plus hilar and mediastinal sampling. Frozen section must confirm that less than 50% is invasive or invasion area is smaller than 5mm. Margins should be larger than 1cm to persevere with wedge resection. If these requirements are not met: solid tumors larger than 10mm or mostly solid/GGO tumors, or GGO tumors greater than 2 cm with >25% solid, or has an invasive component larger than 5mm, we perform an anatomic segmental resection, by VATS or thoracotomy, associated with hilar and mediastinal lymphadenectomy (2,8,9,10). 4.- Even in larger tumors, we will attempt segmental resection in high-risk patients. We consider that although the risk of local recurrence is high, the lower morbidity and mortality rate of sublobar resections justifies this approach in high-risk patients. We believe that a sublobar resection with margins larger than 1 cm, grant better quality of life than a patient who becomes oxygen dependent, dies in the postoperative period or has not been resected due to the impossibility of lobectomy. In our institution, we have a prospective registry of morbidity that allows us to evaluate M&M rate and the relation with VO2 in patients with lobar and sublobar resections (5,9).(Fig1) Finally, in those patients with solid tumors and lymphovascular invasion, that are staged as clinically an pathological N0, the problem is that the intralobar lymph nodes are not completely accessible or evaluable. This implies that actually the N1 barrier is not adequately studied with sublobar resections, especially in those patients undergoing a training program and become candidates to wedge or even anatomical segmental resections as a treatment choise. This lack of information may be acceptable in AIS or MIA tumors, but constitute a greater risk in patients with solid or partially solid tumors, and even greater risk in those with lymphovascular invasion in the paraffin section. Should we consider these patients as potential N1 and add treatment to avoid the risk of relapse? There is no evidence to support this approach yet, but we feel it should be considered. References 1.- De Zoysa MK et al. Is limited pulmonary resection equivalent to lobectomy for surgical management of stage I non-small-cell lung cancer? Interactive CardioVascular and Thoracic Surgery 14(2012) 816-20 2.-Asamura H et al. Radiographically determined noninvasive adenocarcinoma of the lung: Survival outcomes of Japan Clinical Oncology Group 0201. J Thorac Cardiovasc Surg 2013;146:24-30 3.- Sakurai H, Asamura H. Sublobar resection for early stage lung cancer. Transl Lung Cancer Res 2014;3(3):164-172 4.- Suzuki K, Asamura H et al. “Early” peripheral lung cancer: prognostic significance of Ground Glass Opacity on thin-section computed tomographic scan. Ann thorac Surg 2002;74:1635-9 5.- Nakamura H et al. Comparison of the surgical outcomes of thoracoscopic lobectomy, segmentectomy, and wedge resection for clinical stage I non-small-cell lung cancer. 2011 Apr;59(3):137-41. 6.- Shafiek et al. Risk of postoperative complications in chronic obstructive lung disease patients considered fit for lung surgery: beyond oxygen consumption. Eur J Cardiothorac Surg 2016; doi:10/1093/ejcts/ezw104 7.- Salati M, Brunelli A. Risk stratification in lung resection. Curr Surg Rep. 2016; 4:37 8.- Hattori A et al. Prognostic impact of the findings on thin section computed tomography in patients with subcentimetric non small cell lung cancer. JTO 2017;12(6):954-962 9.- Valenzuela R et al. Long term survival of lung cancer in Chile. JTO2017;12(1):S745-S746 10.-Aokage K et al. Limited resection for early-stage non-small cell lung cancer as function-preserving radical surgery: a review. Jpn J Clin Oncol,2017,47(1):7-11 Figure 1 Fig 1: Survival in Resected NSCLC Lung Cancer by peak VO2, adjusted by TNM Patients with peak VO2 less than 15 ml/kg/min present a worse survival. Data obtained in a serie of 55 patients in the last preoperative evaluation, after training. Clinica Santa María, Santiago, Chile

Abstract:
Salvage thoracic surgery has become an increasingly common indication in patients with lung cancer (1). In principle, three different indicative fields of salvage surgery in patients with lung cancer can be distinguished: a) the surgical resection of a persistent or recurring primary lung tumor after stereotactic radiotherapy, b) salvage lung resection after definitive chemoradiation therapy for Stage III non-small-cell lung cancer, or c) palliative surgery in cases with e. g. massive haemoptyses or bronchial obstruction with treatment-resistant retention pneumonia. Common to all indications is that they are always individual case decisions. The published series are all retrospective, comprise only a small number of patients and refer to a long period at a single institution. All studies show that these operations are often surgically challenging and demanding and require careful consideration of individual patient related factors. The presentation will provide an overview of the current literature, and will discuss own clinical experiences from selected cases. SBRT is an increasingly used modality in patients with stage I lung cancer. Whereas in the past SBRT was typically considered an alternative to surgery for patients unfit or at high risk for surgery, the modality is now being used more often also for healthier, potentially operable patients. In a recent study from MD Anderson Cancer Center, Antonoff and colleagues presented a retrospective analysis of the largest series of pulmonary resections after local SBRT failure reported to date, along with a cumulative review that incorporates all patients who have been previously reported. (2) They demonstrated that resection after local failure of SBRT in highly select individuals is feasible and safe, and has an overall acceptable morbidity and mortality, albeit higher than what is typically observed in nonirradiated patients. It is of note that in their series the majority (73%) of patients underwent lobectomy, and only 24% of patients underwent sublobar resections. In considering salvage resection, the authors recommend careful consideration of the patient’s performance status and the likely extent of required resection, to be discussed thoughtfully both with the patient and in a multidisciplinary tumor board setting. Local recurrence is observed in 20% - 35% of patients after definitive chemoradiation therapy for Stage III non-small-cell lung cancer. In selected cases salvage surgery may be considered. A recent study from Italy identified 35 cases that underwent salvage surgery after definitive chemoradiation therapy for locally advanced non–small cell lung cancer over a period of 10 years, representing 1.2% of all lung resections for lung cancer performed at their institution. (3) The authors showed acceptable postoperative survival (2- and 3-year OS was 39% and 33%, respectively) and complication rates (25.7% of both minor and major complications). Another recent study from the Netherlands reported on 15 patients that underwent salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiation therapy for locally advanced non-small cell lung cancer. The authors concluded that selected patients with locoregional recurrence or persistent tumor after high dose chemoradiation therapy, can undergo salvage surgery with acceptable morbidity and mortality, even when a pneumonectomy is required (4). Factors that might have contributed to their favourable results included adequate pre-operative staging, ability to obtain an R0 resection and a good performance status. Based on the favourable results, the authors emphasised that medically operable patients presenting with locoregional recurrence or persistent tumor after definitive chemoradiation therapy for NSCLC, should have all treatment options reviewed in an experienced multidisciplinary tumor board. In conclusion, salvage surgery after stereotactic radiotherapy or after definitive chemoradiation therapy for Stage III non-small-cell lung cancer has become a new challenge for thoracic surgeons. References: 1. Van Schil PE. Salvage surgery after stereotactic radiotherapy: a new challenge for thoracic surgeons. J Thorac Oncol; 2010. p. 1881-2. 2. Antonoff MB, Correa AM, Sepesi B, Nguyen QN, Walsh GL, Swisher SG, Vaporciyan AA, Mehran RJ, Hofstetter WL, and Rice DC. Salvage pulmonary resection after stereotactic body radiotherapy: A feasible and safe option for local failure in selected patients. J Thorac Cardiovasc Surg; 2017;154(2):689-699. 3. Casiraghi M, Maisonneuve P, Piperno G, Bellini R, Brambilla D, Petrella F, Marinis FD, and Spaggiari L. Salvage Surgery After Definitive Chemoradiotherapy for Non–small Cell Lung Cancer. Seminars in Thoracic and Cardiovascular Surgery. Elsevier BV; 2017;. 4. Dickhoff C, Dahele M, Paul MA, van de Ven PM, de Langen AJ, Senan S, Smit EF, and Hartemink KJ. Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiotherapy for locally advanced non-small cell lung cancer. Lung Cancer; 2016;94:108-13.

Abstract:
Endoscopic Staging of Lung Cancer Kazuhiro Yasufuku During the management of patients with lung cancer, accurate lymph node staging is important not only to determine the prognosis but also to decide the most suitable treatment plan. Non-invasive staging such as computed tomography (CT) and positron emission tomography (PET) indicate size and metabolic activity, respectively. However imaging alone is inaccurate and therefore tissue sampling is the preferred and most reliable. Surgical staging by mediastinoscopy has been the gold standard for mediastinal lymph node staging but requires general anesthesia and complications cannot be ignored. Endoscopic ultrasound techniques provide a minimally invasive alternative for surgical staging and have become available for oncologists around the world. The current available endoscopic ultrasound techniques for mediastinal staging include transesophageal endoscopic ultrasound guided fine needle aspiration (EUS-FNA) and endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA). Both procedures are performed in an outpatient setting under local anesthesia. EUS-FNA is a sensitive and safe method of evaluating the inferior mediastinal nodes (stations 7, 8, and 9) and some parts of the anterior mediastinal nodes if the lymph nodes are accessible from the esophagus. However, in spite of the strength of EUS-FNA for evaluating the inferior mediastinal nodes, its ability to evaluate lesions anterior to the trachea is limited. On the other hand, EBUS-TBNA has reach to the paratracheal and subcarinal (stations 2R, 2L, 4R, 4L, 7), as well as the N1 lymph nodes (stations 10, 11, 12). In experienced hands, EBUS can be used through the esophagus for a EUS-like approach to sample inferior mediastinal lymph nodes. With the transvascular approach, AP window lymph nodes (station 5) can be sampled by EUS-FNA and/or EBUS-TBNA. Specialized centers have reported the sampling of station 6 via EUS-FNA. Thus, EUS-FNA and EBUS-TBNA are complementary methods for lymph node staging in lung cancer and most of the mediastinum and the hilum can be evaluated with these endoscopic procedures beyond the reach of mediastinoscopy. Based on the current evidence, EBUS-TBNA and EUS-FNA presents a minimally invasive endoscopic procedure of choice for mediastinal staging of NSCLC with discrete N2 or N3 lymph node enlargement, provided negative results are confirmed by surgical staging. When combined the techniques offer safe and accurate assessment of mediastinum, with accuracy surpassing that of the pervious gold standard – cervical mediastinoscopy. EBUS-TBNA and/or EUS-FNA can also be repeated with ease and have been used for mediastinal restaging in patients who underwent neoadjuvant therapy in preparation for definitive surgical intervention. New size needles are now available for sampling of the lymph nodes during EBUS-TBNA including 25-gauge and 19-gauge needles. Smaller needles may provide greater reach with good quality samples, whereas larger 19-gauge needle may provide bigger tissue for histological evaluation of the lymph nodes samples. There are limitations of using cytological samples obtained during EBUS-TBNA or EUS-FNA for PD-L1 expression. The use of the 19-gauge needle may solve this problem.

Abstract:
In the past several years, X-ray fluoroscopy had been commonly employed to determine the lung field during transbronchial biopsy (TBB); however, precise localization of a PPL has not always been possible leading to low diagnostic yield. For ground glass opacities (GGOs), the value of X-ray fluoroscopy even becomes less. The value of virtual X-ray fluoroscopy and CT fluoroscopy has potential but remains to be known. The advent of endobronchial ultrasound (EBUS) has dramatically increased precise bronchoscopic confirmation of the location of a PPL before sampling. In particular, the radial probe EBUS is used to indicate that a lesion has been reached. For solid peripheral pulmonary lesions (PPLs), Kurimoto et al have described three major types of echogenicities that might differentiate between benignity and malignancy. For GGOs, we have observed constant radial-EBUS patterns that we called blizzard and mixed blizzard signs. Currently, several acquired resistance mechanisms and rare driver oncogenes are identified in non-small cell lung cancer (NSCLC) relapses. Re-biopsy increases valuable information to guide treatment strategies, but the utility and feasibility of bronchoscopic re-biopsy especially endobronchial ultrasound (EBUS) guided re-biopsy has not been investigated. We recently reported the utility of bronchoscopic (EBUS-guided) re-biopsy for detecting the mutation in NSCLC. Re-biopsy by both EBUS-TBNA and EBUS-GS were useful and safe sampling procedures for mutation analysis of EGFR-TKI resistant NSCLC. Another alternative approach, specifically liquid biopsy, now present as a crucial point in the field. Liquid biopsy has grown in importance because the genetic profile of tumors can affect how well they respond to a certain treatment. A recent paper showed that the concordance between re-biopsy and liquid biopsy, including plasma DNA and circulating tumor cell, was 57–60%. The usefulness of monitoring T790M status in liquid biopsy was already reported. Although liquid biopsy has the potential to detect new mutations after chemotherapy, several reports have demonstrated some difficulties in detecting tumor-derived mutations in plasma. Therefore, liquid biopsy and re-biopsy may be considered to be complementary methods of mutation analysis. I would like to share our data and actual cases in this talk. Figure 1Figure 2

