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Masami Sato

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    MS 03 - Best Practice for Small-Sized Early Stage Lung Cancer: Standard Surgery, Limited Resection, SBRT (ID 525)

    • Event: WCLC 2017
    • Type: Mini Symposium
    • Track: Early Stage NSCLC
    • Presentations: 5
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      MS 03.01 - Limited vs. Standard Surgical Resection: North American Experience (ID 7648)

      11:00 - 12:30  |  Presenting Author(s): Nasser Altorki

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS 03.02 - Limited vs. Standard Surgical Resection: Japanese Experience (ID 7649)

      11:00 - 12:30  |  Presenting Author(s): Hisao Asamura

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The extent of pulmonary resection for peripheral, non-small cell lung cancer (NSCLC) has been defined as "lobe", based on the results of clinical experiences and a randomized trial in 1980's. At present, the possibility of lesser resection such as wedge/segmental resection needs to be evaluated from a updated, scientific viewpoint. For these reasons, JCOG (Japan Clinical Oncology Group) has been prospectively deploying series of clinical trials each for different target lesions to define the proper extent of the parenchymal resection for NSCLC, JCOG 0804, 0802, and 1211. Among these, the most important study is JCOG 0802, in which the non-inferiority of segmentectomy was compared with lobectomy in terms of overall survival for patients with diameter ≤ 2 cm invasive peripheral NSCLC. As a second endpoint, the postoperative pulmonary function was also compared to demonstrate the functional superiority for lesser resection. Between Aug 10, 2009 and Oct 21, 2014, 1,106 patients were enrolled. No mortality was noted. Complications (grade ≥ 2) occurred in 26·2% for lobectomy and 27·4% for segmentectomy. Multivariate analysis indicated a pack-year (PY) smoking >20 (vs. none) as a predictor of postoperative complications (grade ≥ 2), and a complex segmentectomy (vs. lobectomy) and PY > 20 as a predictor of pulmonary complications. The final analyses on the prognostic non-inferiority (primary endpoint) will be available after 2020. Through such series of prospective studies, the proper extent of pulmonary resection for NSCLC is to be defined from prognostic and functional viewpoints. Therefore, especially for JCOG 0802 study, both of two endpoints must meet the hypothetical criteria for lesser resection to be judged as appropriate. We should realize that a true progress in the surgical oncology might be achieved only by a prospective, collaborative comparison as an applied science.

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      MS 03.03 - Limited vs. Standard Surgical Resection: European Experience (ID 7650)

