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Young Tae Kim
OA08 - Advanced Models and "Omics" for Therapeutic Development (ID 133)
- Event: WCLC 2019
- Type: Oral Session
- Track: Biology
- Presentations: 1
- Now Available
OA08.06 - Reciprocal Change in Glucose Metabolism of Cancer and Immune Cells Mediated by Different GLUT Predicts Immunotherapy Response (Now Available) (ID 642)
11:00 - 12:30 | Author(s): Young Tae Kim
Tumor metabolism represented by aerobic glycolysis is dynamically changed in tumor microenvironment (TME) to achieve immune escape. However, in vivo properties of glucose metabolism in cancer and immune cells are poorly understood and their clinical implications are still lacking. We scrutinized the association of tumor metabolism and immune properties of TME by comprehensive analyses using tissue RNA-seq, positron emission tomography (PET), and single cell RNA-seq data.Method
Lung squamous cell carcinoma (LUSC) samples with both RNA-seq and 18F-deoxyglucose (FDG) PET (n = 63) were collected to examine the association of in vivo glucose metabolism, gene expression levels related to glucose metabolism, and immune cell enrichment. An overall enrichment score of TME (ImmuneScore) was estimated from tissue RNA-seq data. The gene expression levels of each cell component of TME were analyzed by single cell RNA-seq from lung cancer patients. The expression patterns of glucose transporters (GLUTs) were evaluated in patients who underwent immunotherapy to investigate whether it can predict immunotherapy response.Result
Single cell RNA-seq showed that GLUT1 was mostly expressed in cancer cells while GLUT3 was mostly found in myeloid cells in TME. ImmuneScore showed a negative correlation with GLUT1 (r=-0.70, p<0.01) and a positive correlation with GLUT3 (r=0.39, p<0.01) in LUSC samples, and it was validated in TCGA cohort (r=-0.44, p<0.01 for GLUT1; r=0.26, p<0.01 for GLUT3). LUSC samples were divided into two distinct groups (immure-rich and immune-poor) by ImmuneScore. In immune-poor cluster, FDG uptake was positively correlated with GLUT1 (r=0.27, p=0.04), while not correlated with GLUT3. In immune-rich cluster, FDG uptake was positively correlated with GLUT3 (r=0.78, p=0.01), while not correlated with GLUT1. ImmuneScore was negatively correlated with FDG uptake in immune-poor cluster, while there was positive correlation in immune-rich cluster. We defined GLUT3-GLUT1 ratio (GLUTratio) as a metabolic biomarker representing immune status in TME. High GLUTratio indicates increased metabolic activity in immune cells and decreased metabolic activity in cancer cells in TME. For melanoma patients who underwent anti-PD-1 therapy, GLUTratio was significantly higher in responders than nonresponders (p=0.03).
Our findings support a reciprocal change of glucose metabolism between cancer and immune cells within TME mediated by different GLUTs. A new glucose metabolism-based biomarker, GLUTratio, can reflect reciprocal metabolic activity of immune and cancer cells in TME, and be a feasible predictive biomarker for immunotherapy.
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P2.17 - Treatment of Early Stage/Localized Disease (ID 189)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
P2.17-04 - Role of Lymphadenectomy in Thoracoscopic Lobectomy for Non-Small Cell Lung Cancer (ID 403)
10:15 - 18:15 | Author(s): Young Tae Kim
The adequacy of lymphadenctomy in video-assisted thoracoscopic surgery (VATS) for the patients with non-small cell lung cancer (NSCLC) has been questioned. This study aims to identify the role of lymphadenectomy during VATS lobectomy for NSCLC.Method
To include different level of lymphadenectomy proficiency and heterogeneous lymphadenectomy policy, we included all consecutive surgical cases from April 2005 to June 2013, irrespective of surgeon’s experience, lymph node sampling or dissection, and solid or subsolid nodule. Patients who underwent VATS lobectomy and who were followed up for more than 5 years were included in this study. The relationship between long-term survival and the number of removed lymph nodes was analyzed.Result
During the study period, a total of 2,502 patients underwent curative surgical resection of NSCLC and VATS lobectomy was performed in 1,055 patients (42.2%). The median length of postoperative hospital stay was 5 days and 30-day and 90-day all-cause mortality rates were 0.3% and 0.9%, respectively. Pathological stage I, II, III and IV were 79.0%, 10.6%, 8.7%, and 1.7% and the median number of removed lymph nodes was 24. The 5-year overall and recurrence-free survival rates were 83.9% and 78.5 %, respectively. Recurrences were developed in 233 patients (22.1%) and the most common pattern was distant metastasis (n=153, 14.5%). The number of removed lymph nodes, year of operation, age, tumor size, pathologic stage, histology, and radiologic features were the significant prognostic factor for recurrence-free survival in multivariate analysis. More than 10 lymph node removal was associated with improved recurrence-free survival and the effect lasted until 40. However, the number of removed lymph nodes were not a significant risk factor for overall survival (table).Conclusion
The number of removed lymph nodes was closely related with recurrence-free survival after VATS lobectomy. Proper lymphadenectomy should be performed in VATS lobectomy like as open lobectomy.