Abstract:
Introduction: Malignant airway obstruction can result from primary airway tumors, extension of adjacent primary tumors, or metastatic tumors. Partial or complete airway obstruction can deteriorate functional status of patients and result in impending respiratory failure. Malignant airway obstruction is considered to be one of the most distressing causes of morbidity and mortality in lung cancer patients. Bronchoscopic intervention can provide immediate relief from suffocation, improve general condition, and provide a bridge, allowing time for additional treatment such as surgery, radiation, or chemotherapy in patients suffering from malignant airway obstruction. Indication: Any patients who suffer from respiratory distress due to central airway obstruction are indicated for bronchoscopic intervention. However, patients should tolerate the morbidity of intervention, the length of the airway obstruction less than 4cm, and the duration of obstruction less than 2 month due to the technical limitation. Method: Due to it is safe from massive hemoptysis and respiratory failure, most experienced bronchoscopists prefer rigid bronchoscopy under general anesthesia, using intravenous propofol injection. After the induction of anesthesia, the patients are intubated with a rigid bronchoscope tube and a flexible bronchoscope is introduced through the rigid bronchoscope tube, and the narrowed central airway was evaluated. In every case, the obstructed airway is dilated gently using an 10 mm rigid bronchoscope tube initially and then progressively larger bronchoscope tubes until an adequate airway caliber was established. When indicated, a controlled radial expansion balloon is used to enlarge the airway sufficiently to allow bronchoscopic dilatation. Any intraluminal mass is removed mechanically using rigid bronchoscopic forceps or a snare. Frequently, a neodymium-yttrium aluminum garnet (Nd-YAG) or diode laser is used to ablate the residual endobronchial tumor or to cauterize the tumor bed after most of the tumor had been excised. After mechanical dilatation, the airway is maintained by inserting a silicone stent (Dumon-style stent) in patients whose airway is not maintained due to extrinsic compression or malacia. The silicone stents are inserted through the rigid bronchoscope using a standard Dumon technique. Outcome: In experienced center, the overall success rate is more than 90% after the emergency bronchoscopic intervention. A successful outcome is accompanied by subjective improvement in the symptoms and radiographic findings. After stabilizing the airway with the bronchoscopic treatment, favorable outcome is expected if additional definitive therapy can be applied, such as surgery, radiation, or chemotherapy. Nowadays, bronchoscopic intervention can achieve prolonged survival with sustained significant improvement of quality of life. Complications: Tracheal perforation, massive bleeding, respiratory failure and cardiac arrhythmia can develop after bronchoscopic intervention. However, the overall complication rate is not over 5% in experienced center. Conclusion: Bronchoscopic intervention in patients with malignant airway obstruction is helpful for the palliation the airway, allowing the multimodality therapeutic approach and prolonging the life of the patients. References 1. Jeon K, Kim H, Yu CM, et al. Rigid bronchoscopic intervention in patients with respiratory failure caused by malignant central airway obstruction. J Thorac Oncol 2006;1:319-323. 2. Cavaliere S, Venuta F, Foccoli P, et al. Endoscopic treatment of malignant airway obstructions in 2,008 patients. Chest 1996;110:1536-1542. 3. Han CC, Prasetyo D, Wright GM. Endobronchial palliation using Nd:YAG laser is associated with improved survival when combined with multimodal adjuvant treatments. J Thorac Oncol 2007;2:59-64. 4. Chhajed PN, Eberhardt R, Dienemann H, et al. Therapeutic bronchoscopy interventions before surgical resection of lung cancer. Ann Thorac Surg 2006;81:1839-1843. 5. Stratakos G, Gerovasili V, Dimitropoulos C, et al. J Cancer. 2016;25: 794-802.

Abstract:
World-wide, aside from men in France, Spain and the Netherlands, peripherally located adenocarcinomas have now overtaken squamous cell carcinoma as the predominant lung cancer cell type. With the implementation of lung cancer screening programs using low dose CT and increasing use of CT imaging for clinical investigations, a large number of people are found to have lung nodules. In contrast to symptomatic lung cancer, the size of screening CT detected or incidental lung nodules suspicious of malignancy is much smaller. Over 75% of screening CT detected lung cancers are ≤20 mm with 20% to 47% of the lung cancers found in the first screening CT and 33% to 62% of lung cancers found in annual repeat screening CT are ≤10 mm.[1-4] Because of the small size of these lesions, currently only 20% to 34% of screening CT detected lung cancers are diagnosed by endoscopy. The diagnostic yield of bronchoscopic biopsies is modest.[1,2] In the real world setting, even with advanced bronchoscopic methods such as navigation bronchoscopy and radial ultrasound, the diagnostic yield of peripheral lung lesions is less than 60%.[5,6] Several factors account for the suboptimal diagnostic yield. The diameter of the airways leading to the lesion may be smaller than the 1.4 mm diameter radial EBUS probe. The lesion may be eccentric rather than perpendicular to the biopsy forceps. Removable of the imaging probe from a guide sheath and re-insertion of biopsy forceps or needle may cause displacement or migration of the guide sheath to a different airway. To improve the diagnostic accuracy, other methods are being developed for endoscopic detection and biopsy of peripheral lung lesions ≤20 mm. Bronchoscopic transparenchymal approach to access peripheral lung nodules from more central airways and real time flouroscopic transbronchial guidance systems are under evaluation.[7,8] Flexible 21G peripheral needles are becoming commercially available for transbronchial aspiration or core biopsy. Small optical imaging probes < 0.5 mm that can be inserted within a 21G needle to confirm abnormal pathology in real time using optical frequency domain imaging[9,10] or diffuse reflectance spectroscopy before taking a biopsy. These newer endoscopic approaches hold promise to improve diagnostic accuracy while maintaining the advantage of lower complication rates such as pneumothorax and bleeding compares to CT guided transthoracic lung biopsy. References 1. National Lung Screening Research Team, Church TR, Black WC, et al. Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med. 2013 May 23;368(21):1980-91. 2. Aberle DR, DeMello S, Berg CD, et al. Results of the two incidence screenings in the National Lung Screening Trial. N Engl J Med 2013; 369(10):920-31. 3. McWilliams A, Tammemagi MC, Mayo et al. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med 2013;369:910-9. 4. Horeweg N, van Rosmalen J, Heuvelmans MA, et al. Lung cancer probability in patients with CT-detected pulmonary nodules: a prespecified analysis of data from the NELSON trial of low-dose CT screening. Lancet Oncol. 2014 Nov;15(12):1332-41. 5. Ost DE, Ernst A, Lei X, et al. AQuIRE Bronchoscopy Registry. Diagnostic yield and complications of bronchoscopy for peripheral lung lesions. Results of the AQuIRE Registry. Am J Respir Crit Care Med. 2016 Jan 1;193(1):68-77. 6. Ali MS, Trick W, Mba BI, et al. Radial endobronchial ultrasound for the diagnosis of peripheral pulmonary lesions: A systematic review and meta-analysis. Respirology. 2017; 22(3):443-453. 7. Herth FJ, Li S, Jiayuan Sun J, Nader D. Bronchoscopic TransParenchymal Nodule Access: Evaluation of safety and feasibility of Archimedes System. Am J Respir Crit Care Med 2017;195:A7597. 8. Stoy SP, Whitten PE, Al-Zubaidi A, Hogarth K. Bronchoscopic peripheral lung nodule navigation by a novel Live fluoroscopic overlay guidance technology. Am J Respir Crit Care Med 2017;195:A2865. 9. Tan KM, Shishkov M, Chee A, et al. Flexible transbronchial optical frequency domain imaging smart needle for biopsy guidance. Biomed Opt Express 2012; 3::1947-1954. 10. Pahlevaninezhad H, Lee AM, A. R, et al. Endoscopic Doppler optical coherence tomography and autofluorescence imaging of peripheral pulmonary nodules and vasculature. Biomedical Optics Express. 2015; 6(10):4191-9.

Background:
The new 2015 WHO classification broadly divided pulmonary neuroendocrine tumor (NET) of the lung in low-grade typical carcinoid (TC) and atypical carcinoid (AC), to the high-grade large-cell neuroendocrine carcinoma (LCNEC) and the small-cell carcinoma (SCLC). The molecular alterations underlying the pathogenesis of these tumors have been studied showing two blocks of entities with independent cellular mechanisms. Many of the differences between the two NETs blocks can be ascribed to tobacco consumption, which induces epithelial to mesenchymal transition activation, responsible for invasive and metastatic behavior. These correlations further highlight the difference in OS for patients with low and high grade metastatic NETs. Therefore, epithelial to mesenchymal transition (EMT) genes profile emerge promise as indicator of invasion and metastasis in NETs.

Method:
Fresh frozen tissue from SCLC (n = 10), LCNEC (n = 4), AC (n = 5), TC (n = 5) and matched normal tissue samples were collected for qRT-PCR analysis carried out on StepOnePlus™ Real-Time PCR System (Applied Biosystems) with RT[2] Profiler PCR Array System for the EMT pathway with 84 target genes (Qiagen, Dusseldorf, Germany). Linear regression was done to evaluate association between gene expressions. Clinical variable such as age, gender, tobacco history, lymph node metastasis and histologic types were associated with gene expression. Differences were regarded as statistically significant at P < 0.05.

Result:
High expression of membrane receptor EGFR (p = 0.003), protein of the matrix metalloproteinase MMP3 (p = 0.044), transcriptional factor TCF3 (p = 0.022) and signaling pathway factor WNT5A (p = 0.013) were observed in patients with tobacco history. Metastatic LCNEC and SCLC presented significant lower expression of JAG1 gene and higher level of EGFR (p<0.01), transmembrane protein DSP (p = 0.03), TCF3 (p = 0.01), TGF-B3 (p = 0.04) and WNT5A (p = 0.01) compared to TC and AC. In addition to these genes, AKT1 and MAP1B were equally high expressed in metastatic NE carcinomas. Importantly, increased expression of these genes added of MMP2 gene was significantly associated with poor OS of the patients.

Conclusion:
A panel of 84 EMT genes was tested and the best biomarkers included EGFR, MMP2, MMP3, TCF3, WNT5A, JAG1, TGFB3, AKT1 and MAP1B with impact on unfavorable prognostic and overall survival of patients, highlight that EMT play a fundamental role in pathogenetic pathway of metastasis in NETs. Supported by CNPq project 301411/2016-6; FAPESP 2013/10113-7.

Background:
Small-cell lung cancer (SCLC) has been occasionally detected in never-smokers as smoking rates decrease worldwide. We investigated the clinical and genetic characteristics of SCLC in never-smokers (Geno1.3-CLICaP)

Method:
A cohort of patients diagnosed with SCLC were grouped into smokers (n=10) and ever/never-smokers (n=10). For both groups, somatic mutation profiling was carried out using a comprehensive NGS assay (TruSight Tumor 170) targeting the full coding regions of 170 cancer-related genes. Epidermal growth factor receptor (EGFR) mutation was confirmed by RT-PCR (Cobas[TM]). The clinical outcomes of the two groups were compared using Kaplan-Meier and Cox proportional models.

Result:
Median age was 58 years (r, 46-81), 55% (n = 11) were men, most patients had extended disease (85%) and the dominant tumor involvement site was pleura and lungs (65%). No significant differences were found in age, disease distribution, baseline performance status and cerebral metastases in relation to tobacco exposure. The ORR to first-line therapy were 50% and 90% between smokers and ever/never-smokers, respectively (p=0.032). The median overall survival (OS) was 29.1 months in ever/never-smokers (95%CI 23.5-34.6) versus 17.3 months in smokers (95%CI 4.8-29.7; p=0.0054). Never-smoking history (HR 0.543, 95%CI 0.41-0.80), limited stage disease (HR 0.56, 95%CI 0.40-0.91) and response to first line platinum based chemotherapy (HR 0.63, 95%CI 0.60-0.92) were independently related with good prognosis. Among ever/never smokers main genetic mutations were TP53 (80%), RB1 (40%), CYLD (30%), EGFR (30%), MET (20%), SMAD4 (20%) and BRIP1 (20%). None of the smokers had mutations in EGFR, MET or SMAD4, but there was a greater involvement in RB1 (80%, p=0.04), CDKN2A (30%, p=0.05), CEBPA (30%, p=0.05), FANCG (20%), GATA2 (20%), and PTEN (20%).

Conclusion:
Never-smokers with SCLC are increasingly prevalent and have a better prognosis than their smoker counterpart. EGFR, MET and SMAD4 are frequent mutations among SCLCs of ever/never smokers, and RB1, CDKN2A and CEBPA among smokers. Figure 1

Background:
Although small cell lung cancer (SCLC) is sensitive to initial therapy, almost all patients relapse and survival remains poor. Outgrowth of treatment-resistant subclones could be responsible for recurrence. However, genomic evolution of SCLC after treatment hasn’t been well investigated, partially due to the challenge of obtaining longitudinal samples. CT is the standard modality for response assessment and disease monitoring. But it doesn’t always accurately assess the disease status. SCLC is characterized by early hemagenous spread, which makes circulating tumor DNA (ctDNA) analysis a promising modality for genomic profiling and disease monitoring of SCLC.

Method:
Targeted-capture deep sequencing (mean target coverage 538x-1866x) of 545 cancer genes was performed to 44 ctDNA samples collected before therapy as baseline and at different timepoints during treatment from 23 SCLC patients. Pretreatment tumor biopsies from 8 patients were also sequenced (mean target coverage 348x-1281x) of the same gene panel. DNA from peripheral blood mononuclear cells was served as the germline control.

Result:
Mutations were identified in all 44 ctDNA samples with a median of 16 mutations per sample (average mutation burden of 6.6/Mb). TP53 and RB1 were the most frequently mutated genes, detected in 91% (21/23) and 65% (15/23) patients, respectively. 74 mutations were identified from the 8 tumor biopsies, among which, 69 (93.2%) were detected in matched ctDNA. We inferred subclonal architecture of each ctDNA sample based on cancer cell fraction derived using PyClone. A median of 10 (ranging 2-26) subclones was inferred from each ctDNA sample and only 17% (2% to 60.%) of mutations were clonal mutations suggesting substantial genomic heterogeneity. Single gene mutations were not associated with survival. However, mean variant allele frequency of clonal mutations (clonal-VAF) at baseline was associated with progression-free survival (PFS) and overall survival (OS) independent of stage, age, or platinum sensitivity. The median PFS of patients with higher versus lower than median clonal-VAF was 5.2 months (95% CI, 4.6 to 5.8 months) versus 10.0 months (95% CI, 9.3 to 10.7 months), p=0.002. The median OS was 8.1 months (95% CI, 5.5 to 10.7 months) versus 24.9 months (95% CI, 0.0 to 51.2 months) in patients with higher versus lower than median clonal-VAF, respectively, p=0.004. Analysis of serial ctDNA before and during treatment showed that clonal-VAF closely tracked closely with treatment responses.

