Journal Thoracic Oncology

Recommendations

Info

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017 vascularization mechanism such as intussusceptive angiogenesis or vesselcooption. Reliable biomarkers for the prediction of response to antivascular drugs are also yet to be identified and clinically validated. SESSION MTE13: BASIC IMMUNOLOGY FOR THE CLINICIAN (TICKETED SESSION) TUESDAY, DECEMBER 6, 2016 - 07:30-08:30 MTE13.02 BASIC IMMUNOLOGY FOR THE CLINICIAN Edgardo Santos Florida Atlantic University, Eugene M. and Christine E. Lynn Cancer Institute, Boca Raton/FL/United States of America Lung cancer remains the number one cause of cancer-related death worldwide. Cancer immunotherapy nowadays has become not only a growing field but also a fascinating area as recent clinical trials have improved both PFS and OS in first line and second line treatment for patients with advanced NSCLC. The idea of immunotherapy in cancer is to modify the host immune system, so cytotoxic T-cells (CTCs) can recognize tumor-associated antigens (TAAs) as abnormal and be destroyed by an immune response. For many decades, we have tried unsuccessfully many vaccines against different lung cancer antigens. It was thought at one point that lung cancer was a non immunogenic tumor very different from melanoma and kidney cancers. Whole-cell vaccines (e.g. belagenpumatucel-L) and antigen-specific vaccines (e.g., CIMAvax, MAGE-A3, L-BPL25) showed just promising results in clinical trials, but failed to significantly improve clinical outcomes [1-4]. The major reason why vaccines failed in lung cancer was due to tumor escape mechanisms from host immune surveillance [5, 6]. One of this mechanisms was recently elucidated, checkpoint pathway. Lung cancer has been found to have high levels of CTLA-4 expression, programmed death-1 (PD-1), PD ligand 1 (PD-L1), B7-H3 and B7-H4 expression on tumor-infiltrating lymphocytes (TILs), and regulatory CD4+ T-cells (Tregs) suggesting that lung cancer is immunogenic. For many years, cancer immunology was centered on the adaptive immune system and T-cell activation. Stimulation of the T-cell response involves antigen presenting cells (APCs), or dendritic cells (DCs), expressing tumor antigens from the tumor microenvironment, which then bind to the T-cell receptor (TCR) on CD4+ or CD8+ T-cells. Meanwhile, B7-1/CD80, or B7-2/CD86 on the APC, bind to CD28 on the T-cell in a costimulatory fashion to stimulate tumor-antigen specific T-cells to proliferate. However, cross talk between APCs and T-cells at the immunological synapse is regulated very closely and can be attenuated. One of this attenuation signal is mediated by CTLA-4, which is also stimulated by CD80 and CD86. Although CTLA-4 and CD28 have the same ligands, CTLA-4 has a much higher affinity for them; hence, T-cell proliferation occurs despite the effects of CTLA-4 because of the intracellular location, short half-life and quick degradation of CTLA-4 [7, 8]. Another example of a tumor immune checkpoint is PD-1 which binds B7-H1/PD-L1 and B7-DC/PD-L2 [9]. By using PD-1 inhibitors, we are able to remove the interaction between PD-1 receptor located in the T-cells and its ligand expressed in the tumor cells which causes inhibitory signaling over the T-cells. Hence, an immune response cannot be mounted. CTLA-4 has been studied in lung cancer in combination with platinum-based doublet (carboplatin/paclitaxel). Outcomes from that study were not enough to grant approval from regulatory entities. However, investigators found better response to CTLA-4 inhibition in patients with squamous cell histology; this population has higher