WS05 - Staging Workshop Part 2: The Importance of Invasive Nodal Staging in Thoracic Malignancies (ID 106)
- Event: WCLC 2019
- Type: Workshop
- Track: Staging
- Presentations: 1
- Now Available
- Moderators:Jose Maria Matilla, Ricardo Beyruti
- Coordinates: 9/09/2019, 15:45 - 17:15, San Francisco (2009)
WS05.05 - Lymphnode Dissection in Thymic Malignancies: Implications of the ITMIG/IASLC Lymph Node Map of the Tnm Classification and Staging (Now Available) (ID 3688)
15:45 - 17:15 | Presenting Author(s): Young Tae Kim
The significance of lymph node metastases and lymph node dissection (LND) remains unclear and underestimated in thymic malignancies. Given the fact that LND is an important surgical procedure for most of the solid organ malignancies, the role of LND in thymic malignancies should be established.
The ITMIG and the IASLC proposed a new lymph node map and separated N stage in the eighth edition of TNM stage classification system for thymic malignancies. They recommended that any suspicious nodes should be routinely removed. For stage I or II thymoma, adjacent nodes as well as anterior mediastinal nodes should be removed, and for stage III thymoma, systematic anterior mediastinal node dissection and systematic sampling of appropriate intrathoracic nodes were recommended. For the thymic carcinoma, a systematic sampling of anterior mediastinal, intrathoracic, supraclavicular, and lower cervical nodes were recommended. However, there is no prospective study to validate such recommendations as these recommendations are based on the old map and old staging system. As a consequence, a revised recommendation based on a new map and a new staging system is necessary.
Four aspects should be considered with regards to the appropriate LND during thymectomy. The first aspect is an indication. In what circumstances, the LND should be performed?. The second one is the lymph node stations to be dissected. Proper understanding of lymphatic pathway in thymus would be helpful to select lymph node to dissect. The third aspect is the adequate number of the lymph node to dissect. Often time, the quality of LND is evaluated by the number of the dissected lymph node. The last aspect is the surgical approach. It is sometimes challenging to dissect every nodal station by means of minimally invasive surgery.
What are the surrogate markers to predict lymph node metastasis in thymic malignancies? In many studies, histologic type and T stage have been reported as predictors of lymph node metastasis. Lymph node metastasis is more frequent in thymic carcinoma and carcinoid compared with that in thymoma. Also, it is frequent in tumors invading adjacent structures (T2 or T3).
Which lymph nodes stations are essential to dissect? Murakami et al. reported that the main lymphatic flow is a cranial direction to the cervical area, and they nicely described that the right paratracheal node group is the largest collecting area. In our group, we found that the right paratracheal lymph node station is the most common area of lymph node metastasis among deep regional node groups.
Can we score adequacy of LND in thymic malignancies? Our group previously showed that lymph node dissection more than 10 nodes predict prognosis better. When we divided patients into N0a when LND less than 10 were performed, N0b when LND was performed more than 10, and Nx when no LND was performed, the prognosis of N0a group was inferior to N0b and was similar to Nx group.
In our recent paper, we reviewed 131 thymic malignancy patients who underwent LND using 8th TNM staging and ITMIG Lymph node map. Lymph node metastasis was detected in 13 patients (N1 in six and N2 in seven). Six N2 patients (86%) had right paratracheal node metastases. The rates of node metastasis were 1% in T1 as compared to 37.5% in T2 or T3 (p < 0.001). The rates of node metastasis were 8% in the M0 as compared to 43% in the M1 (p = 0.03). The rate was higher in thymic carcinoma (25%) than in thymoma (5.1%, p = 0.01), and the rates also differed between the subtypes of thymoma. There was no node metastasis of the A, AB, or B1 histologic subtypes. Tumor size was also a significant factor which can predict node metastasis. The optimal cutoff value for the node metastasis was 6 cm, and the specificity was 62%. Only 16% of the patients had received a preoperative histologic diagnosis. All patients with node metastasis had cTNM stage II or higher thymic malignancy. The freedom from recurrence rate of the pN1 or pN2 was significantly worse than that of the pN0 (5-year rate 38.5% versus 87.9%, p < 0.001).
Based on the previously mentioned information, we proposed a revised recommendation for LND in thymic malignancies. For N1, peri-thymic, prevascular, and supradiaphragmatic lymph nodes should be included as a routine en-bloc dissection. Lower cervical lymph nodes and paraaortic nodes should be either sampled or dissected, especially in c-stage II or higher. For right paratracheal N2 nodes, sampling for c-stage I, dissection for c-stage II or higher is recommended. For other N2 nodes, sampling is recommended in c-stage II or higher, or in thymic carcinoma.
Almost all of the anterior regional nodes can be dissected during total thymectomy. During MIS, the paratracheal node can be dissected via right side approach. The paraaortic and subaortic nodes can be dissected via left side approach. The cervical lymph node can be dissected by adding cervical approach if it is necessary. However, the routine dissection of the cervical node is not recommended. A bilateral approach may be recommended, especially if the left side is chosen for the resection of the primary tumor.
In summary, LND is recommended in locally advanced thymoma and thymic carcinoma. As the frequent metastatic stations are peri-thymic and right paratracheal lymph nodes, LND of these stations are necessary. LND may be possible during minimally invasive surgery, and the bilateral approach may be recommended in tumors with higher than T2, especially in left-sided tumors.