Conclusion:
ctDNA sequencing is a promising modality for genomic profiling and disease monitoring for SCLC patients. Clonal VAF may be a better ctDNA metric than single gene mutations.

Abstract not provided

Background:
Lurbinectedin (PM01183) is a new anticancer drug that binds to DNA, inhibits transactivated transcription and modulates tumor microenvironment. Preclinical evidence of synergism was observed for PM01183 in combination with doxorubicin (DOX).

Method:
Multicenter, phase I clinical trial to determine the recommended dose (RD) of the combination of PM01183 and DOX. An expansion cohort was recruited after finding striking activity in second-line small cell lung cancer (SCLC) patients. Due to hematological toxicity, the trial was amended to use a lower DOX dose and thus improve safety of the combination in selected indications. SCLC patients <75 years with ECOG performance status (PS) 0-1 and pretreated with no more than one chemotherapy line were included. Stable brain metastases were allowed. DOX was interrupted after 10 cycles and PM01183 could be continued as single-agent. Primary G-CSF prophylaxis was not mandatory.

Result:
48 patients were treated: 21 in Cohort A (PM01183 3-5 mg flat dose [FD] Day (D)1 + DOX 50 mg/m2 D1 every 21 days [q21d]), and 27 in Cohort B (PM01183 2 mg/m2 D1 + DOX 40 mg/m2 D1 q21d). Males: 74%; median age: 64 (48-77) years, ECOG 0-1: 37%-63%; known central nervous system (CNS) involvement: 10%; bulky disease (>50 mm): 67%. 85% responded to first line, including 4% with complete response (CR). Median chemotherapy free interval (CTFI): 3.4 months. Refractory (CTFI<30 days) 23%; resistant (CTFI 30-90 days) 34%; sensitive (CTFI>90 days) 43%. RD: PM01183 4 mg FD (or 2 mg/m2) + DOX 50 mg/m2 D1 q21d. Confirmed ORR: 50% (95CI: 35-65%) with 6% CR in both cohorts; ORR=69% (95CI: 49-85%) with 10% CR in sensitive patients. Cohort A: ORR=67% (95%CI: 43-85%) with 10% CR; ORR=92% (95%CI: 62-100%) in sensitive patients. Cohort B: ORR=37% (95%CI: 19-58%) with 4% CR; ORR=53% (95%CI: 28-77%) in sensitive patients. Median PFS (mPFS) 4.6 months (95%CI: 3.1-5.8), with mPFS 1.5 months (95%CI: 1.2-3.8) in resistant patients and 5.8 months (95%CI: 3.6-7.9) in sensitive patients. In both cohorts, grade 4 neutropenia/anemia/thrombocytopenia appeared in 73%/4%/15% of patients and febrile neutropenia in 21% (11% at RD). Non-hematological toxicity was mainly fatigue (G3=14%) and nausea (G3=5%).

Conclusion:
PM01183/DOX combination showed remarkable activity as second line in SCLC, especially in patients with CTFI>90 days, regardless of dose. Activity is higher than reported for CAV or topotecan in this setting. Reversible myelosuppression was the most frequent and expected side effect. A phase III trial with this combination in relapsed SCLC is ongoing.

Background:
Small cell lung cancer (SCLC) has poor prognosis and systemic chemotherapy is the standard treatment. Irinotecan is a topoisomerase-I inhibitor that has been used in treating SCLC. Etirinotecan pegol (NKTR-102) is a polyethylene glycol conjugate of irinotecan uniquely designed for prolonged tumor cell exposure by using the polymer conjugate technology. This is a single arm phase II study to evaluate single agent etirinotecan pegol in patients with relapsed SCLC (NCT01876446). In WCLC 2016 we reported its promising activity with an acceptable toxicity profile in treatment of chemotherapy-sensitive SCLC. Here we report the results in chemotherapy-resistant SCLC.

Method:
A total of 38 patients who have received only one prior systemic therapy for SCLC were enrolled. There were 2 patient cohorts: those progressing on first-line chemotherapy <3 months after completion of treatment (Group A: chemotherapy-resistant, N=20) and those progressing on first-line chemotherapy ≥3 months after completion of treatment (Group B: chemotherapy-sensitive, N=18). Etirinotecan pegol was administered at 145 mg/m[2] IV once every 3 weeks. Cycles were repeated every 21 days until disease progression, unacceptable toxicity, or withdrawal from study. The primary endpoint was the 18-week progression free survival (PFS) rate. The secondary endpoints were objective response rate (ORR), duration of response (DOR), overall survival (OS) and toxicity. A single-stage design was used to assess the primary endpoint separately for each patient group.

Result:
Group A has completed targeted enrollment of 20 patients and the results are presented here. Median age was 60.4 (46.1-74.8) years, with 50% male and ECOG PS 0 (9/20) or 1 (11/20). Prior chemotherapy included cisplatin/etoposide (25%) or carboplatin/etoposide (70%). Patients received a median of 2 (1-10) cycles of etirinotecan pegol, with dose reduction in 15%. PFS rate at week 18 was 35% (7/20, 95% Confidence Interval (CI): 16-55%). ORR was 20% (4/20), all of which were partial response. Another 30% (6/20) of patients had stable disease. Median DOR was 4.8 (1.6-10.5) months. Median PFS was 9.4 (95% CI: 5.8, 21.6) weeks, and OS was 8.1 (95% CI: 2.9, 11.9) months. The most common treatment-related adverse events (AEs) of any grade were diarrhea (50%), fatigue (35%), weight loss (35%), nausea (30%), and vomiting (30%). The most common AEs ≥grade 3 were diarrhea, leukopenia and neutropenia (2 cases each, all grade 3).

Conclusion:
Etirinotecan pegol has demonstrated promising activity with an acceptable toxicity profile and a convenient schedule in treatment of patients with chemotherapy-resistant relapsed SCLC and therefore warrants further investigation.

Background:
SCLC is featured by both a rapid response and progression during/after standard upfront therapy. Thus, maintenance strategies emerged as potential treatment opportunities, although to date all drugs failed to significantly improve prognosis. SCLC cells harbor a neuroendocrine phenotype, frequently expressing somatostatine (SST) receptors. This study aimed to investigate the efficacy of somatostatine (SST) analogue Lanreotide (LAN) as a maintenance strategy for SCLC patients (pts) after response to standard upfront treatment.

Method:
A multicentre, randomized, open-label, no-profit national trial was conducted, randomizing (1:1) SCLC (limited/extended disease, L/ED) pts expressing SST receptors (by SST receptor scintigraphy) with objective response (CR or PR) after upfront platinum-based chemotherapy plus/minus radiotherapy to receive maintenance LAN 120 mg subcutaneously every 28 days, up to progressive disease (PD) for 1 year (Arm A), versus observation (Arm B). Primary end-point was 1-year Progression-Free Survival (PFS). Primary intention-to-treat (ITT) analysis was planned (power: 80%; 2-tailed alpha-error: 5%) after 47 PFS events.

Result:
Seventy-one pts (median age 66 [37-82]; male/female 72/28%; L/ED 39/61%; ECOG-PS 0-1/2 97/3%; previous best response CR/PR 6/94%) were randomized in 9 Italian centers. Median time from diagnosis and end-of-1[st] line to inclusion was 5.7 months (3-160) and 30 days (0-119), respectively. Median number of LAN doses and treatment duration (Arm A) was 4 (1-12) and 83 days (1-392), respectively. With a median follow-up of 9.4 months and 62 events, median PFS was 3.6 (95% CI 3.2-3.9) versus 2.3 months (95% CI 1.7-2.9), for Arm A and B (log-rank p=0.11; HR 1.51, 95% CI 0.90-2.50), with a 1-year PFS of 10.3% versus 7.3%, respectively. At the cox-proportional multivariate modelling, stage (ED versus LD, HR 2.88 [95% CI 1.64-5.04, p<0.0001) and treatment arm (B versus A, HR 1.63 [95% CI 0.97-2.72], p=0.06) were independent predictors for PFS. Median PFS of arm A and B was 7.0 [95% CI <1-13.5] and 3.8 months [95% CI <1-8.6] in LD pts (p=0.21), and 3.0 (95% CI 2.2-3.8) and 2.2 (95% 1.7-2.7) in ED pts (p=0.19). Median OS was 9.5 (95% CI 4.8-14.3) and 4.7 months (95% CI 1.7-16.6), for Arm A and B (log-rank p=0.47), respectively. LAN was well-tolerated: serious treatment-related adverse events were grade 3 abdominal pain and electrolyte disorder in overall 2 pts.

Conclusion:
Although the primary end-point was not met, the overall efficacy of LAN as a maintenance strategy after response to standard upfront treatment for SCLC deserves future investigations, particularly in pts with LD.

Abstract not provided

Background:
Small cell lung cancer (SCLC) comprises ~10-15% of lung cancers. The majority of patients with SCLC present with extensive disease (ED) and have extremely poor outcomes; <5% survive 2 years. Although first-line (1L) treatment is typically platinum-based, many patients are platinum-resistant with few effective options after relapse. The study objective was to compare treatment patterns across regions and by platinum resistance/sensitivity.

Method:
This study used data from the Oncology Monitor (Ipsos Healthcare), a global clinical database of oncology patients collected through retrospective medical chart reviews. Treating physicians were invited to submit information on their patients with SCLC treated from January 2014 through December 2016 in the United States (US), the European Union 5 (EU5; France, Germany, Italy, Spain, and the United Kingdom), or Japan.

Result:
A total of 5849 patients with SCLC were included (2605 in the US, 2203 in the EU5, and 1041 in Japan). Mean age was 65.6 years (standard deviation: 8.8); 66.3% were male and 94.0% diagnosed with ED. In all, 73.4% of patients were receiving 1L, 19.8% second-line (2L), and 6.8% third-or-later-line therapy. Platinum/etoposide was the most frequently prescribed 1L therapy, although it was significantly more common in the US (87.0%) than the EU5 (82.1%) or Japan (73.3%) (P<0.05). Cisplatin/etoposide was prescribed more often in 1L in the EU5 (40.8%) than in the US (26.6%) or Japan (23.7%) (P<0.0001). Platinum/irinotecan was an uncommon 1L treatment in the US (2.0%) and EU5 (0.5%) but common in Japan (22.7%; P<0.0001). Platinum-resistance (relapse within ≤3 months of 1L treatment completion) was observed in >40% of patients (US: 45.4%, EU5: 40.9%, Japan: 56.1%). Regardless of platinum-resistance versus sensitivity, the most common 2L treatment in the US and EU5 was topotecan (42.3% vs 47.6%) and (59.5% vs 56.1%), and amrubicin in Japan (52.1% vs 53.1%). Among platinum-resistant patients in the US, EU5, and Japan, 27.3%, 10.8%, and 36.4% received a platinum-based 2L therapy. Additionally, 52.3%, 66.7%, and 44.9% of platinum-sensitive patients did not receive 2L platinum re-challenge.

Conclusion:
Current NCCN and ESMO guidelines (endorsed by JSMO) recommend platinum-resistant patients receive non–platinum-based 2L therapies. The guidelines also recommend that platinum-sensitive patients (relapse >6 months) receive the original 1L regimen as a 2L re-challenge. However, this real-world study found that a significant proportion of platinum-resistant patients were re-challenged with a 2L platinum-based therapy. Conversely, in patients where platinum re-challenge is recommended, a large proportion did not receive platinum-based therapies in 2L.

Background:
The prognosis for patients with extensive stage small-cell lung cancer (ES-SCLC) is dismal. Immune suppression and systemic inflammation have been linked with outcomes for patients with a variety of malignancies, including lung cancer. The purpose of this study was to investigate the impact of baseline immune suppression and systemic inflammation as assessed with hematologic markers such as total lymphocyte count (TLC) and neutrophil-to-lymphocyte ratio (NLR) on overall survival (OS) in patients with ES-SCLC.

Method:
We retrospectively investigated 253 consecutive patients with pathologically and radiographically proven ES-SCLC treated at a single tertiary cancer center from 1998 through 2015. Potential correlations between initial complete blood counts & differential and other clinicopathologic characteristics were sought. Hematologic markers such as pretreatment TLC, NLR, platelet count, and platelet-to-lymphocyte ratio and other clinical characteristics including age, sex, performance status, race, TNM stage (M1a vs. M1b), weight loss, smoking status, number of initial chemotherapy cycles (<4 vs. ≥4 cycles), thoracic radiation therapy (TRT) dose (<45 Gy vs. ≥45 Gy), and receipt of prophylactic cranial irradiation (PCI) were evaluated for correlation with OS. Median values for each hematologic marker were used as cutoffs. Factors identified as important by univariate analysis were selected as covariates to construct a multivariate Cox model for OS.