      11:00 - 12:30  |  Presenting Author(s): Paul Emile Van Schil

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Until the beginning of the new century limited resection for pathologically proven, early-stage lung cancer was not frequently applied in Europe. The main reason for this practice were the results of the randomized phase III trial of the Lung Cancer Study Group published in 1995, showing that for peripheral, clinical T1N0 tumors, lobectomy yields better locoregional control with less recurrences compared to sublobar resection (1). This study was very influential in Europe. A majority of thoracic surgeons adopted the principle that lobectomy was the minimally acceptable lung volume to be resected for patients with an early-stage bronchogenic carcinoma and a low cardiopulmonary risk. Limited resection for lung cancer was only considered for elderly persons, patients with severe chronic obstructive pulmonary disease precluding lobectomy, patients with a high comorbidity score and limited life expectancy due to debilitating disease. Quite a substantial variation in practice is observed, not only within countries but also when comparing North America and Europe. In an interesting analysis of the thoracic surgical databases of the Society of Thoracic Surgeons (STS) and European Society of Thoracic Surgeons (ESTS), some important differences were discovered regarding the daily practice of lung resections performed during the period 2010-2013 (2). Patients in the STS database were more frequently operated by video-assisted thoracic surgery (VATS) compared to the ESTS dataset (63% versus 22%), and were more likely to undergo sublobar resection (43% versus 31%). However, most of the sublobar resections were wedge resections. Anatomical segmentectomies were more frequently performed in the ESTS database than in the STS dataset (7.4% versus 3.9%). For the ESTS patients 30-day mortality of wedge resections was lower compared to the STS data (0.1% versus 1.9%); however, mortality for lobectomy was higher (2.6% versus 1.4%) (2). With the start of European screening studies, although not at the scale of the National Lung Screening Trial, a new clinical problem arose for thoracic surgeons, namely how to deal with small pulmonary nodules and how to limit the false-positive rate? Thoracic surgical issues of screening were addressed in a recent paper by a task force of the ESTS (3). Recommendations were made for implementation of CT screening in Europe focussing on the training of thoracic surgeons, their clinical profile and the use of minimally invasive thoracic surgery. In general, it has been clearly demonstrated that the main goal of surgery for an invasive lung cancer is to obtain a complete resection which is a major prognostic factor. This mostly implies a lobectomy for tumors > 2cm, and at least a lobe-specific systematic nodal dissection as defined in 2005 by a working group of the International Association for the Study of Lung Cancer (IASLC) (4). Unfortunately, quite a lot of resections have to be considered uncertain due to the fact that the required number of lymph nodes, especially mediastinal, have not been removed for further pathological analysis (5). The new adenocarcinoma classification published in 2011 by a common task force of the IASLC , American Thoracic Society (ATS) and European Respiratory Society (ERS) and accumulating phase II data mainly coming from Japan, had important surgical implications (6). As new entities, adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) were introduced and the confusing term bronchioloalveolar cell carcinoma (BAC) is not used anymore. This clearly resulted in a paradigm shift and the concept of sublobar resection was reconsidered for smaller, early-stage lung cancers < 2cm. Anatomical segmentectomy is generally preferred to wide wedge resection because of concerns of local recurrence (7). Regarding the overall oncological results several meta-analyses