percentage of TILs than their non-squamous counterparts. Why the combined therapy (chemotherapy plus ipilimumab) had limited effect remains unclear. Conversely, studies using PD-1 inhibitors pembrolizumab and nivolumab have shown OS advantage over docetaxel in second line therapy, and more recently, OS and PFS advantage in first line against chemotherapy when tumor cells expressed > 50% of PD-L1 [10]. We also understand that PD-L1 is not the perfect predictive biomarkers so efforts are directed to discover more specific markers which can help us to tailor checkpoint inhibitors in lung cancer. The approval of nivolumab in NSCLC came from two phase III trials CheckMate 017 and CheckMate 057 which studied nivolumab vs docetaxel in second-line for squamous and non-squamous advanced NSCLC, respectively. The CheckMate 017 reached the “trifecta” proving that nivolumab was statistically superior to docetaxel for OS, PFS and response rate (RR). Interestingly, OS benefit was independent of PD-L1 expression. The CheckMate 057 showed OS and RR in favor of nivolumab. There was no difference in PFS between nivolumab and docetaxel in non-squamous NSCLC patients. In this study, PD-L1 expression levels at different cut-off matter for OS. For those patients who had ≥1%, ≥ 5%, and 10%, the hazard ratio (HR) for OS were 0.59 (p < 0.06), 0.43 (p < 0.001), and 0.40 (p < 0.001), respectively. In both studies, nivolumab was well tolerated and had better treatment-related adverse event profile. In case of pembrolizumab, it was KEYNOTE-010 study which proved OS advantage over docetaxel in second line therapy. Herein, pembrolizumab at a dose of 10 mg/kg and 2 mg/kg shown an OS of 12.7 months (HR 0.61; p < 0.001) and 10.4 months (HR 0.71; p < 0.001); OS for docetaxel was 8.5 months. Noteworthy, OS was better in patients whose tumors expressed PD-L1 ≥50%; these patients had an OS of 17.3 and 14.9 months when received pembrolizumab at 10 mg/kg and 2 mg/kg, respectively. Again, grade 3-5 treatment-related AEs were less common for both pembrolizumab doses than for docetaxel. Recently, press release on KEYNOTE-024 phase III study, reported OS in favor of pembrolizumab over platinum-based doublet in first-line therapy for advanced NSCLC patients with PD-L1 expression. The clinical results from KEYNOTE-024 may change the landscape of lung cancer treatment at first-line for advanced NSCLC. Also in development are the PD-L1 inhibitors which affect the interaction between PD-L1 and B7.1 and PD-1 receptor and PD-L2; the later interactions are not affected by PD-1 inhibitors. Atezolizumab and darvulumab have several phase III trials ongoing in first line for advanced NSCLC. Phase II trials for both compounds have shown promising results. The role of PD-L1 as predictive biomarker is still not well defined. PD-L1 expression is a dynamic process and it also varies as part of an adaptive immune resistance exerted by the tumor. There are other possible predictive biomarkers such as higher nonsynonymous mutation burden, molecular smoking signature, higher neo-antigenic burden, DNA repair pathway mutations, high levels of PD-L1 expression, T-helper type 1 gene expression, and others. There is no question that we must continue looking for a better predictive biomarker which can help us to determine the therapeutic benefit of PD-1/PD-L1 inhibitors.References. 1. Nemunaitis J, Dillman RO, Schwarzenberger PO, et al. Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer. J Clin Oncol. 24, 4721–30 (2006). 2. González G, Crombet T, Neninger E, Viada C, Lage A. Therapeutic vaccination with epidermal growth factor (EGF) in advanced lung cancer: analysis of pooled data from three clinical trials. Hum Vaccin. 