Result:
Pretreatment TLC was below the lower limit of normal (i.e., <1.0×10[3]/µL) in 58 patients (23%). Median OS was 11.0 months for the entire cohort. Median OS time was significantly worse in patients with lower pretreatment TLC (TLC ≤1.5×10[3]/µL: 9.8 months, 95% confidence interval [CI] 8.9‒10.7 vs. TLC >1.5×10[3]/µL: 11.6 months, 95% CI 9.3‒13.9) and higher pretreatment NLR (NLR >4.0: 9.3 months, 95% CI 8.8‒9.8 vs. NLR ≤4.0: 13.9 months, 95% CI 11.2‒16.6). Multivariate analysis identified lower pretreatment TLC (hazard ratio [HR] 0.735, 95% CI 0.561‒0.962, P=0.025) and elevated pretreatment NLR (HR 1.534, 95% CI 1.182‒1.991, P=0.001) as being independent predictors of inferior survival. Six other clinicopathologic factors (age >63 years, being male, performance status score ≥2, having <4 initial chemotherapy cycles, TRT <45 Gy, and no PCI) were also shown to be independent predictors of worse OS in multivariate analysis (P<0.05).

Conclusion:
Pretreatment TLC and NLR are useful prognostic markers for OS in patients with ES-SCLC. These findings have important implications for stratifying patients with ES-SCLC for various treatment approaches, possibly including immune modulation.

Background:
The optimal thoracic radiation dose/fraction for limited-stage small cell lung cancer (SCLC) is still in debate. This study mainly aims to retrospectively compare the impact on local/regional progression-free survival (LRPFS) of different thoracic radiation dose/fraction schedules from two prospective trials.

Method:
Patients in the hyperfractionated arm received thoracic radiotherapy consisted of 1.5 Gy twice a day in 30 fractions to 45 Gy. Patients in the hypofractionated arm received 2.5 Gy daily in 22 fractions to 55 Gy. Kaplan-Meier method was used to estimate survival data. Multivariate prognosis analysis was made by Cox proportional hazard regression analysis.

Result:
Nighty-two and 96 patients were accrued into to the hyperfractionated and hypofractionated arm respectively. The 1-year, 2-year LRPFS rates of the two arms were 82.1%, 60.7% and 84.9%, 68.8% respectively (P=0.27). The median OS time (months) of the two arms were 28.3 and 22.0 respectively, while 1-year, 3-year, 5-year OS rates were 85.2%, 40.8%, 27.1% and 76.9%, 34.3%, 26.8% respectively (P=0.37). On multivariate Cox regression study, the time (days) from the initiation of chemotherapy to thoracic radiotherapy (TCT) ≤ 43 (HR: 0.397, 95%CI: 0.207-0.762, P=0.005) was independently associate with improved LRPFS. The time (days) from the start of chemotherapy to end of thoracic radiotherapy (SER) ≤ 63 (HR: 0.508, 95%CI: 0.322-0.762, P=0.044) and PCI (HR: 0.433, 95%CI: 0.298-0.630, P=0.000) were favorably related to OS. Grade 2 and 3 acute radiation esophagitis were observed in 28.3%, 8.7% and 15.5%, 2.1% of patients in hyper- and hypofractionated arm respectively (P=0.009). Figure 1



Conclusion:
Both hyperfractionated and hypofractionated radiotherapy had achieved good LRPFS and OS in this study, although there was no statistical significance between the two arms. Keep TCT ≤ 43, SER ≤ 63 resulted in better LRPFS and OS. However, the incidence of acute radiation induced esophagitis was significantly more common in the hyperfractionated arm than in hypofractionated arm.

Abstract not provided

Abstract:
Superior sulcus tumors (SSTs), involving structures at the thoracic inlet, have posed a challenging problem for surgeons, radiation oncologists and medical oncologists alike, ever since they were first described[1)]. Pre-operative radiotherapy had long been the community standard in the management of SSTs. However, both the complete resection rate (approximately 50%) and long-term survival (approximately 30%) rate had remained poor and unchanged over 40 years, since the first treatment strategy was reported in the 1960’s. Local control had remained the main problem, adversely affecting the quality of life as well as the survival of the patients[2)]. Encouraged by the promising data of concurrent chemoradiotherapy for mediastinal node-positive N2 NSCLC, two prospective studies applied this modality as preoperative therapy for patients with SSTs; one from the US (led by the Southwest Oncology Group SWOG9416-Intergroup Trial 0160[3)]), and the other from Japan (by the Japan Clinical Oncology Group, JCOG 9806[4)]). In both trials, patients with SSTs received two cycles of cisplain-based chemotherapy (etoposide-cisplatin in US, mitomycin-vindesine-cisplatin in Japan), concurrently given with thoracic radiotherapy 45Gy/27fr. Then they underwent surgical resection. Boost radiotherapy was given to unresected/imcompletely resected tumors. In spite of minor differences, the results of the two trials were strikingly similar (Table). The intensive trimodality approach was found to be feasible in both reports, with a reasonably low toxic death rate of 4%. The resection rate, which had remained unchanged at about 50% for almost 40 years with conventional preoperative radiotherapy, was approximately 70% in both studies. Particularly noteworthy was the reproducibility of the favorable survival data, with a 5-year OS of 44% in the US trial and 56% in the Japanese trial, which were clearly superior to the historical value of 30%. Although T factor (T3 vs. T4) was not a significant prognostic factor in the US trial, T3 patients did far better than T4 in the Japanese study (Figure), reflecting lower resection rate (78% vs. 40%).Figure 1 A shift in the trend of clinical problems also became clear. The relapse patterns changed from predominantly locoregional to mainly distant recurrences in cases with complete resection, and a significant number of such patients suffered from metastasis in the brain as the initial site of relapse. In the JCOG study, 7-year follow-up data[5)] revealed that 21 (41%) of the 51 patients who underwent R0 resection relapsed; initial site of relapse included locoregional only in 1, distant metastasis only in 14 (5 were “brain only”), and both in 6. In contrast, out of the 24 patients who failed to get R0 resection, 18 got tumor recurrence, with 13 locoregional relapses. In order to improve the outcome, SWOG subsequently launched another trial, S0220, with docetaxel consolidation after the induction therapy[6)]. However, the overall survival was no better than the initial two reports, with the 3-year OS of 61%. The relapse pattern remained predominantly distant. Preoperative chemoradiotherapy was compared to conventional pre-operative radiotherapy in the Massachusetts General Hospital. In their retrospective analysis, Wright et al[7)] did show that pre-op chemoradiotherapy was better that pre-op radiotherapy, with 4-year OS of 84% vs. 49%. In their single-institute trial (#92-038) at the MD Anderson Cancer Center, Gomez et al reported[8)] the results of initial surgery followed by chemoradiotherapy in “resectable” SST. The result was comparable with those of the multi-institutional studies (Table), which included many “marginally resectable” tumors. Given the potential selection biases, the evidence would favor pre-operative chemoradiotherapy strategy.

Trial	JCOG9806	SWOG9416	MDA92-028
Patient accrual	76/ 3.6 years	116/ 4.3 years	32/ 13 years
No. institutions	19	NR (5 groups)	1
Chemotherapy	Pre-op	Pre- & post-op	Post-op
Chemotherapy	MVP	EP	EP
Radiotherapy	Pre-op	Pre-op	Post-op
Radiotherapy	45Gy/25fr	45Gy/25fr	60Gy/50fr
%T4 disease	26%	29%	22% (pathological)
Radiological ORR	61%	42%	N/A
Resection rate	75%	80%	100%
Complete resection rate	68%	76%	72%
Pathological CR rate	16%	29%	N/A
Toxic death rate	4%	4.5%	0
OS at 3-years	62%	NR	NR
OS at 5-years	56%	44%	50%
OS at 7-years	52%	41%	50%

In summary, preoperative chemoradiotherapy is the current standard of care for patients with SSTs. Several critical questions remain unsolved, however, including effective suppression of micrometastases in cases with R0 resection, prevention of brain metastases, and management of N2 SSTs, which were excluded from the hitherto reported trials. References 1) N Engl J Med 337: 1370-1376, 1997 2) J Thorac Cardiovasc Surg 119: 1147-1153, 2000 3) J Clin Oncol 25: 313-318, 2007 4) J Clin Oncol 26: 644-649, 2007 5) Proc Am Soc Clin Oncol 28 suppl: 2010, (abstr 7025) 6) Ann Thorac Surg. 98: 402–410, 2014 7) Ann Thorac Surg 73:1541-4, 2002 8) Cancer 118: 444-51, 2012

Abstract:
Pancoast tumors or superior pulmonary sulcus tumors (SSTs) are a rare subgroup of non-small cell lung carcinomas and occur in about 3-5% in patients with lung cancer. It is one of the most challenging thoracic malignancy to treat because of their proximity to vital structure in the thoracic inlet. In the last two decades improvements in appropriate preoperative staging, in multimodality treatment and development of new operative techniques have resulted in more curative treatment and better long-term results. However, in the preoperative assessment the role of positron emission tomography (PET) and magnetic resonance imaging (MRI) has not been studied specifically in SSTs, also imaging methods to access pathological response after induction treatment is not clearly defined. Furthermore, management of STSs with invasion of spine or subclavian vessels remains controversial. Invasion of these structures was traditionally considered as a contraindication to surgery because of technical difficulties and poor long-term results. Also, patients with SST and N2 or N3 disease had an extremely poor prognosis due to loco regional recurrences, so that due to previous recommendations, this group of patients should not be treated surgically except in a protocol setting. The surgical approach (anterior/posterior/combined) varies dependent on tumor spread and although lobectomy is recommended as the standard type of pulmonary resection, many authors reported no significant different survival rates after sublobar operations. Finally, brain metastases remain the most common form of distant relapse, the use of prophylactic cranial irradiation is not generally accepted. Clinical diagnosis and appropriate staging has to be conducted. SSTs are well accessible by transthoracic fine-needle aspiration. MRI is the modality of choice for imaging structures of the thoracic inlet, including the brachial plexus, subclavian vessels, spine and neural foramina. It shows local extent of the disease and is important for preoperative planning. EBUS-TBNA and PET is recommended for evaluation of mediastinal disease and distant metastasis before starting the induction treatment, mediastinoscopy is indicated to access pathological nodal response before surgery. A prospective phase II trial (SWOG INT 0160) showed that induction treatment with preoperative two cycles chemotherapy and concurrent radiotherapy with 45 Gy followed by surgery resulted in better tumor response and local control, higher rates of R0 resections and improved long-term overall survival, by low perioperative morbidity and mortality. Today, induction chemo radiotherapy followed by surgery has been established as standard treatment regimen for SSTs. Although vertebral body invasion and subclavian artery involvement are declared as negative prognostic factors, improvement in surgical techniques and cooperation of different surgical specialists, resulted in promising results for these difficult group of patients. Several authors described surgical techniques for tumor resection involving the transverse process only, or the intervertebral foramina, requiring hemivertebrectomies with spinal fixation, or the vertebral body, requiring total vertebral body resection with spinal fixation. In highly selected patients these extensive resections could be performed with acceptable morbidity and mortality in specialized centers with interdisciplinary teams of thoracic and spine surgeons. The en bloc resection technique provided acceptable recurrent rate (local 15%, distant 45%) and good long-term survival (25%-30% at 5-years). The introduction of the anterior approach made the resection of SSTs with subclavian artery involvement easier. After resection, the subclavian artery was reconstructed either with a ring supported polytetrafluoroethylene (PTFE) graft or direct by end-to-end anastomosis. Some authors reported about resection along the subadventitial plane to obtain tumor free margins or the use of autologous grafting. Five-year survival rates range between 25% and 32%. Extrapolating from the favorable results in other lung cancers, investigators have also considered induction chemoradiation for SSTs with mediastinal lymph node involvement (N2 disease), a group of patients previously considered hopeless. It is noteworthy that in two studies, no difference in median and overall survival was found between positive or negative pretreatment mediastinal N2 disease. Although these data should be interpreted with caution because they are liable to selection, they show that surgery is feasible with an acceptable outcome. Another important issue is that some authors found that ipsilateral supraclavicular lymph node is a local lymph node, so that patients with SSTs and N3 status (ipsilateral supraclavicular node involvement) showed a better prognosis than patients with N2 status (ipsilateral mediastinal node involvement). This have been confirmed in two larges and a few small series and underlines that ipsilateral supraclavicular N3 involvement could represent only local extension and may have a prognostic importance near to that of N1 disease. The influence of the type of lung resection, lobectomy versus sublobar resection, on the survival rates remains controversial. Lobectomy was associated with better survival compared with patients with wedge resections, but these data came predominantly from the pre-induction era with trimodality treatment. One important question is the necessity of lobectomy in patients with SSTs and pathological complete response (pCR). Some authors reported no significant different survival rates after sublobar operations in pCR patients and a higher incidence of wedge resection was found using the anterior approach only. Infiltration of the thoracic inlet increases the technical complexity of surgery, requiring extended resections and demanding reconstructive procedures. Completeness of resection represents one of the main factors influencing the long- term outcome of patients, pointed out in all publications about SSTs. Brain metastases remain one of the most common forms of relapse, prophylactic cranial irradiation (PCI) may be useful addition to preoperative chemoradiotherapy. Improvements in the combined preoperative treatment and surgical approach have significantly influenced local control and survival rates of SSTs. Further refinement of these techniques, also the addition of other chemotherapy agents or biologic agents as angiogenetic inhibitors or tyrosine kinase inhibitors could give some new perspectives in the treatment of SSTs. Further studies are needed to examine the effect of PCI on the survival after relapses in the brain. I declare no conflicts of interest.