have been performed. Their results are somewhat conflicting but overall, good long-term results are described for tumors until 2 cm treated by segmentectomy when no lymph node invasion is present. However, for small, early-stage lung cancer no high-level evidence is currently available and the reported evidence should be interpreted with caution. As most studies were not randomized, there was probably a clear selection bias regarding comorbidity, histology and tumor size. Recent guidelines and evidence from a randomized trial indicate that small nodules of ≤10 mm or ≤500 mm[3] that are clearly 100% pure ground-glass opacities (GGO) on chest CT may be considered as AIS or MIA, and hence may be suitable for close follow-up or sublobar resection rather than a formal lobectomy (8). Subcentimeter lung cancers, currently T1a disease, represent a specific subgroup as they comprise the smallest lesions. It should also be emphasized that for subsolid lesions the current tumor size is determined by the solid or invasive part only which represents a major change in the 8[th] TNM (tumor, node, metastasis) classification (9). For thoracic surgeons another important topic is the accuracy of intraoperative frozen section analysis to determine the intraoperative extent of resection. Recent studies show that a concordance rate of more than 80% can be reached between the frozen section and definitive pathological report (10) . However, AIS and MIA are more difficult to diagnose on frozen section and accuracy becomes less for lesions below 10 mm, which represent the main category to be considered for sublobar resection. This implies that a second intervention to perform a completion lobectomy may be indicated in patients with poor prognostic histological features who initially underwent a limited resection for a presumably low-malignant lesion. In conclusion, sublobar resection is currently more often applied in European countries but more high-level evidence on long-term oncological results is required to refine its indications and make this procedure a generally accepted intervention, not only by thoracic surgeons but also by thoracic oncologists and pulmonary physicians. References 1. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg. 1995; 60:615-22; discussion 22-3. 2. Seder CW, Salati M, Kozower BD, Wright CD, Falcoz PE, Brunelli A, et al. Variation in Pulmonary Resection Practices Between The Society of Thoracic Surgeons and the European Society of Thoracic Surgeons General Thoracic Surgery Databases. Ann Thorac Surg. 2016; 101:2077-84. 3. Pedersen JH, Rzyman W, Veronesi G, D'Amico TA, Van Schil P, Molins L, et al. Recommendations from the European Society of Thoracic Surgeons (ESTS) regarding computed tomography screening for lung cancer in Europe. Eur J Cardiothorac Surg. 2017; 51:411-20. 4. Rami-Porta R, Wittekind C, Goldstraw P, International Association for the Study of Lung Cancer Staging C. Complete resection in lung cancer surgery: proposed definition. Lung Cancer. 2005; 49:25-33. 5. Verhagen AF, Schoenmakers MC, Barendregt W, Smit H, van Boven WJ, Looijen M, et al. Completeness of lung cancer surgery: is mediastinal dissection common practice? Eur J Cardiothorac Surg. 2012; 41:834-8. 6. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, 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. Sihoe AD, Van Schil P. Non-small cell lung cancer: when to offer sublobar resection. Lung Cancer. 2014; 86:115-20. 8. van Klaveren RJ, Oudkerk M, Prokop M, Scholten ET, Nackaerts K, Vernhout R, et al. Management of lung nodules detected by volume CT scanning. N Engl J Med. 2009; 361:2221-9. 9. Travis WD, Asamura H, Bankier AA, Beasley MB, Detterbeck F, Flieder DB, 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 Thorac Oncol. 2016; 11:1204-23. 10. Yeh YC, Nitadori J, Kadota K, Yoshizawa A, Rekhtman N, Moreira AL, et al. Using frozen section to identify histological patterns in stage I lung adenocarcinoma of