3(1), 8-13 (2007). 3. Vansteenkiste J, Zielinski H, Linder A, et al. Final results of a multi-center, double-blind, randomized, placebo-controlled phase II study to assess the efficacy of MAGE-A3 immunotherapeutic as adjuvant therapy in stage IB/II non-small cell lung cancer (NSCLC). J Clin Oncol. 25(18S), 7554 (2007). 4. Palmer M, Parker J, Modi S, et al. Phase I study of the BLP25 (MUC1 peptide) liposomal vaccine for active specific immunotherapy in stage IIIB/IV non-small-cell lung cancer. Clin Lung Cancer. 3(1), 49-57 (2001). 5. Gross S, Walden P. Immunosuppressive mechanisms in human tumors: why we still cannot cure cancer. Immunology Letters. 116(1), 7–14 (2008). 6. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 3, 991–8 (2002). 7. Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat immunol 3(7):611-618, 2002. 8. Zang X, Allison JP. The B7 family and cancer therapy: costimulation and coinhibition. Clin Cancer Res 13(18):5271-5279, 2007. 9. Blank C, Mackensen A. Contribution of the PD-L1/ PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. CancerI Immunol Immunother 56(5):739-745, 2007. 10. http://www.businesswire.com/news/home/20160616005393/en/ Merck%E2%80%99s-KEYTRUDA%C2%AE%C2%A0-pembrolizumab- Demonstrates-Superior-Progression-Free-Survival. Access online September 20, 2016. Keywords: lung cancer, checkpoint pathway, Immunotherapy, PD-L1 SESSION MTE15: LYMPH NODE MAPPING IN LUNG CANCER (TICKETED SESSION) TUESDAY, DECEMBER 6, 2016 - 07:30-08:30 MTE15.02 LYMPH NODE MAPPING IN LUNG CANCER David Waller Thoracic Surgery, Glenfield Hospital, Leicester/United Kingdom The How and Why? The Aim will be to outline the various methods to map the extent of lymph node metastasis from a primary NSCLC and to assess the clinical application and implications of each intervention. The Aim will also be to highlight the following areas of clinical debate and controversial issues 1.Preoperative Non-invasive – Lymph node mapping may start with simple Ultrasound guided cervical node aspiration cytology [1] . Can this be all that is needed in some advanced cases? c Can computed tomography/ positron emission tomography (CTPET) be relied upon to obviate the need for invasive nodal mapping ? Can newer techniques including CT lymphography [2] improve the accuracy of mapping ? Does magnetic resonance imaging (MRI) have a role in preoperative lymph node mapping. Invasive – We will consider in detail the debate between endobronchial and endoluminal ultrasound (EBUS/EUS) and surgical lymph node mapping. What role, if any, does cervical mediastinoscopy have in addition to EBUS/EUS [3] ? Does the increased sensitivity of more invasive surgical mediastinal procedures like VAMLA [4] and TEMLA contribute significantly to preoperative mapping ? We will discuss why these investigations should influence primary therapy and which patients should undergo induction therapy and which should have primary resection. Evidence from the latest TNM revision suggest that mediastinal nodal disease needs more accurate mapping than previously appreciated. We will consider how many of these stages of mapping are required before making S84 Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017 a decision to operate and will propose a controversial algorithm for surgical treatment of N2 disease [5]. 