Abstract:
Complete en bloc resection is the corner stone of the treatment of solid tumors. Those located in the superior sulcus (SS) or thoracic inlet are known to have bad reputation because their resection represents a real technical challenge. The complexity of such surgery is due to the congestion of a very tight space (SS) by major neurovascular structures as well as to the proximity of the esophagus, the trachea and the spine. The preoperative work-up, in order to assess the involvement of such structures by SS tumors, may include, further to the routine bronchoscopy and cervico thoracic CT scan, an MRI to rule out spinal extension, venous angiography, subclavian arteriography or esophagoscopy. Many surgical approaches to remove SS tumors and many anatomical classifications have been reported during the last 6 decades. The goal of the surgical approach is to allow a wide and safe exposure of the SS, complete en-bloc resection of the tumor and all the involved structures and a potential arterial or spinal resection and reconstruction. The main goal of an anatomical classification is to facilitate the choice of the most appropriate surgical approach according to the extension of the tumor. After an anatomical description of the SS, we will review all the surgical approaches described in the literature to remove benign or malignant tumors developed in the SS. The emergence of new surgical techniques during the last 2 decades, such video-assisted and robotics surgeries had modify the surgical approaches in thoracic surgery. We will describe all the surgical approaches currently available to resect SS tumors with their advantages and their limits. Based on our experience we will describe a simplified anatomical classification of SS tumors. After identification of all contra-indications to SS tumor resection, we will describe the surgical approaches we use currently allowing when needed arterial and spinal resections and reconstructions.

Abstract:
In 2003, an IASLC Consensus Report recommended that ‘superior sulcus tumors (Pancoast tumors, T3 or T4) should preferentially undergo trimodality treatment, including chemoradiation and surgery’ [Eberhardt WE, Lung Cancer 2003]. This recommendation was based on the early results of the phase II Intergroup Trial 0160) trial, findings which have been subsequently updated [Rusch VW, J Clin Oncol 2007]. Results of two other prospective phase II trials, namely the JCOG 9806 and the SWOG-Intergroup Trial S0220, support the use of the trimodality approach in superior sulcus tumors [Kunitoh H, J Clin Oncol 2008; Kernstine KH, Ann Thorac Surg 2014]. Between 30-40% of patients with a locally-advanced NSCLC can develop local disease recurrence following full-dose chemoradiation [Baker S, Radiat Oncol 2016]. As the impact of a local recurrence for patients with superior sulcus tumors can be great, the role of surgery remains relevant for this site. Recent ESMO guidelines have identified this patient subgroup as having an increased risk of an incomplete resection [Eberhardt WE, Ann Oncol 2015], and consequently, the role of concurrent CT-RT as an induction scheme is considered standard at centers with the available surgical expertise. This overview will address radiation-related topics such as dose and fractionation schemes, treatment fields, newer radiation delivery techniques (MRI-guided radiotherapy, protons), salvage radiotherapy for small volume recurrences, and the treatment of second primary lung tumors.

Abstract:
Superior sulcus tumors have been long defined as a distinct clinical entity. Symptoms including Horner’s syndrome and other neurologic findings as well as severe shoulder pain and SVC syndrome characterize this disease. Early on, the use of preoperative therapy was recognized as potentially useful. Over time, initial chemoradiotherapy followed by surgery has emerged as standard of care for patients with T3 or T4 lesions and N0 or N1 disease. 3-year survival rates of approximately 60% have been reported for surgically resectable patients with advanced disease. More recently, the addition of consolidation chemotherapy following subsequent surgery was evaluated, but its exact contributions to increasing survival remain unclear. The majority of patients will progress, usually with systemic disease and a large fraction of patients develop brain metastases. Patients with unresectable disease receive concurrent chemoradiotherapy as definitive therapy. Here, commonly used regimens such as the combination of cisplatin/etoposide, carboplatin/paclitaxel, and cisplatin/pemetrexed are utilized. However, more effective therapies are needed and special emphasis on increasing the systemic antitumor activity against micrometastatic disease will be required. The use of targeted therapies such as erlotinib or crizotinib for EGFR mutated or ALK fusion-related adenocarcinomas is currently under investigation. Of high recent interest is the possible addition of immune oncology agents such as the PD-1 or PD-L1 inhibitors. A recent report on the use of the PDL1 inhibitor durvalumab after completion of concurrent chemoradiotherapy in patients with unresectable stage IIIB disease has been reported as meeting its primary endpoint. It is likely that this and other studies will be relevant for superior sulcus tumors as well. Currently ongoing trials of increasing progression-free survival and their scientific basis will be reviewed.

Abstract:
The natural history of GGO-containing tumors, i.e., subsolid nodules (SSNs), is a major concern not only in CT lung cancer screening, but in daily clinical practice. SSNs are classified into pure ground-glass nodules (GGNs) and part-solid GGNs on the basis of their consistency. SSNs are classified according to their status as transient or persistent. Articles in the literature related to the natural history or long-term follow-up results of SSNs are summarized in Table. In the largest CT lung cancer screening cohort reported to date, nonsolid nodules (synonymous with pure GGNs) and part-solid nodules were detected in 4.2% (2392 of 57,496) and 5.0% (2892 of 57,496), respectively, of the participants at baseline (Table). The numbers of SSNs reported in the articles ranged from 19 to 3433 (median, 139). The median follow-up periods ranged from 1.1 years to 12 years (median, 2.9 years). The percentages of pure GGNs that grew ranged from 3% to 58% (median, 15%). The percentages of lung cancers among the SSNs ranged from 1% to 71% (median, 7%). An inherent limitation of studies of the natural history of SSNs is that not all of the SSNs are pathologically confirmed. The changes in persistent SSNs on sequential thin-section CT images in the Research Center for Cancer Prevention and Screening (RCCPS) examinations have tentatively been classified into six types; increasing type, stable type, decreasing type, fluctuating type, sudden onset type, and overtaking type. Some of the SSNs were evaluated on the basis of semiautomatic volumetry. Although the natural history of SSNs had gradually been clarified, the complete natural history of SSNs as a whole remains unknown. In the current era of ultralow-dose chest CT at a chest x-ray equivalent dose, a lifelong follow-up study should be considered.

			SSNs¶			Grew	Lung Cancer
Author	Journal	Year	Total	Consistency,n	Follow-up Period (yr.)	n (%)	n (%)
Kodama	Ann Thorac Surg	2002	19	PGGN*, 19	Median, 2.7	11 (58)	5 (26)
Hiramatsu	J Thorac Oncol	2008	125	PGGN, 95	Median, 2.9	14 (15)	8 (6)
				PSN**, 30		12 (40)
Silva	J Thorac Oncol	2012	76	PGGN, 48	Mean, 4.2	8 (17)	4 (5)
				PSN, 28		12 (43)
Takahashi	Jpn J Radiol	2012	150	PGGN, 150	Mean, 5.5	19 (13)	8 (5)
Chang	Chest	2013	122	PGGN, 122	Mean, 4.9	12 (10)	11 (9)
Kobayashi	J Thorac Oncol	2013	108	PGGN, 82	Median, 4.2	29†(27)	25 (23)
				PSN, 26
Matsuguma	Chest	2013	174	PGGN, 98	Mean, 2.4	14 (14)	53 (30)
				PSN, 76		27 (36)
Lee	Respir Med	2013	175	PGGN, 143	Median, 3.8	28 (20)	26 (15)
				PSN, 32		18 (56)
Attina	Radiol Med	2013	146	PGGN, 140	Mean, 2.3	41 (29)	5 (3)
				PSN, 6		6 (100)
Kim	Ann Thorac Surg	2013	139	PGGN, 69	Mean, 3.7	2 (3)	7 (5)
				PSN, 70		21 (30)
Tamura	J Thorac Oncol	2014	63	PGGN, 63	Mean, 2.2	29 (46)	45 (71)
Eguchi	Lung Cancer	2014	124	PGGN, 124	Median, 4.8	64 (52)	32 (26)
Scholten	Eur Respir J	2015	117	PGGN, 69	Median, 7.9	33≠	28 (24)
				PSN, 48		46≠
Kakinuma	Radiology	2015	439	PGGN, 439	Median, 6.0	45 (10)	4 (1)
Silva	Diagn Interv Radiol	2015	95	PGGN, 95	Median,1.7ø	18 (19)	n/a
Yankelevitz	Radiology	2015	2877	Nonsolid$,2392^	Median[1]	1764[&]	84 (3)
				Nonsolid,485^^	Median[2]	163[&]
Lee	Eur Radiol	2016	213	PGGN, 136	Median, 2.3	18 (13)	49 (23)
				PSN, 77		24 (31)
Zhao	Br J Radiol	2016	70	PGGN, 62	Median, 2.1	6† (9)	5 (7)
				PSN, 8
Kakinuma	J Thorac Oncol	2016	1231	PGGN, 1046	Mean, 4.3	116 (11)	85 (7)
				HGGN***, 81		23 (28)
				PSN, 104		45 (43)
Cho	J Thorac Oncol	2016	453	PGGN, 438	Median, 6.4	11 (3)	7 (2)
				PSN, 15		4 (27)
Henschke	AJR	2016	3433	PSN, 2892^	Median[3]	2325[&]	107 (3)
				PSN, 541^^	Median[4]	164[&]
Sawada	Chest	2017	226	PGGN, 166	§, #	39†(17)	124(55)
				PSN, 60
Mets	Eur Radiol	2017	89	PGGN, 63	Median, 1.6	35†(39)	n/a
				PSN, 26

Footnotes. ¶ SSN, subsolid nodule; * PGGN, pure ground-glass nodule; ** PSN, part-solid nodule; n/a, not available. † This study did not report the numbers of pure and part-solid GGNs separately. ≠ Growth was calculated by comparing actual mass to mass when first detected and is expressed as a percentage. $ A synonym of PGG.; ^ Baseline; ^^ Annual repeat screening. ø Follow-up period of the “grew” group. [1 ]Among the 1764 cases in which the nonsolid nodules were stable or growing, the median time to pathologic diagnosis was 1.7 years; the median follow-up time in the cases without a pathologic diagnosis was 1.4 years. [2] The median time from the initial identification of the nonsolid nodules to pathologic diagnosis was 1.2 years; the median follow-up time in the cases without a pathologic diagnosis was 1.7 years. [&] This study did not report the number of SSNs that grew and number of stable SSNs separately. ***HGGN, heterogeneous GGN. [3] Among the 2325 cases in which the PSNs were stable or growing, the median time to pathologic diagnosis was 0.5 years; the median follow-up time in the cases without a pathologic diagnosis was 1.1 years. [4] The median time from the initial identification of the PSN to pathologic diagnosis was 0.8 years; the median follow-up time of 0.7 years for cases without pathologic diagnosis. § Fifty-seven patients had stopped receiving follow-up examinations after a median of 5.6 years because of the presence of stable disease in 42 and reduced disease in 15. # Forty-five patients were continuing to undergo follow-up examinations, and their median follow-up period was 12 years; 40 were stable and 5 showed growth.