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      MS 03.04 - Technical Aspects of Limited Resection (ID 7651)

      11:00 - 12:30  |  Presenting Author(s): Harvey I Pass

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Since its first report by Churchill and Belsey in 1939, and its evolution in lung cancer management described by Jensik in 1973 (Figure), pulmonary segmentectomy use for early lung cancer diagnosis and treatment has remained controversial. Definitive answers must wait regarding the results of the JCOG and Alliance randomized trials before true standards for surgical care for the lung cancer less than 2 cm are determined. Nevertheless, sublobar resections including wedge resection and segmentectomy are being adopted at an increasing rate compared to its use in previously published large databases (SEER, 5%; ACS NSQIP, 4%). Proper preoperative teaching and intraoperative performance of the technical aspects of sublobar resection are now becoming priorities for general thoracic resident and fellow training in an era where minimally invasive techniques are becoming increasingly the standard of care. General thoracic surgeons must have meticulous attention to detail in performing these resections in order to decrease the likelihood of collateral damage to neighboring segments as well as to minimize local recurrence whether there are performing the operation open, hybrid, standard VATS, uniportal VATS, or robotic. The technical aspects of sublobar resection begin before the patient goes to the operating room, and prime objectives in planning these resections include (1) expertise in the segmental anatomy for that particular patient (2) location and size of the nodule with relation to adjoining segmental bronchovascular components (3) careful study and possible supplementation of high resolution computerized tomography with newer 3-D methods to define the spatial relationships of the nodule and segments (4) pre- and intraoperative methods for locating the nodule if there is suspicion that parenchymal palpation will fail (5) whether to perform wedge resection first or proceed directly to anatomic segmentectomy (6) defining and managing the fissure between segments and recognizing when extended segmentectomy is possible or whether to convert to lobectomy and (7) to use other intraoperative strategies to avoid technique related complications. Preoperative planning includes careful examination of the CT scan in the axial, coronal and sagittal plans in order to get a first appreciation of the depth, size, segmental anatomy and relationship of the nodule bronchovascular elements. Three-dimensional reconstruction can be as simple as navigational bronchoscopy planning images, or newer techniques for total 3-D pulmonary reconstruction which are in development (1). When there is a question of whether up front segmentectomy is to be performed and a part solid or non-solid nodule may not be palpable, intraoperative localization techniques such as navigation bronchoscopy(2) or placement of fiducials/microcoils (3) can be very useful. When there is no preoperative histologic diagnosis, whether a wedge or segmentectomy is performed initially will depend on the location and depth of the lesion as well as the fitness of the patient. Segmentectomy for initial diagnosis with intraoperative frozen section of both the primary lesion and suspicious level 13 and 14 stations can be prudent, especially if wedge resection could compromise performing the segmentectomy(4). In order to avoid positive margins, meticulous attention to detail with compulsive dissection and skeletonizing of the bronchovascular elements must be performed. If it is difficult to preserve the margin in a single segment resection, an extended resection of the parenchyma of adjacent segments or bisegmentectomy can be performed(5). There is controversy regarding the chance for loco-regional recurrence for segmentectomy especially in cases of pure solid lesions or segmentectomies which involve portions of the basilar segments or right upper lobe (6-8). Defining the fissure and the method with which it is divided can be one of the most important yet challenging portions of the operation. A variety of methods to define the fissure have evolved including inflation of the residual lung after segment occlusion, selective inflation of the segment to be removed, or the use of indocyanine green to define the intersegmental vein (4, 5), and the fissure can be divided either with stapling alone or in combination with harmonic scalpel(9). A variety of fibrin sealants are available to decrease postoperative fistulae. With regard to the optimal approach, to date there have been no studies which show any superiority regarding conventional VATs or uniportal VATs for segmental resection, or any difference between the VATs approaches and robotic segmentectomy (10). A recent meta-analysis of over 7438 patients revealed a trend towards increased conversion to open with VATs, while postoperative complications, operation time, length of stay, chest tube duration, and number of lymph nodes were comparable(11). Figure 1 Reference List (1) Yao F, Wang J, Yao J, Hang F, Lei X, Cao Y. Three-dimensional image reconstruction with free open-source OsiriX software in video-assisted thoracoscopic lobectomy and segmentectomy. Int J Surg 2017;39:16-22. (2) Zhao ZR, Lau RW, Yu PS, Wong RH, Ng CS. Image-guided localization of small lung nodules in video-assisted thoracic surgery. J Thorac Dis 2016;8:S731-S737. (3) Donahoe LL, Nguyen ET, Chung TB, Kha LC, Cypel M, Darling GE, et al. CT-guided microcoil VATS resection of lung nodules: a single-centre experience and review of the literature. J Thorac Dis 2016;8:1986-94. (4) Landreneau RJ, D'Amico TA, Schuchert MJ, Swanson SJ. Segmentectomy and Lung Cancer: Why, When, How, and How Good? Semin Thorac Cardiovasc Surg 2017;29:119-28. (5) Oizumi H, Kato H, Endoh M, Inoue T, Watarai H, Sadahiro M. Techniques to define segmental anatomy during segmentectomy. Ann Cardiothorac Surg 2014;3:170-5. (6) Hattori A, Matsunaga T, Takamochi K, Oh S, Suzuki K. Locoregional recurrence after segmentectomy for clinical-T1aN0M0 radiologically solid non-small-cell lung carcinoma. Eur J Cardiothorac Surg 2017;51:518-25. (7) Hattori A, Matsunaga T, Takamochi K, Oh S, Suzuki K. The oncological outcomes of segmentectomy in clinical-T1b lung adenocarcinoma with a solid-dominant appearance on thin-section computed tomography. Surg Today 2016;46:914-21. (8) Ueda K, Tanaka T, Hayashi M, Tanaka N, Li TS, Hamano K. What proportion of lung cancers can be operated by segmentectomy? A computed-tomography-based simulation. Eur J Cardiothorac Surg 2012;41:341-5. (9) Kuroda H, Dejima H, Mizumo T, Sakakura N, Sakao Y. A new LigaSure technique for the formation of segmental plane by intravenous indocyanine green fluorescence during thoracoscopic anatomical segmentectomy. J Thorac Dis 2016;8:1210-6. (10) Veronesi G, Cerfolio R, Cingolani R, Rueckert JC, Soler L, Toker A, et al. Report on First International Workshop on Robotic Surgery in Thoracic Oncology. Front Oncol 2016;6:214. (11) Liang H, Liang W, Zhao L, Chen D, Zhang J, Zhang Y, et al. Robotic Versus Video-assisted Lobectomy/Segmentectomy for Lung Cancer: A Meta-analysis. Ann Surg 2017.