2.Intraoperative We will discuss the arguments surrounding the necessary extent of intraoperative lymph node dissection. We will consider the relative merits of the methods for intraoperative sentinel node identification including Near Infrared thoracoscopy and radiolabelling [6,7]. We will ask whether the investment in technology and time is beneficial for the patient. Is the added information about metastases of clinical value ? We will evaluate the argument between nodal sampling vs systematic nodal dissection [8] and attempt to formulate an intraoperative mapping algorithm. Intraoperative nodal mapping has been proposed as a prerequisite to direct the extent of lung resection. We will examine how the findings of nodal disease have been used to discriminate between lobectomy vs pneumonectomy or between lobectomy vs segmentectomy. We will consider the argument that nodal metastatic disease is not a justification for more extensive sacrifice of functioning lung tissue. Is there any role for intraoperative nodal analysis in determining the extent of resection? How reliable is this method of nodal mapping. 3.Postoperative Once the pathologist has the resected lymph nodes we will attempt to rationalize how they should be analysed, asking the question : “ What are the minimum sampling requirements ?”. We will also analyse whether the more detailed nodal mapping of micrometastatic disease by immunohistochemistry significantly influences patient management or outcome [10] ? Finally we will discuss how these pathological results could influence the use of adjuvant chemotherapy/ radiotherapy or more interestingly targeted therapies. We intend the session to be interactive between presenters and delegates with a free exchange of ideas and experience. We hope to stimulate delegates to re-evaluate their own approach to lung cancer staging.References 1. Chang DB, Yang PC, Yu CJ, Kuo SH, Lee YC, Luh KT.Ultrasonography and ultrasonographically guided fine-needle aspiration biopsy of impalpable cervical lymph nodes in patients with non-small cell lung cancer.Cancer. 1992 Sep 1;70(5):1111-4 2. Suga K, Yuan Y, Ueda K, Kaneda Y, Kawakami Y, Zaki M, Matsunaga N Computed tomography lymphography with intrapulmonary injection of iopamidol for sentinel lymph node localization. Invest Radiol. 2004 Jun;39(6):313-24. 3. Annema JT, van Meerbeeck JP, Rintoul RC, Dooms C, Deschepper E, Dekkers OM, De Leyn P, Braun J, Carroll NR, Praet M, de Ryck F, Vansteenkiste J, Vermassen F, Versteegh MI, Veseliç M, Nicholson AG, Rabe KF, Tournoy KG. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial .JAMA. 2010 Nov 24;304(20):2245- 52 4. Witte B, Hürtgen M.Video-assisted mediastinoscopic lymphadenectomy (VAMLA).J Thorac Oncol. 2007 Apr;2(4):367-9 5. De Leyn P, Dooms C, Kuzdzal J, Lardinois D, Passlick B, Rami-Porta R, Turna A, Van Schil P, Venuta F, Waller D, Weder W, Zielinski M. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg. 2014 May;45(5):787-98 6. Hachey KJ, Colson YL. Current innovations in sentinel lymph node mapping for the staging and treatment of resectable lung cancer. Semin Thorac Cardiovasc Surg. 2014 Autumn;26(3):201-9 7. Tomoshige K, Tsuchiya T, Otsubo R, Oikawa M, Yamasaki N, Matsumoto K, Miyazaki T, Hayashi T, Kinoshita N, Nanashima A, Nagayasu T.Intraoperative diagnosis of lymph node metastasis in non-small-cell lung cancer by a semi-dry dot-blot method.Eur J Cardiothorac Surg. 2016 Feb;49(2):617-22 8. Darling GE, Allen MS, Decker PA, Ballman K, Malthaner RA, Inculet RI, Jones DR, McKenna RJ, Landreneau RJ, Rusch VW, Putnam JB Jr. Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial . J Thorac Cardiovasc Surg. 2011 Mar;141(3):662-70 9. Nomori H, Cong Y, Sugimura H. Utility and pitfalls of sentinel node identification using indocyanine green during segmentectomy for cT1N0M0 non-small cell lung cancer. Surg Today. 