Abstract:
The radiological term GGO or ground-glass opacity was established when high-resolution CT (HRCT) became part of standard practice, and describes “a hazy attenuation of lung, with preservation of bronchial and vascular margins: caused by partial filling of air spaces, interstitial thickening, partial collapse of alveoli, normal expiration, or increased capillary blood volume…” (1). As such GGO is a nonspecific finding but depending on the clinical circumstances it may suggest a specific diagnosis and have consequences for the diagnostic and therapeutic approach. Most primary lung tumours present with masslike areas of consolidation, however there are other patterns. A specific subtype of adenocarcinoma may present as GGO, and this was described as bronchioloalveolar carcinoma (BAC) (2). It reflects the unique lepidic growth pattern along the alveolar septa with a relative lack of acinar filling. The classification BAC was used for a broad spectrum of tumours including small non-invasive peripheral lung tumours, invasive adenocarcinoma with minimal invasion, mixed subtype invasive adenocarcinoma, mucinous and nonmucinous subtypes, and widespread disease. As in this larger group GGO is present in only a minority, it is difficult to conclude from the chemotherapy trials done specifically in BAC (3) what the efficacy of chemotherapy in tumours with as feature GGO is, nor has the pathological feature of lepidic growth been reported in these studies. Overall the response rate in BAC of single agents seems not to be different from other types of NSCLC. At a later stage, it seemed that gefitinib was especially effective in the non-mucinous subtype (4), in retrospect this might be explained by the molecular characteristics of both. EGFR mutation was more related to lepidic growth, whereas KRAS was especially found in mucinous types (5). It became clear that the term BAC leads to confusion and is representing a very heterogeneous group of tumours. It was therefore recommended to discontinue the use of the term BAC (6), and use a more descriptive classification based on histological findings. Within this new grouping the radiological description of ground-glass opacity was related to the pathological pattern of adenocarcinoma: pure GGO would favour adenocarcinoma in situ (AIS) or possibly minimally invasive adenocarcinoma (MIA), and GGO with a solid component > 5 mm in diameter would favour lepidic adenocarcinoma (7). The natural course of pure GGO or GGO with a small solid component is rather benign. In a large Japanese cohort followed for 4.3 + 2.5 years (mean) the frequency of change from pure GGO towards a - still small - solid component was found in 6.6% (69 out of 1046), of the cases initially diagnosed with a very small solid component change into part-solid nodules was seen in almost 20% (16 of 81) (8). All these observations come from resected tumours and cannot be diagnosed in small biopsies, this makes it difficult to characterize more advanced adenocarcinoma in the same way. The likely most GGO containing advanced tumours will be those diagnosed with (dominant) lepidic growth (9). Reports of chemotherapy efficacy are infrequent but do not show a real difference in sensitivity if treated with one of the commonly used regimens carboplatin – paclitaxel (10). Although the LACE-Bio study contains only small numbers of cases with lepidic growth, combining these patients with the ones with the prognostically less unfavourable histology (papillary, acinar) failed to demonstrate benefit of adjuvant chemotherapy (11). The frequency of finding more than one GGO (with or without a solid component) is rather high and reported as almost 30% (12). If this is in a patient with stage IV NSCLC it is questionable whether these are separate primaries or metastases. The behaviour of these lesions has not been systematically reported, personal observations confirm the rather indolent role of these lesions, usually without any pathological proof of malignancy, and no change during systemic therapy for an other stage IV tumour. The question whether the presence of GGO as such, either as part of the stage IV tumour or as a different lesion, should affect the choice of systemic therapy can not be answered. References: 1. Austin JHM, Müller NL, Friedman PJ et al. Glossary of terms for CT of the lungs: recommendations of the Nomenclature Committee of the Fleischner Society. Radiology 1996; 200: 327-331. 2. Jang HJ, Lee KS, Kwon OJ et al. Bronchioloalveolar carcinoma: focal area of ground-glass attenuationat thin-section CT as an early sign. Radiology 1996; 199: 485-488. 3. Miller VA, Hirsch FR, Johnson DH. Systemic Therapy of Advanced Bronchioloalveolar Cell Carcinoma: Challenges and Opportunities. J Clin Oncol 2005; 23:3288-3293 4. Cadranel J, Quoix E, Baudrin L et al. IFCT-0401 Trial. A Phase II Study of Gefitinib Administered as First-Line Treatment in Advanced Adenocarcinoma with Bronchioloalveolar Carcinoma Subtype. J Thorac Oncol. 2009;4: 1126–1135. 5. Yoshizawa A, Sumiyoshi S, Sonobe M et al. Validation of the IASLC/ATS/ERS lung adenocarcinoma classification for prognosis and association with EGFR and KRAS gene mutations: analysis of 440 Japanese patients. J Thorac Oncol. 2013; 8: 52-61 6. Travis WD, Brambilla E, Noguchi M et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011; 6: 244-85 7. Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization Classification of Lung Tumours: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thor Oncol 2015; 10: 1243-1260. 8. Kakinuma R, Noguchi M, Ashizawa K et al. Natural History of Pulmonary Subsolid Nodules: A Prospective Multicenter Study. J Thorac Oncol 2016; 11: 1012-1028. 9. Travis WD, Asamura H, Bankier AA et al. The IASLC lung cancer staging project: proposals for coding T categories 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 Thor Oncol 2016; 11: 1204-1223. 10.Cadranel J, Gervais R, Merle P et al. Erlotinib versus carboplatin and paclitaxel in advanced lepidic adenocarcinoma: IFCT-0504. Eur Respir J 2015; 46: 1259–1261. 11. Tsao MS, Marguet S, Le Teuff G et al. Subtype classification of lung adenocarcinoma predicts benefit from adjuvant chemotherapy in patients undergoing complete resection. J Clin Oncol 2015; 33: 3439-3446. 12. Kim HK, Choi YS, Kim J et al. Management of Multiple Pure Ground-Glass Opacity Lesions in Patients with Bronchioloalveolar Carcinoma. J Thorac Oncol. 2010;5: 206–210.

Abstract:
A ground glass opacity (GGO) is a radiographic finding defined as hazy, increased attenuation of the lung with preservation of bronchial vascular margin. A subsolid nodule (SSN) includes pure ground glass nodules and partsolid nodules in which both solid and ground glass components are present. These nodules are nowadays more commonly found with the introduction of CT screening programs. The optimal management of patients with SSN is of growing clinical concern. The newly (1) introduced adenocarcinoma classification makes a clear distinction between pre-invasive lesions (atypical adenomatous hyperplasia), adenocarcinoma in situ (AIS: ≤ 3cm pure lepidic growth without invasion), minimally invasive adenocarcinoma (MIA: ≤ 3cm lepidic growth with ≤ 5mm invasion) and invasive adenocarcinoma (IA) of different subtypes. Preinvasive lesions or MIA have an excellent survival and might be treated with sublobar resection. IA (especially certain subtypes) are more aggressive and should be treated with lobar resection combined with systematic nodal dissection. Pure GGO lesions can be non-specific inflammation, fibrosis or neoplasm. Recent guidelines (2) recommends for pure GGO nodules ≥6mm follow-up scan at 6 to 12 months and then every 2 years until 5 years. In a retrospective study (3) 83 patients with pure GGO lesion that had surgery and proved to be adenocarcinoma were described. 79,5 % were non IA and 20,5 % (IA). In a multivariate logistic regression analysis both preop GGO size on CT and pleural retraction were predictive factors for IA. Pure GGO lesions ≥ 10 mm should be resected if they persist or grow on follow-up CT. Partsolid nodules. When a nodule is partially solid or when in a GGO lesion a solid part appears, the risk of IA increases. In a prospective multicentric study Suzuki et al looked at radiologic criteria for predicting pathologic early (non-invasive) adenocarcinoma (4). In this study, the consolidation/tumor (C/T)ratio was measured in lung and mediastinal window settings. Radiologic non-invasive longadenocarcinoma could be defined as a subsolid nodule ≤2cm with a (C/T) ratio of 0.25 or less. Asamura et al (5) re-evaluated the radiology pathology correlation in this study in term of the prognosis. The radiologic criteria of a C/T ratio of 0.25 or less in tumor ≤3cm as well as 0.25 or less in tumors ≤2cm could be used to define a homogeneous group of patients with an excellent prognosis after surgery. These criteria can be used to select patients with early lung adenocarcinoma in which a sublobar resection (wedge or segmentectomy) would be safely indicated. For lesions with a tumor diameter of 2.0cm and a C/T ration >0.25 a prospective randomized fase III study comparing lobectomy and segmentectomy is ongoing (6). The incidence of N2 disease in clinical T1-T2N0 was evaluated (7). The incidence of unforeseen N2 disease was 1.5% in pure GGO lesions. N2 disease was found in 4.3% of semi solid tumors and 12.6% in pure solid tumors. In a multivariate analysis, tumors with any GGO components were less likely to have N2 disease (Odds ratio 0.14, 0.001). A recent study (8) used a nomogram for predicting the risk of IA in patients with solitary peripheral subsolid nodules. In a multivariate analysis the occurrence of IA was significantly correlated with lesion size, spiculation, vascular convergence and pleural tag. There are different subtypes of IA. The micropapillary and solid types are aggressive subtypes with a high rate of N2 (9). These types cannot be used for sublobar resection. Huang et al (10) analyzed histology obtained by CT guided needle biopsy or EBUS. Concordant subtyping of adenocarcinoma between the predominant pattern on resections and biopsy section was only observed in 58.6% of the cases. For high grade adenocarcinoma detection, preoperative biopsy had a low sensitivity (16.5%). So preoperative obtained histology cannot show us which type of resection we should perform. The degree of invasion is often overestimated in frozen section. However, frozen section has a high specificity for micropapillary and subsolid pattern (11). If this subtype is found during surgery by frozen section, lobectomy and lymph node dissection should be performed. Conclusion By modern imaging subsolid nodules containing GGO lesions are more often seen. When the C/T ratio is more than 50% there is a high risk of IA with certain subtypes which are very aggressive. These lesions should be managed by lobectomy and lymph node dissection until results from prospective studies are known. For lesions ≤2cm, with C/T ratio ≤25% wedge or segmentectomy can be the appropriate intervention. When a limited resection is performed, the margins and the lymph nodes should be examined by frozen section. 1.Travis WD, Brambilla E, Noguchi M et al. International Association for the Study of Lung cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma. J Thorac Oncol 2011;6:244-285 2.MacMahon H, Naidich D, Goo JM et al. Guidelines for management of incidental pulmonary nodules detected on CT images : from the Fleischner Society 2017. Radiology 2017;284:228-243 3.Moon Y, Sung SW, Lee KW et al. Pure ground-glass opacity on chest computed tomography: predictive factors for invasive adenocarcinoma. J Thorac Dis 2016;8:1561-1570 4.Suzuki K, Koike T, Asakawa T et al. A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan clinical oncology group 0201). J Thorac Oncol 2011;6:751-756 5.Asamura H, Hishida T, Suzuki K et al. Radiographically determined noninvasive adenocarcinoma of the lung : survival outcomes of Japan Vlinical Oncology Group 0201. J. Thorac Cardiovasc Surg 2013;146:24-30 6.Nakamura K, Saji H, Okada M et al. A phase III randomized trial of lobectomy versus limited resection for small-sized peripheral non-small cell lung cancer (JCOG0802/WJOG4607L). Jpn J Clin Oncol 2010;40:271-274 7.Gao SJ, Kim AW, Puchalsky JT et al. Indications for invasive mediastinal staging in patients with early non-small cell lung cancer staged with PET-CT. Lung Cancer 2017;109:36-41 8.Jin C, Cao J, Cai Y et al. A nomogram for predicting the risk of invasive pulmonary adenocarcinoma for patients with solitary peripheral subsolid lesions. J Thorac Cardiovasc Surg 2017;153:462-9 9.Hung JJ, Yeh YC, Wu YC et al. Factors predicting occult lymph node metastasis in completely resected lung adenocarcinoma of 3 cm or smaller. Europ J Cardio-Thorac Surg 2016;50:329-336 10.Huang KY, Ko PZ, Yao CW et al. Inaccuracy of lung adenocarcinoma subtyping using preoperative biopsy specimens. J Thorac Cardiovasc Surg 2017;154:332-9 11.Yeh YC, Nitadori JI, Kadota K et al. Using frozen section to identify histologic patterns in stage I lung adenocarcinoma ≤3 cm: accuracy and interobserver agreement. Histopathology 2015;66:922-938

Abstract:
With the advent of Chest CT screening, the identification of abnormalities has increased substantially. In addition to very small nodules of indeterminate significance, “ground glass opacities” (GGO) are often seen. Numerous series have been collected around the world attempting to define characteristics that predict the malignant potential of these GGOs. It is clear that a substantial fraction includes a component of invasive adenocarcinoma and warrant resection for cure prior to developing disseminated cancer. This presentation will review the literature for developing a rational algorithm for selection of those patients requiring which operation, as well as review outcomes. 1. Radiological determinants of malignancy using high-resolution CT and CT/PET 2. Criteria for patient section for resection or observation 3. Techniques for pre-resection localization for intraoperative identification of lesion 4. Appropriate selection lesions for extent of resection (lobe, segment or non-anatomic wedge) 5. Approach for resection 6. Outcomes after treatment Selected References Matsunaga T, Suziki K, Takamochi K, Oh S. What is the radiological definition of part-solid tumor in lung cancer? Eur J Cardiothorac Surg 2017; 51:242-247 Eguchi T, Kondo R, Kakkami S, Matsushita M, Yoshizawa A, Hara D, Matsuoka S, Tkeda T, et al. CT attenuation predicts the growth of pure GGO nodules Lung Can 2014;84:242-247 Suzuki K, Asamura H, Kusumoto M, Kondo H, Tsuchiya R. Early peripheral lung cancer: prognostic significance of GGO on thin section CT scan Ann Thorac Surg 2002;74:1635-9 Lee S, Leem C, Kim T, Lee K, Chung J, Jheon WS, Lee C. The long term follow-up of GGO detected on thin-section CT Respir Med 2013;107:904-10 Suzuki K, Shimohira M, Hashizume T, Ozawa Y, Sobue R, Mimura M, Mori Y, Ijima H, Watanabe K, Yano M, Yoshioka H, Shibamoto Y. Usefulness of CT-guided hookwire marking before VATS for small pulmonary lesions J Med Imag Rad Oncol 2014; 58:657-662. Mong-Wei L, Yao-Hui T, Yee-Fan L, Min-Shu H, Wei-Chun K, Jo-Yu C, Hsao-Hsun H, Yeun-Chung C, Jin-Shing C. Comuted tomography-guided patent blue vital dye localization of pulmonary nodules in uniportal thoracoscopy J Cardiovasc Surg 2016; 152:535-44 Fukui M, Suziki K, Matsunaga T, Oh S, Takamochi K. Surgical intervention for GGO-dominant lesions: observation or outright resection? Pan J Clin Oncol 2017;18:1-6 Cao C, Gupta S, Chandrakumar D, Tian D, Black D, Yan T. Meta-analysis of intentional sublobar resections versus lobectomy for very early stage non-small cell lung cancer Ann Cardiothorac Surg 2014; 3:134-141 Kodama K, Higashiyayma M, Tkami K, Oda K, Okami J, Maeda J, Koyama M, Nakayama T. Treatment strategy for patients with small peripheral lung lesions: Prospective study Eur J Cardiothoracic Surg2008; 34:1068-74 Yoshioka M, Ichiguchi O. Selection of sublobar resection for c-stage1A non-small cell lung cancer based on a combination of structural imaging by CT and functional imaging by FDG-PET Ann Thorac Cardiovasc Surg 2009; 15:82-8. Kohno T, Fujimoro S, Kishi K, Fujii T. Safe and effective minimally invasive approaches for small GGOs Ann Thorac Surg 2010; 89; 1114-7 Tsutani Y, Miyata Y, Nakayama H, Okurmura S, Adachi S, Yoshimura M, Okada M. Appropriate sublobar resection choice for GGO-dominant clinical stage 1A lung Adenocarcinoma Chest 2014; 145:66-71 Sook Y, Sung S, Mankoong M, Park K. The effectiveness of mediastinal node evaluation in a patient with GGO tumor J Thorac Dis 2016; 8:2617-2623 Wei S, Khao K, Guo C, Mei J, Pu Q, Ma L, Che G, Chen G, Wu Z, Wang Y, Kuo Y, Lin Y, Li W Lui L. Diagnosis and surgical treatment of lung GGO: a review of 663 cases. Sichan Da Xue Bao Yi Xue Ban 2017:48:359-362 Moon Y, Lee K, Moon S, Park J. Sublobar resection margin does not affect recurrence of clinical N0 non-small cell lung cancer presenting as GGO. World J Surg 2017;41:472-9 Hattori A, Matsunaga T, Takamochi K, Oh S, Suzuki K. Surgical Management of Multifocal Ground-Glass Opacities of the Lung: Correlation of Clinicopathologic and Radiologic Findings Thorac Cardiovasc Surg 2017; 65:142-14 Shimada Y, Saji H, Otani K, Maehara S, Maeda J, Yoshida K, Kato Y, Hagiwara M, Kakihana M, Kajiwara N, Ohira T, Akata S, Ikeda N. Survival of a surgical series of lung cancer patients with synchronous multiple ground-glass opacities, and the management of their residual lesions Lung Cancer 88 (2015) 174-180