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      MS 03.05 - SBRT Experience (ID 7652)

      11:00 - 12:30  |  Presenting Author(s): Joe Y Chang

      • Abstract
      • Presentation
      • Slides

      Abstract:
      In the early 2000s, the revolution in computer-driven radiotherapy technology enabled exquisitely precise direction of radiation beams to specific tumor targets. The advent of 4-dimensional computed tomography (CT), MRI and on-board image-guided intensity-modulated radiotherapy (IMRT), stereotactic ablative radiotherapy (SABR), particle therapy have equipped radiation oncologists with novel tools to tightly conform ablative radiation doses to targets while avoiding inadvertent irradiation of surrounding critical normal structures. SABR, also called stereotactic body radiation therapy (SBRT), as a non-invasive curative therapy, achieves >90% local control, improves survival with minimal toxicity and has become standard therapy in medical inoperable peripheral located stage I NSCLC (1, 2). Particularly for elderly patient, SABR’s effectiveness based on lung cancer-specific survival and progression-free survival is the same in the elderly (>75 year old) as it is the average age population (<75 year old). It also poses no increased toxicity. Compared to historical outcomes with surgery in the elderly, SABR outcome is considered comparable for stage I disease but has less morbidity (3). The pattern of failure study showed that the dominant failure of SABR in stage I NSCLC is distant metastasis (10 to 20%), followed by regional lymph node recurrence (10 to 15%) and then local failure ( 5 to 10%) (4). Up to 1 in 6 patients who received SABR for early-stage NSCLC may develop isolated local-regional recurrence that could be salvaged with definitive treatment. The first long-term results for the largest group of salvaged patients with local-regional recurrence after SABR (n=103) was reported in ASCO 2017 annual meeting (Brooks et al, ASCO 2017 oral presentation in Chicago). 912 patients with clinically early-stage I-II NSCLC from MDACC were treated with SABR with isolated local recurrence (LR, n = 49) or regional recurrence (RR, n = 53). Salvage was performed in 79.6% of LR and 90.6% of RR patients. Median follow-up from time of initial SABR was 57.2 months. 5-year OS was 52% for LR and 27.8% for RR patients. Of LR and RR patients, those receiving salvage had significantly better 5-year OS compared to those not receiving salvage (57.9% LR, 31.1% RR, 0% no salvage; p = 0.006). 5-year OS for LR salvaged patients was not statistically different from patients with NR (53.5% NR, p = 0.92) and 5-year OS for salvaged RR was lower than that of NR (p=0.022). 60% patients never recurred after salvage but subsequent DM occurred in 27.6% of local-regional recurrent patients at a median of 10.5 months. No salvaged patient experienced grade 5 toxicity. There is debate about what is the optimal treatment for operable stage I NSCLC. Majority of the population-based retrospective propensity-matched studies have indicated that SABR has effectiveness comparable to that of surgery for this population, with reported 3-year overall survival rates of 48-91% and local control rates of 85-96% that is significantly better than conventional radiotherapy (5). A pooled analysis of two prospective randomized trials for operable patients showed a better overall survival rate at 3 years for SABR than for surgery (6); however, the efficacy, pattern of failure, and toxicity reported were mostly based upon relatively short follow-up and patient’s number is small; therefore, larger studies with longer follow up are needed and are ongoing around the world. Recently, a phase II prospective study investigating SABR for early-stage NSCLC with median follow-up of 7 years demonstrated outstanding OS of 47% with low rates of local (8%), regional (14%) and distant failure (14%) 7 years after SABR, comparable to those of surgery but with lower toxicity (7). Second malignancy remains one of the most common issues with longer follow-up (21%), again consistent with surgical data. There are two major limitations of SABR in treating early stage NSCLC. First, critical nearby normal tissue dose constraints such as esophagus, bronchial tree, brachial plexus, heart, major vessels etc. may limit the ablative dose that could be safely delivered (8); second, the efficacy of SABR is reduced and toxicity is increased with increasing size of the lesion, particularly when the lesion is >5 cm (9). Most of outstanding clinical outcome with SABR reported in the literature are based on lesions less than 5 cm, typically <3 cm, and not close/next to critical normal structures. Finally, we need to keep in mind that cancer is a biological disease, not just a technologic challenge. As our ability to control local tumors improves with the use of new technology, the importance of systemic disease control grows in parallel—after all, in most cases it is metastatic disease that kills the patient. During the past decade, the development of genomic profile–based targeted therapy and immune checkpoint pathway– based immunotherapy has revolutionized the management of stage IV lung cancer. More and more data indicated that cancer cells killed by radiation release tumor-associated antigens and immunoregulatory cytokines, thereby functioning as a kind of cancer-specific vaccine in situ; they further activate tumor-specific systemic immune responses to eradicate tumors even outside the radiation field (the abscopal effect). These effects seem to be more prominent when the radiation used with immunotherapy involves giving high (ablative) doses, a type of therapy for which we coined the term “I-SABR” (immunotherapy and stereotactic ablative radiotherapy, 10). I-SABR protocols are underway for both early-stage disease and advanced cancer. In summary: SABR/SBRT, a novel non-invasive approach with low toxicity, achieves outstanding clinical outcome and is the standard treatment in medical inoperable stage I NSCLC. It remains controversial whether SABR should be used for operable early stage NSCLC and more randomized studies are ongoing. The dominant pattern of failure after SABR is distant metastasis, followed by regional or intra-lobar failure. Patient with isolated local/regional recurrence should be salvaged aggressively and long-term surveillance is crucial to detect early recurrence and the secondary lung cancer. Combined SABR with systemic therapy such as immunotherapy may further improve the efficacy and cure rate. REFERENCES 1. Timmerman R, et al. Jama. 2010;303(11):1070-6. 2. Onishi H, et al. Cancer. 2004;101(7):1623-31. 3. Brooks ED,et al. Int J Radiat Oncol Biol Phys. 2017;98(4):900-907 4. Senthi S, et al. Lancet Oncol. 2012;13(8):802-9. 5. Shirvani SM, et al JAMA Surg. 2014;149(12):1244-53. 6. Chang JY, et al.Lancet Oncol. 2015;16(6):630-7. 7. Sun B, et al. Cancer. 2017. E-pub ahead of print 8. Timmerman R, et al. JCO. 2006;24(30):4833-9. 9. Tekatli H,et al. J Thorac Oncol. 2017;12(6):974-982. 10. Bernstein MB, el al. Nat Rev Clin Oncol. 2016;13(8):516-24