2016 Aug;46(8):908-13 10. Deng XF, Jiang L, Liu QX, Zhou D, Hou B, Cui K, Min JX, Dai JG Lymph node micrometastases are associated with disease recurrence and poor survival for early-stage non-small cell lung cancer patients: a meta-analysis. J Cardiothorac Surg. 2016 Feb 16;11:28. Keywords: lung cancer. lymph node metastasis. nodal mapping SESSION MTE16: PRECISION MEDICINE IN NSCLC: LESSONS LEARNED AND PERSPECTIVES (TICKETED SESSION) TUESDAY, DECEMBER 6, 2016 - 07:30-08:30 MTE16.02 PRECISION MEDICINE IN NSCLC: LESSONS LEARNED AND PERSPECTIVES Christian Manegold Surgery, Medical Faculty Mannheim, University of Heidelberg, Mannheim/Germany Medical therapy in advanced NSCLC in 2016 is characterized by personalization, individualization, and therapy precision. Not only clinical factors are used for treatment differentiation but also the histological type (squamous versus non-squamous) and the molecular profile (mutant versus wild type). In addition, the complexity of the treatment algorithm has gradually increased over time by the incorporation of a number of approved molecules for 1 st , 2 nd -, subsequent line therapy (Peters, 2012; Masters, 2015; NCCN, 2016). NSCLC – 1 st -line-therapy - wild-type: For patients with wild-type non-squamous NSCLC it is generally accepted that upfront platinum based doublet chemotherapy (DCT) remains the backbone for individuals with good performance and that this approach should be modified according to feasibility and tolerability, co-morbidity, and age over 70 years. Progress has been made through pemetrexed, which is recommended as the favorite partner of platinum-based components (Scagliotti; 2008/2011). In addition, it has lately been demonstrated that the extension of induction chemotherapy by single agent pemetrexed until progression - in case of non-progression under four cycles of DCT not containing pemetrexed (switch maintenance) (Ciuleanu, 2009) or containing pemetrexed (continuation maintenance) (Paz-Ares, 2012/2013) - prolongs survival. In this case survival may also be prolonged by erlotinib, when used in the switch maintenance setting, but erlotinib’s benefit seem to be restricted to patients, which have experienced disease stabilization to induction chemotherapy (Cappuzzo, 2010; Coudert, 2012). Bevacizumab, when added to platinum-based to DCT, significantly improves response rate, progression free survival, as well as overall survival in eligible patients (Sandler, 2006/2010; Reck, 2009/2010). In wild-type squamous NSCLC platinum based DCT (no pemetrexed, no bevacizumab) remains standard. Nonetheless, necitumumab has recently shown to improve survival when combined with cisplatin/gemcitabine (Thatcher, 2015). Maintenance therapy in squamous tumors with docetaxel or erlotinib (switch) or gemcitabine (continuation) may be justified in some patients even so study evidence is weaker than for non-squamous tumors (Fidas, 2009; Perol, 2012). NSCLC – 1 st -line-therapy - mutant: For patients with advanced NSCLC expressing specific molecular features – mainly non-squamous tumors – 1 st - line treatment with targeted agents has been established. In tumors with EGFR mutations gefitinib, erlotinib, and afatinib have shown to prolong progression free survival over standard chemotherapy (Mok, 2009; Rosell, 2012; Sequist, 2013). In tumors bearing ALK-/ROS1-gene-rearrangements crizotinib has also shown to prolong progression free survival when compared to platinum/pemetrexed. (Solomon, 2014). Therefore, erlotinib, gefitinib or afatinib should be prescribed for patients with tumors bearing EGFR-mutations. For patients with tumors bearing ALK-/ROS1 crizotinib should be