Abstract:
Purpose/Objective(s): The popularization of computed tomography (CT) in clinical practice have increased a frequency of discovering ground-glass opacity (GGO)-containing tumor in lung. Surgery has been regarded as the general treatment including a purpose of histological examination for such tumors and its prognosis is better than that of solid-type tumors. Stereotactic body radiation therapy (SBRT) is a rapidly prevailing treatment modality in the radical treatment of mainly inoperable or high risk operable cases with stage I non-small cell lung cancer (NSCLC), but the most tumors treated with SBRT were solid type because SBRT has been performed principally for the pathology-proven tumors and it is generally difficult to acquire histological specimen in the tumors composed of GGO. Therefore a prognosis of the stage I NSCLC cases treated with SBRT when their tumors contained GGO has not been clear. The purpose of this presentation is to review the treatment outcomes for SBRT for the patients with GGO-containing tumor in our multi-institutional SBRT study group of Japanese Radiological Society (JRS-SBRTSG), and to discuss how we consider the validity of SBRT for them. Materials/Methods: GGO was defined as hazy opacity that does not obscure underlying bronchial structures or pulmonary vessels at high-resolution computed tomography. We have reviewed 174 patients (89 men, 85 women; mean age, 74 years) treated with SBRT whose lung tumor showed appearance of GGO accompanying solid component ratio to the whole tumor (S/T ratio) less than 50 % in diameter of the tumor and no metastases. SBRT was done because of the pathological proof, positive accumulation on PET study or growth of the tumor. In histology, 69 tumors were adenocarcinoma, 8 were squamous cell carcinoma, 5 were unclassified carcinoma and 92 cases were histology-unproven. The median tumor size was 23 mm (range, 9-53 mm). SBRT was performed using non-coplanar multiple static ports or dynamic arcs. A total dose of 40 -70 Gy (6-15 Gy / fraction) was prescribed in 4-10 fractions. Median biological effective dose (BED) was 108 Gy (range, 72-150 Gy) based on alpha/beta = 10 Gy. Survival, recurrence, and metastases rates were calculated using Kaplan-Meier method. Results: Median follow-up was 32 months. The 3-year local recurrence, regional lymph-node metastases, and distant metastases rates were 3.8%, 4.1%, and 8.6%, respectively. Mean S/T ratios of the subgroup with any recurrences and the subgroup with no recurrence were 22% and 4%, respectively. The rates of cause-specific and overall survival (OS) at 3 years were 98.1% and 85.6%, respectively. The 3-year OS rates of medically operable and inoperable subgroups were 96.2% and 85.6%, respectively. The 3-year OS rate of medically operable and histology-proven subgroup was 88.1%. The 3-year OS of female subgroup was 95.0% and it was significantly better overall survival rate than male. The treatment-related pneumonitis of grade 3 or more was observed in 3.4% of the total patients. Summary and Discussion: Natural course of GGO-containing tumor is much better than that of solid-type tumors. Sublober limited resection would be acceptable in the subgroup of stage I NSCLC if the tumor appears GGO for the most part because they have mostly no invasion nor metastases. SBRT is a so localized treatment only for the tumor that a study comparing SBRT versus limited surgery without regional lymph node resection might have a rationale of randomization for such candidates, however, we have to demonstrate the prognosis and risk factors regarding recurrence, survival, and late toxicity after SBRT with longer follow-up (more than 10 years). In conclusion, the outcomes of SBRT for patients with GGO-containing tumor (solid component was less than 50 % in total diameter) were excellent but some cases had local recurrence or metastases. GGO-containing in most of the tumor seldom produced local progression, lymph node metastases, or distant metastases after SBRT. Although more cases and longer follow up are mandatory, SBRT may be one of the radical treatment options for stage I NSCLC patients with GGO-containing tumor. We hope to have a further discussion regarding the validity of SBRT for them.

Abstract:
Studies conducted over many years have documented the highly symptomatic nature of lung cancer. Presenting symptoms are largely due to the cancer; however, the common co-morbidities frequently seen in patients with lung cancer, complicate diagnosis, treatment, and all areas of care. Even in early stage disease, high rates of COPD and cardiovascular disease influence treatment. In advanced disease at presentation, typically over 90% of patients will have at least two major symptoms and 80% will report three or more. In addition to symptoms, side effects of treatment must be considered. Further affecting care is the fact common patient issues can be both symptoms of the lung cancer and side effects of treatment. This includes anorexia and fatigue which are reported by the majority of patients prior to treatment and are complications of radiation therapy and chemotherapy. In a recent trial, these two symptoms were more predictive of survival than respiratory symptoms or pain. New therapeutic modalities, such as checkpoint inhibitors and TKIs have offered new opportunities and challenges. When effective, both of these modalities can positively influence patient reported outcomes (PROs) fairly rapidly and make management of symptoms easier for patients. On the other hand, they can be associated with complications that previously were uncommon such as cutaneous toxicities, diarrhea, and endocrine abnormalities. While pulmonary toxicities have long been an occasional problem with radiotherapy and some chemotherapeutic agents, this complication can be especially severe with the newer modalities. Many recent trials in advanced lung cancer have focused on combinations of systemic therapy. This includes combinations of immuno-oncology agents, or combinations of immune-oncology agents with chemotherapy. Not surprisingly, these approaches are associated with increased side effects. Careful analysis will be required to examine the true survival and quality of life benefits of such combinations when the agents are given together or sequentially. Patient reported outcomes have many roles. Following patients for benefit in quality of life and symptom control is of great value. These aspects are crucial in new agent evaluation as well, and need to be better performed in future studies. There are, however, additional roles for PROs. Several new studies indicate that aspects of PROs provide a better assessment of a patient’s ‘tumor burden’ that is only partially estimated by performance status. Newer, simple PRO tumor burden assessments at baseline are highly predictive of survival (more so than performance status), and can indicate risk groups of patients likely to require hospitalization. Use of these PRO tumor burden assessments may allow better identification for additional health care resources for patients with the greatest needs, may guide better stratification for clinical trials, and may identify futility in treatment at an earlier point than imaging and standard assessments. Enhanced evaluation of patients’ symptoms and risks, may guide in appropriate treatment selection. In turn this may allow prevention of side effects with better individualized treatment choices. Precision medicine is meant to go beyond molecular assessment or the results of laboratory analysis. Challenges include identifying tumor burden assessments that are practical for clinical use and incorporating these approaches in daily care.

Abstract:
Advanced lung cancer is characterized by a number of debilitating symptoms from the disease itself and also potentially its treatment. Toxicities from systemic therapies undoubtedly contribute significantly to patient experiences. For patients with oncogene-addicted lung cancer, long-term treatment is now considered routine given the excellent outcomes with EGFR, ALK, and ROS1-directed therapies. Nevertheless, toxicities from therapies can be debilitating often requiring dose reduction. Whilst toxicities for EGFR-directed therapy are common, variation between agents used contributes to differences in tolerability and rates of grade 3-4 adverse events, ranging from 29-42%. Moreover, whilst variation in rates of serious class-specific adverse events eg diarrhoea are again observed, most data is limited to patients suitable for randomization against chemotherapy and performance status (PS) 0/1, whilst the majority of patients with lung cancer have comorbidities and poorer PS. Thus, the TIMELY trial of afatinib in EGFR mutant non-small cell lung cancer (NSCLC) patients with comorbidities that precluded use of chemotherapy identified a grade 3 or more toxicity rate of 59%, considerably more frequent than in other studies of afatinib. Moreover, the management of tyrosine kinase inhibitor (TKI)-associated toxicities has been poorly investigated with limited data suggesting that prophylaxis improves cutaneous toxicities, and that further investigating additional causes of diarrhea can be beneficial. The implementation of immune-checkpoint inhibitors into routine clinical practice has markedly changed survival for those that respond. Nevertheless, such therapies can be associated with marked toxicities, with grade 3-5 toxicities seen in around 20% of patients, and immune-related toxicities seen in 11-16%, from pooled data, with a slight excess in pneumonitic events with PD1 inhibitors. These drugs result in a different spectrum of patient symptoms reported principally from immune-related adverse events (irAEs). Nevertheless, the reporting of irAEs in the literature is generally suboptimal for onset, management, and reversibility. The recognition of irAEs is key to optimal management and maintaining quality of life, with consensus around management of irAEs with international guidelines. Such symptom experiences and their temporal change can be measured through use of health-related quality of life measures or patient-reported outcome measures (PROMs). These include the EORTC-QLQ-C30 questionnaire, dividing symptoms into 4 domains, and is supplemented by the lung cancer-specific module QLQ-LC13 evaluating 133 items. These two latter instruments are the commonest used in lung cancer populations. The FACT-L questionnaire is another popular module, specific to lung cancer by modifying the original FACT-G module. Finally, the Lung Cancer Symptom Scale (LCCS) is a highly popular brief inventory analyzing the functional and physical aspects of lung cancer symptoms on routine quality of life. The implementation of PROMs into routine clinical care has been shown to impact on improving communication, patient satisfaction, and potentially outcome. Whilst tools for evaluating PROMS are previously validated, no tool has yet been prospectively validated for immune-checkpoint inhibitor therapy, with efforts currently ongoing. Nevertheless, current trial data using established PROMs measures suggests improvements in many quality of life domains for patients receiving immune-checkpoint inhibitor therapy compared to chemotherapy.

Abstract not provided

Background:
Our previous study has shown the feasibility and clinical application of circulating tumor DNA(ctDNA) detection in stage I-IIIA surgical non-small cell lung cancer (NSCLC) patients(NCT02645318). The aim of this prospective study is to investigate the perioerative changes of ct DNA in surgical NSCLC patients.

Method:
From 11/2016, suspected lung cancer patients who proposed radical tumor resection were enrolled prospectively. Six precise time points plasma samples were obtained before surgery(time A) and after tumor resection (time B to F, 5min-3days) before discharge. A series driver mutations were quantitatively evaluated by multiplex assay based on circulating single-molecule amplification and resequencing technology (cSMART). Positive plasma mutations were validated in tumor tissue by targeted sequencing. Normal tissue and white blood cell DNA were used as controls. Study protocol (NCT02965391) was approved by Medical Ethics Committee (2016PHB156-01).

Result:
The consort diagram was shown in Fig 1. Thirteen R0 resected patients met the inclusion criteria. Fifteen genetic alterations were identified including four EGFR, seven TP53, two PIK3CA, one KRAS mutation and one ALK rearrangement. Ten (76.9%) cases had a gradually decrease of mutation ratio as time went on, and the average mutation ratio was 3.32%, 2.68%, 1.38%, 0.07%, 0.04% and 0 at the time-points A to F, respectively. Eight patients’ and three patients’ mutation ratio in time point D and time point E were not decease to zero, respectively. Advanced stage patients were more likely to have a positive ctDNA in time D and E, although there was no significant difference. All the mutations’ ratio dropped to zero in time F. No patients’ had positive ctDNA one month after surgery.Figure 1



Conclusion:
This is the first prospective study to evaluate the dynamic changes of ctDNA in surgical lung cancer patients. ctDNA has a rapid clearance in R0 resected lung cancer patients, but is not completely regression until 72h after surgery.

Background:
cfDNA is a promising biomarker for early recurrence detection and disease monitoring in the NSCLC curative setting. However, less is known about cfDNA shedding characteristics and correlation with tumor burden in advanced NSCLC.

Method:
We reviewed cfDNA results of NSCLC patients tested at our institution between November 2015 and December 2016 with Guardant 360, a comprehensive cfDNA assay that detects genomic alterations in 70-73 cancer genes. 141 cases with evaluable imaging were selected for this analysis, enriching for EGFR and KRAS mutated cases to facilitate comparisons of major genomic subtypes (Table 1). Tumor burden was approximated using the sum of longest diameters (SLD), per RECIST v1.1.

Result:
There was a statistically significant correlation of moderate strength between cfDNA maximum variant allele frequency (VAF) detected and SLD (Spearman’s rho = 0.35, p < 0.001). This correlation was strongest in KRAS mutant cases (rho = 0.52, p = 0.001) and weakest in EGFR mutated tumors (rho = 0.21, p < 0.24). Multi-variate regression that included stage, histology, and mutation status confirmed the predictive value of cfDNA VAF for SLD (p = 0.03). TP53 mutants had higher cfDNA VAF (Wilcox p < 0.001), even after accounting for SLD. Increased cfDNA VAF was also seen with EGFR mutants and patients with visceral metastasis, though possibly confounded by concomitant EGFR amplification and increased tumor burden, respectively. CNS metastasis was not associated with differential cfDNA shedding. Figure 1



Conclusion:
In this primarily metastatic cohort, cfDNA VAF correlated with radiographic assessment of tumor burden by RECIST. This correlation was partially mediated by the presence of key driver mutations. TP53 and EGFR mutant tumors and the presence of visceral metastasis are associated with higher cfDNA VAF. These findings have potential implications for the use of cfDNA in advanced-stage NSCLC disease monitoring, where RECIST is more clinically applicable than formal volumetrics.