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Author of

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    P2.16 - Surgery (ID 717)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Surgery
    • Presentations: 1
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      P2.16-004 - Alternative Subpreural Lymph Flow Pathways in Human Lung – a Hundred Cases Experience and Analysis (ID 8352)

      09:30 - 16:00  |  Author(s): Masami Sato

      • Abstract

      Background:
      Pulmonary lymph flows are predominantly regarded to run along bronchi. In addition, limited resections such as segmentectomy are increasing recently. However there are some cases suggesting alternative lymph pathways, such as the skip metastases. We herein observed pleural lymph flows by the indocyanine green (ICG) fluorescence method with a near-infrared camera device in patients who underwent lung resections.

      Method:
      After thoracotomy, we injected ICG to subpleural spaces of the lung lobe that planned to resect in 100 cases. Intraoperative fluorescence images were observed in real time using a near-infrared camera. Patients with pleural involvement were excluded.

      Result:
      In 58 out of 100 cases, ICG movements were observed in subpleural space. In 18 cases, ICG flowed into adjacent lobes over the interlobular line. In 5 cases, ICG flowed into the mediastinum directly. Subpreural lymph flow detection rates were significantly lower in patients with smoking pack-year >40 than those with pack-years <40.

      Conclusion:
      In our study, in more than half of the cases, pleural lymph flows were observed and there were lymph flows that flowed into the mediastinum directly. In addition, the reduction of subpleural lymph flows in smokers with >40 pack-year suggests that smoking might modify lymph flow patterns. In the future, these findings may help us to select appropriate procedures for patients with possible skip metastasis.