prescribed. However, for these patients molecular testing is critical and should be used to select patients for EGFR/ALK/ROS1 targeted therapy. Patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics (ethnicity, gender, smoking status) (Lindeman, 2013). NSCLC - 2 nd /subsequent-line therapy - wild-type: In patients with disease progression during or after completion of 1 st -line chemotherapy, 2 nd -, subsequent-line therapy is indicated when the patient remains in good clinical condition. Approved older treatment options include docetaxel, pemetrexed and erlotinib. Two anti-angiogenic agents and two immune-checkpoint inhibitors have recently been added. These include nintedanib and ramucirumab (Reck, 2014; Thatcher, 2015), as well as nivolumab and pembrolizumab (Brahmer, 2015; Borghaei, 2015; Herbst, 2016). Nintedanib/docetaxel increases significantly survival in patients with adenocarcinoma who specifically progressed within 9 months after the start of 1 st -line therapy, who have experienced disease progression as best response to 1 st -line therapy and decreases tumor burden and decelerates tumor growth. Nintedanib/docetaxel has been approved in the EU for the treatment of patients with adenocarcinoma. Ramucirumab/docetaxel has also been approved in the US and EU for patients with disease progression on or after DCT for wild-type non-squamous and squamous NSCLC. This approval has been based on phase III study evidence indicating survival advantage in non-squamous NSCLC (statistically significant) and squamous NSCLC (numerically longer). Comparing head-to head nivolumab and docetaxel in patients with squamous and non-squamous NSCLC after failure of DCT has demonstrated superior overall survival in patients receiving nivolumab. Nivolumab has received US and EU approval for advanced NSCLC with progression on or after DCT. Nivolumab appears to be most effective in patients with more than 6 months from completion of the latest treatment regimen to randomization in comparison to patients with less than 3 months to randomization. Pembrolizumab has received approval in the US and EU for patients with advanced NSCLC who’s tumors expressed PD-L1 and who have disease progression on or after chemotherapy. Approval has been based on head-to-head comparison of pembrolizumab and docetaxel in patients with previously treated PD-L1 positive squamous and non-squamous NSCLC, which has demonstrated a significant survival benefit for pembrolizumab. NSCLC-2 nd /subsequent-line therapy - mutant: Resistance to first and second generation EGFR-TKIs is a multifactorial process with a variety of clinically patterns. Its management requires different, case adapted approaches. Several strategies are currently under investigation, but some have already find its way into todays practice although study evidence is still rather weak. In case of oligoprogression the EGFR-TKI therapy may continue but local therapies (radiation, surgery) should be added. In case of diffuse progression EGFR-TKI therapy may continue, but in combination with chemotherapy; EGFR-TKI therapy may be switched to chemotherapy, but at the moment of chemotherapy resistance patients may be re-exposed to EGFR-TKI therapy; admission to clinical trials offering investigational agents may be a valid option for some patient. Osimertinib has just been approved and is Copyright © 2016 by the International Association for the Study of Lung Cancer S85
Page 1 and 2:
Volume 12 • Issue S1 • January
Page 3 and 4:
Abstracts Journal of Thoracic Oncol
Page 5 and 6:
Page 7 and 8:
Page 9 and 10:
Page 11 and 12:
Page 13 and 14:
Page 15 and 16:
Page 17 and 18:
Page 19 and 20:
Page 21 and 22:
Page 23 and 24:
Page 25 and 26:
Page 27 and 28:
Page 29 and 30:
Page 31 and 32:
Page 33 and 34:
Page 35 and 36: Abstracts Journal of Thoracic Oncol
Page 85: Abstracts Journal of Thoracic Oncol
Page 137 and 138:
Page 139 and 140:
Page 141 and 142:
Page 143 and 144:
Page 145 and 146:
Page 147 and 148:
Page 149 and 150:
Page 151 and 152:
Page 153 and 154:
Page 155 and 156:
Page 157 and 158:
Page 159 and 160:
Page 161 and 162:
Page 163 and 164:
Page 165 and 166:
Page 167 and 168:
Page 169 and 170:
Page 171 and 172:
Page 173 and 174:
Page 175 and 176:
Page 177 and 178:
Page 179 and 180:
Page 181 and 182:
Page 183 and 184:
Page 185 and 186:
Page 187 and 188:
Page 189 and 190:
Page 191 and 192:
Page 193 and 194:
Page 195 and 196:
Page 197 and 198:
Page 199 and 200:
Page 201 and 202:
Page 203 and 204:
Page 205 and 206:
Page 207 and 208:
Page 209 and 210:
Page 211 and 212:
Page 213 and 214:
Page 215 and 216:
Page 217 and 218:
Page 219 and 220:
Page 221 and 222:
Page 223 and 224:
Page 225 and 226:
Page 227 and 228:
Page 229 and 230:
Page 231 and 232:
Page 233 and 234:
Page 235 and 236:
Page 237 and 238:
Page 239 and 240:
Page 241 and 242:
Page 243 and 244:
Page 245 and 246:
Page 247 and 248:
Page 249 and 250:
Page 251 and 252:
Page 253 and 254:
Page 255 and 256:
Page 257 and 258:
Page 259 and 260:
Page 261 and 262:
Page 263 and 264:
Page 265 and 266:
Page 267 and 268:
Page 269 and 270:
Page 271 and 272:
Page 273 and 274:
Page 275 and 276:
Page 277 and 278:
Page 279 and 280:
Page 281 and 282:
Page 283 and 284:
Page 285 and 286:
Page 287 and 288:
Page 289 and 290:
Page 291 and 292:
Page 293 and 294:
Page 295 and 296:
Page 297 and 298:
Page 299 and 300:
Page 301 and 302:
Page 303 and 304:
Page 305 and 306:
Page 307 and 308:
Page 309 and 310:
Page 311 and 312:
Page 313 and 314:
Page 315 and 316:
Page 317 and 318:
Page 319 and 320:
Page 321 and 322:
Page 323 and 324:
Page 325 and 326:
Page 327 and 328:
Page 329 and 330:
Page 331 and 332:
Page 333 and 334:
Page 335 and 336:
Page 337 and 338:
Page 339 and 340:
Page 341 and 342:
Page 343 and 344:
Page 345 and 346:
Page 347 and 348:
Page 349 and 350:
Page 351 and 352:
Page 353 and 354:
Page 355 and 356:
Page 357 and 358:
Page 359 and 360:
Page 361 and 362:
Page 363 and 364:
Page 365 and 366:
Page 367 and 368:
Page 369 and 370:
Page 371 and 372:
Page 373 and 374:
Page 375 and 376:
Page 377 and 378:
Page 379 and 380:
Page 381 and 382:
Page 383 and 384:
Page 385 and 386:
Page 387 and 388:
Page 389 and 390:
Page 391 and 392:
Page 393 and 394:
Page 395 and 396:
Page 397 and 398:
Page 399 and 400:
Page 401 and 402:
Page 403 and 404:
Page 405 and 406:
Page 407 and 408:
Page 409 and 410:
Page 411 and 412:
Page 413 and 414:
Page 415 and 416:
Page 417 and 418:
Page 419 and 420:
Page 421 and 422:
Page 423 and 424:
Page 425 and 426:
Page 427 and 428:
Page 429 and 430:
Page 431 and 432:
Page 433 and 434:
Page 435 and 436:
Page 437 and 438:
Page 439 and 440:
Page 441 and 442:
Page 443 and 444:
Page 445 and 446:
Page 447 and 448:
Page 449 and 450:
Page 451 and 452:
Page 453 and 454:
Page 455 and 456:
Page 457 and 458:
Page 459 and 460:
Page 461 and 462:
Page 463 and 464:
Page 465 and 466:
Page 467 and 468:
Page 469 and 470:
Page 471 and 472:
Page 473 and 474:
Page 475 and 476:
Page 477 and 478:
Page 479 and 480:
Page 481 and 482:
Page 483 and 484:
Page 485 and 486:
Page 487 and 488:
Page 489 and 490:
Page 491 and 492:
Page 493 and 494:
Page 495 and 496:
Page 497 and 498:
Page 499 and 500:
Page 501 and 502:
Page 503 and 504:
Page 505 and 506:
Page 507 and 508:
Page 509 and 510:
Page 511 and 512:
Page 513 and 514:
Page 515 and 516:
Page 517 and 518:
Page 519 and 520:
Page 521 and 522:
Page 523 and 524:
Page 525 and 526:
Page 527 and 528:
Page 529 and 530:
Page 531 and 532:
Page 533 and 534:
Page 535 and 536:
Page 537 and 538:
Page 539 and 540:
Page 541 and 542:
Page 543 and 544:
Page 545 and 546:
Page 547 and 548:
Page 549 and 550:
Page 551 and 552:
Page 553 and 554:
Page 555 and 556:
Page 557 and 558:
Page 559 and 560:
Page 561 and 562:
Page 563 and 564:
Page 565 and 566:
Page 567 and 568:
Page 569 and 570:
Page 571 and 572:
Page 573 and 574:
Page 575 and 576:
Page 577 and 578:
Page 579 and 580:
Page 581 and 582:
Page 583 and 584:
Page 585 and 586:
Page 587 and 588:
Page 589 and 590:
Page 591 and 592:
Page 593 and 594:
Page 595 and 596:
Page 597 and 598:
Page 599 and 600:
Page 601 and 602:
Page 603 and 604:
Page 605 and 606:
Page 607 and 608:
Page 609 and 610:
Page 611 and 612:
Page 613 and 614:
Page 615 and 616:
Page 617 and 618:
Page 619 and 620:
Page 621 and 622:
Page 623 and 624:
Page 625 and 626:
Page 627 and 628:
Page 629 and 630:
Page 631 and 632:
Page 633 and 634:
Page 635 and 636:
Page 637 and 638:
Page 639 and 640:
Page 641 and 642:
Page 643 and 644:
Page 645 and 646:
Page 647 and 648:
Page 649 and 650:
Page 651 and 652:
Page 653 and 654:
Page 655 and 656:
Page 657 and 658:
Page 659 and 660:
Page 661 and 662:
Page 663 and 664:
Page 665 and 666:
Page 667 and 668:
Page 669 and 670:
Page 671 and 672:
Page 673 and 674:
Page 675 and 676:
Page 677 and 678:
Page 679 and 680:
Page 681 and 682:
Page 683 and 684:
Page 685 and 686:
Page 687 and 688:
Page 689 and 690:
Page 691 and 692:
Page 693 and 694:
Page 695 and 696:
Page 697 and 698:
Page 699 and 700:
Page 701 and 702:
Page 703 and 704:
Page 705 and 706:
Page 707 and 708:
Page 709 and 710:
Page 711 and 712:
Page 713 and 714:
Page 715 and 716:
Page 717 and 718:
Page 719 and 720:
Page 721 and 722:
Page 723 and 724:
Page 725 and 726:
Page 727 and 728:
Page 729 and 730:
Page 731 and 732:
Page 733 and 734:
Page 735 and 736:
Page 737 and 738:
Page 739 and 740:
Page 741 and 742:
Page 743 and 744:
Page 745 and 746:
Page 747 and 748:
Page 749 and 750:
Page 751 and 752:
Page 753 and 754:
Page 755 and 756:
Page 757 and 758:
Page 759 and 760:
Page 761 and 762:
Page 763 and 764:
Page 765 and 766:
Page 767 and 768:
Page 769 and 770:
Page 771 and 772:
Page 773 and 774:
Page 775 and 776:
Page 777 and 778:
Page 779 and 780:
Page 781 and 782:
Page 783 and 784:
Page 785 and 786:
Page 787 and 788:
Page 789 and 790:
Page 791 and 792:
Page 793 and 794:
Page 795 and 796:
Page 797 and 798:
Page 799 and 800:
Page 801 and 802:
Page 803 and 804:
Page 805 and 806:
Page 807 and 808:
Page 809 and 810:
Page 811 and 812:
Page 813 and 814:
Page 815 and 816:
Page 817 and 818:
Page 819 and 820:
Page 821 and 822:
Page 823 and 824:
Page 825 and 826:
Page 827 and 828:
Page 829 and 830:
Page 831 and 832:
Page 833 and 834:
Page 835 and 836:
Page 837 and 838:
Page 839 and 840:
Page 841 and 842:
Page 843 and 844:
Page 845 and 846:
Page 847 and 848:
Page 849 and 850:
Page 851 and 852:
Page 853 and 854:
Page 855 and 856:
Page 857 and 858:
Page 859 and 860:
Page 861 and 862:
Page 863 and 864:
Page 865 and 866:
Page 867 and 868:
Page 869 and 870:
Page 871 and 872:
Page 873 and 874:
Page 875 and 876:
Page 877 and 878:
Page 879 and 880:
Page 881 and 882:
Page 883 and 884:
Page 885 and 886:
Page 887 and 888:
Page 889 and 890:
Page 891 and 892:
Page 893 and 894:
Page 895 and 896:
Page 897 and 898:
Page 899 and 900:
Page 901 and 902:
Page 903 and 904:
Page 905:
Page 912:
LILLY ONCOLOGY IS DEDICATED TO ADVA
show all

Journal Thoracic Oncology

Create successful ePaper yourself

Delete template?

Save as template?