Background:
Identifying biomarkers to select patients who respond to immune checkpoint blockade in non-small cell lung cancer (NSCLC) remains a challenge. Cell-free circulating tumor DNA (ctDNA) has emerged as a non-invasive, quantitative method of monitoring genomic alterations in the peripheral blood. We evaluated the clinical utility of ctDNA mutant allele frequency (MAF) and tumor burden based on imaging as biomarkers for response to immune checkpoint blockade in NSCLC.

Method:
From a cohort of 136 patients with ctDNA samples, 20 patients were retrospectively identified with ctDNA testing before initiation of anti-PD-1/PD-L1 treatment or within 90 days of therapy initiation. ctDNA testing was performed by Guardant360 (Guardant Health, Redwood City, CA). MAF of the dominant clone was identified quantitatively for each patient. In addition, baseline tumor burden was estimated using RECIST version 1.1. MAF and tumor burden were correlated with progression free survival (PFS) and overall survival (OS). Logistic regression of response rate (RR) and clinical benefit rate (CBR) was also performed.

Result:
Higher median ctDNA MAF was correlated with significantly shorter PFS and OS (hazard ratio (HR) 3.4, p=0.03 and HR 10.4, p=0.03, respectively) (Figure 1). There was no significant association between tumor burden estimation and PFS and OS. However, tumor burden was significantly correlated with MAF (r=0.58, p=0.007). MAF and tumor burden estimation did not correlate with RR or CBR in this small sample. Figure 1



Conclusion:
ctDNA MAF appears to be a promising, non-invasive, prognostic biomarker for response to immune checkpoint blockade in NSCLC with higher MAF associated with shorter PFS and OS. ctDNA MAF may also serve as a surrogate for tumor burden. Prospective studies with serial ctDNA sampling are necessary to further validate these findings.

Background:
CheckMate 032 is a phase 1/2 clinical trial evaluating nivolumab ± ipilimumab in solid tumors, including small cell lung cancer (SCLC). Initial results have shown durable responses and encouraging survival, with benefit seen regardless of PD-L1 status. There is a need for improved biomarkers in SCLC. SCLC is nearly universally found in smokers and is characterized by high tumor mutation burden (TMB). The association of high TMB and clinical benefit from nivolumab ± ipilimumab in patients with SCLC was evaluated in an exploratory analysis of CheckMate 032.

Method:
CheckMate 032 evaluated nivolumab ± ipilimumab in non-randomized and randomized cohorts, which were pooled for this analysis. Whole exome sequencing (WES) was conducted on tumor and matched blood samples. TMB was defined as the total number of nonsynonymous somatic mutations. For the exploratory analyses, patients were equally divided into TMB tertiles (defined as low, medium, and high). Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier methods.

Result:
Among 401 patients in the intent-to-treat (ITT) population, 211 (53%) had an evaluable TMB result for these analyses (86% of the 246 patients with tissue available to attempt WES). Baseline characteristics and outcomes were similar between the ITT and TMB-evaluable populations. In TMB-evaluable patients treated with nivolumab (n=133), objective response rate (ORR), PFS, and OS were improved in the high TMB cohort vs the medium and low TMB cohorts (ORR: 21.3% vs 6.8% and 4.8%; 1-year PFS: 21.2% vs 3.1% and not calculable; 1-year OS: 35.2% vs 26.0% and 22.1%). Similar benefits were seen in TMB-evaluable patients treated with nivolumab + ipilimumab (n=78) in the high vs medium and low TMB cohorts (ORR: 46.2% vs 16.0% and 22.2%; 1-year PFS: 30.0% vs 8.0% and 6.2%; 1-year OS 62.4% vs 19.6% and 23.4%).

Conclusion:
In patients with SCLC, efficacy with nivolumab ± ipilimumab was enhanced in those with high TMB. Among patients with high TMB, ORR and 1-year OS rates were approximately double with nivolumab + ipilimumab compared with nivolumab monotherapy. TMB has a potential role as a biomarker in lung cancer. Optimization of TMB cutoff and prospective investigation are warranted.Acknowledgements: All authors contributed to and approved the abstract; writing and editorial assistance was provided by Beth Burke, PhD, CMPP, of Evidence Scientific Solutions, funded by Bristol-Myers Squibb.Trial Registration: clinicaltrials.gov, NCT01928394

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Background:
Resistance to EGFR tyrosine kinase inhibitors (TKIs) limits treatment outcomes among patients with EGFR-mutant NSCLC. Resistance mechanisms have previously been conceptualized as binary “positive/negative” variables, but emerging evidence suggests resistant cancers are heterogeneous, and subclones may be appreciated through multiple biopsies.

Method:
We retrospectively analyzed 221 EGFR mutant pts at MGH who had >1 biopsy after progression on their initial EGFR inhibitor. Data on acquired resistance (AR) mechanisms observed at each biopsy, adverse events, and treatment were collected.

Result:
Among 221 pts with a total of 355 post-AR tissue biopsies, median age was 59 (range, 28-88), 69% were female, 64% had EGFR del19, 33% L858R and 3% other activating mutations. Median number of biopsies per patient was 1 (range, 1-4). Biopsies at first resistance to EGFR TKI showed 61% T790M, 5% MET amplification (amp), 3% SCLC transformation, 2% acquired PIK3CA and 1% acquired BRAF mutations. 83 pts had two biopsies during their post-resistance course; 43/83 (52%) had heterogeneity between biopsy 1 and 2. In particular, 20% “lost” T790M, while 11% “gained” T790M. Among 17 pts who lost T790M, 3 gained a separate resistance mechanism, including MET amp and BRAF V600E. In some cases, synchronous biopsies identified spatial heterogeneity. For example, an osimertinib-resistant patient had a T790M/C797S lung nodule, while a concurrent mediastinal lymph node was wild-type at both loci (both sites retained the activating EGFR mutation). Similarly, another osimertinib-resistant patient with MET amp in a pleural effusion cell block had a lung nodule biopsy which lacked MET amp; the patient was treated with combination EGFR and MET inhibitors with a partial response. Additional details regarding concurrent liquid biopsies, treatment histories and clinical outcomes will be presented.

Conclusion:
In this large cohort of EGFR mutant NSCLC patients, we frequently observed variations in resistance mechanisms in patients with > 1 post-AR biopsy. Our data highlights the heterogeneity of resistant cancers and the limitations of a single biopsy in fully capturing the spectrum of resistance mechanisms in each patient. Serial biopsies or non-invasive methods may be required to characterize resistance and identify potential therapeutic targets.

Background:
Cancers are composed of heterogeneous cell populations in terms of somatic mutations and dysregulated signaling pathways. We hypothesized that such heterogeneity, together with selection advantages conferred by distinct microenvironments, may contribute to tumor evolution and metastatic patterns.

Method:
We collected tumor specimens and non-cancer tissues from treatment-naïve autopsied patients to study the innate genetic evolution and spatial heterogeneity by RNA-sequencing. Our cohort consists of four NSCLC patients and one SCLC patient. Each patient had 5 – 9 primary and metastatic lesions, including metastases to lung, liver, colon (distant metastases), visceral or parietal pleura (pleural metastases), and intra- or extra-thoracic lymph nodes (lymph nodes metastases). Comprehensive data analyses were performed, including gene expression / pathway analyses and fusions / somatic variants detection.

Result:
Global unsupervised clustering analysis of expression data reveals that lesions from each patient clustered together, indicating that tumor cells themselves have greater effects on the gene expression signature than the microenvironment. Pathway analyses in individual patients revealed that the primary lesion is distinct from metastatic lesions in NSCLCs (Figure-left). For the SCLC patient, distant metastases and lymph node metastases clustered according to different parts of the primary tumor (Figure-right). Pathway analyses also revealed that cell-cycle, DNA replication, RNA polymerase, and spliceosome-related pathways are upregulated, while immune-related pathways are downregulated in all metastatic patterns compared with primary lesions. In particular, we observed that multiple immune-related pathways, related to NK cells and T-cells, were downregulated in pleural metastases. Detection of fusions / somatic variants identified the KIF5B-RET fusion as a founder mutation in a never-smoking adenocarcinoma patient. Notch signaling was upregulated, in this patient, in all metastatic lesions but not the primary site.Figure 1



Conclusion:
These data demonstrate the similarity and the heterogeneity between primary and metastatic lesions in lung cancer patients. In addition, we identified the correlation between tumor heterogeneity and metastatic patterns.

Background:
Oncogenic reactivation of transcription factors involved in fetal lung development is integral to lung adenocarcinoma (LUAD) biology, as observed with TITF1/NKX2-1 and the ETS transcription factors ETV4 and ETV5. ELF3 is an uncharacterized ETS family member implicated in fetal lung development encoded at 1q32.1. Interestingly, chromosome 1q is a region of frequent gain in LUAD that lacks a bona fide oncogene. We hypothesize that ELF3 is a novel oncogene and putative therapeutic target in LUAD.

Method:
Multiple independent datasets encompassing 1,685 clinical samples of LUAD, lung squamous cell carcinoma (LUSC), small cell lung cancer, and non-malignant lung tissues were analyzed to establish the frequency of ELF3 overexpression and underlying genetic mechanisms of selection. Protein-protein interaction (PPI) networks were constructed around ELF3, and integrated pathway analysis was performed to decipher the signaling network disruptions resulting from ELF3 overexpression. Isogenic cell lines were established to assess the ability of ELF3 to regulate oncogenic phenotypes. The effect of ELF3 loss on tumour growth was assessed in xenograft mouse models.

Result:
Strong ELF3 overexpression was frequently observed in LUAD (>2-fold: TCGA 40% p=1.5E-07; BCCA 73% p=1.6E-21), but was not observed in other lung cancer subtypes. Similarly, high ELF3 expression was significantly associated with poor overall survival of LUAD patients (all Stages p<0.0001, Stage I p<0.0001), but not LUSC patients (p>0.05). These clinical associations prompted further examination of ELF3 in the LUAD subtype of lung cancer. While mutations in ELF3 were rare, up to 80% of LUAD patients harboured focal amplification, DNA gain, and/or promoter hypomethylation at the ELF3 locus, which resulted in transcript overexpression. ELF3 overexpression induces remodeling of 23 direct PPI networks, resulting in loss of interaction with proteins such as MYC and GLI2, while forming new interactions with NKX2-1, HOXA5 and CDK8, among others. This reprogramming of PPI networks affects multiple oncogenic pathways including MAPK, TGF-beta and WNT. ELF3 knockdown in LUAD cell lines resulted in significantly reduced proliferation, viability, and anchorage-independent growth, demonstrating ELF3 has oncogenic properties. Loss of ELF3 abolished the ability of LUAD cells to establish tumours in xenograft mouse models, demonstrating the requirement of ELF3 expression for tumour growth.

Conclusion:
ELF3 is a novel LUAD oncogene encoded on chromosome 1q, activated in up to 73% of patients, and strongly associated with poor overall survival. As ELF3 inhibition abolished tumour growth, therapeutic targeting of ELF3 could benefit LUAD patient outcome.

Background:
The incidence of lung cancer has significantly increased over the last century and remains the most common cause of cancer deaths worldwide. Our better understanding of the tumor microenvironment and the systemic actions of tumors, combined with the recent advent of the liquid biopsy, may allow molecular diagnostics to be done with non-invasive method for detection and monitoring of patient tumors. Sputum has been the target for the discovery of non-invasive biomarkers for lung cancer because it contains airway epithelial cells, and molecular alterations identified in sputum are most likely to reflect tumor-associated changes. Since January of 2017, sputum samples have been prospectively collected at the time of diagnosis for future evaluation of actionable mutations in EGFR, KRAS, BRAF and NRAS in patients with non-small cell lung cancer in our center. Currently, from 20 sputum samples already collected, 5 are confirmed for driver mutations (one in KRAS and 4 in EGFR) in tissue biopsy, with 2 of the samples being positive for T790M in circulating tumor DNA (ctDNA) isolated from plasma. Our aim is to evaluate whether sputum may be representative in the detection of these mutations.

Method:
DNA was extracted from sputum using QIAamp DNA midi kit (Qiagen). Tumor somatic mutations were investigated by target-sequencing using a custom Ion Ampliseq™ Panel (ThermoFisher Scientific), containing hotspot regions of 14 genes frequently mutated in solid tumors (including EGFR). Multiplex amplification was performed with 10 ng of DNA using Multiplex PCR Master Mix (Qiagen) and high-throughput sequencing was performed using Ion Proton platform. Somatic mutations were considered if the variant allele was present in more than 0.5% of the reads, considering a minimum coverage depth of 20,000X. A medium coverage of 172,524X was obtained in the five samples.

Result:
We detected mutations in 3 out of 5 sputum samples of patients with previously known driver mutations (two exon 19 deletions and one exon 18 G719A in EGFR). The highest frequency was detected in the only patient with spontaneous sputum collection (23%).The other two mutations were detected in low frequencies (0.5 and 0.6%) in samples derived from sputum induction. We found T790M in one patient positive for T790M in ctDNA isolated from plasma.

Conclusion:
These preliminary findings indicate that driver mutations can be identified in sputum routinely obtained from sputum samples. Thus, the ability to examine sputum might provide a convenient source of sampling and may be adapted for future large-scale screening.

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