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Kazuya Kondo
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MA20 - Thymic Tumors: From Molecular to Clinical Results and New Challenges in Other Rare Thoracic Tumors (ID 149)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Thymoma/Other Thoracic Malignancies
- Presentations: 13
- Now Available
- Moderators:Kazuya Kondo, Edith Michelle Marom
- Coordinates: 9/10/2019, 11:30 - 13:00, San Francisco (2009)
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Intro (ID 4090)
11:30 - 13:00 | Presenting Author(s): Edith Michelle Marom
- Abstract
Abstract not provided
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MA20.01 - Global Quantitative Mass Spectrometry Reveals Potential Novel Actionable Targets in Thymic Epithelial Tumors (TET) (Now Available) (ID 2294)
11:30 - 13:00 | Presenting Author(s): Udayan Guha | Author(s): Xu Zhang, Yue Qi, Fatos Kirkali, Ting Huang, Tapan Maity, Khoa Dang Nguyen, David S Schrump, Olga Vitek, Arun Rajan
- Abstract
- Presentation
Background
Thymomas (T) and thymic carcinomas (TC), that constitute the thymic epithelial tumors (TETs) are rare epithelial tumors. There are limited treatment options for patients with advanced TETs. The complexity and rarity of the disease hampers the development of effective therapeutics. Next-generation sequencing (NGS) analyses of TETs by the TCGA have confirmed the very low mutational burden and few actionable targets for therapy. Thus, novel strategies are needed for better elucidating the molecular pathways involved in tumor pathogenesis and identification of novel drug targets. Here, we have used quantitative mass spectrometry (MS) to characterize the global proteome and phosphoproteome of TETs with aim of identifying potential actionable drivers in thymomas and thymic carcinomas.
Method
Three-state SILAC quantitative mass spectrometry was used to quantify the global proteomes and phosphoproteomes of two thymoma (IU-TAB1 and T1682) and three thymic carcinoma cell lines (MP57, T1889 and Ty82). 10-plex TMT quantitative proteomics was used to quantify the global proteomes and phosphoproteomes of 54 TET tumors. All tumor tissues were pooled together to make the reference channel and labeled with TMT10-131. Basic RPLC followed by TiO2 enrichment and tandem MS were performed in a Q ExactiveTM HF mass spectrometer. MS data was processed using MaxQuant and Perseus. Protein quantification, normalization and statistical testing for the TMT experiments was done using free R package MSstatsTMT.
Result
We identified 4756 proteins and 5690 phosphosites from TET cell lines. Hierarchical clustering of SILAC ratios of quantitation demonstrated that T1682 and MP57 were more similar to each other than T1889 and Ty82. Several metabolic enzymes (LDHB, GSTP1, and AKR1B1) had higher expression in TC lines, while mitochondrial glutamate carrier SLC25A22 had greater abundance in thymoma lines. Ingenuity pathway analysis revealed that the top enriched canonical pathways associated with the significantly changed proteins in TET included remodeling of epithelial adherens junction, mitochondria dysfunction, and oxidative phosphorylation. RAS signaling pathway was enriched among the significantly changed phosphosites in the thymic MP57 and the B1 thymoma T1682 cells. We further analyzed the proteome and phosphoproteome of 54 TET tumor samples from 28 patients (23 thymoma and 5 thymic carcinoma) undergoing surgery or biopsy using TMT mass spectrometry. In total, 8320 proteins and 17716 phosphosites were identified. Hierarchical clustering of the TMT ratios to the pool for both proteins and phosphosites demonstrated that thymomas and thymic carcinomas clustered separately. Different locations of tumors from the same patient were grouped together. Only a few sites from the thymoma patients clustered in the thymic carcinoma group. GTF2I had higher abundance in thymomas compared to the TCs. MCM complex proteins and solute carrier family proteins had lower abundance and several collagens had higher abundance in TC patients. Several kinases, including PDGFRB, RIOK1, TNIK, and MAP4K4, and the metabolic enzyme glutathione S-transferase (GSTP1) had higher expression in TC patients. Further bioinformatics analysis and validation experiments are currently underway. Sensitivity data to inhibitors of metabolic enzymes and target kinases will be presented.
Conclusion
Global quantitative proteome and phosphoproteome analyses revealed potential novel kinases and metabolic enzymes for targeted therapy of TETs.
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MA20.02 - GAD1 Expression and Its Methylation Become Indicators of Malignant Behavior in Thymic Epithelial Tumor (Now Available) (ID 2370)
11:30 - 13:00 | Presenting Author(s): Shiho Soejima | Author(s): Kazuya Kondo, Mitsuhiro Tsuboi, Reina Kishibuchi, Kyoka Muguruma, Bilguun Tegshee, Koichiro Kajiura, Yukikiyo Kawakami, Naoya Kawakita, Mitsuteru Yoshida, Hiromitsu Takizawa, Akira Tangoku, Nuliamina Wusiman
- Abstract
- Presentation
Background
Genome-wide screening for aberrantly methylated CpG islands was performed in 7 thymic carcinoma (TC) samples and 8 type-B3 thymoma samples using HumanMethylation450 K BeadChip (Illumina, Santa Clara, CA, USA) analysis. We identified 93 genes as commonly hypermethylated in TC comparing to type-B3 thymoma. GAD1 （glutamic acid decarboxylase 1） was one of the most significant hypermethylated genes in TC. GAD1 catalyzes the production ofγ-aminobutyric acid (GABA). Some recent reports showed that GAD1 expression is significantly increased in neoplastic tissues. However, the underlying mechanism of elevated GAD1 remains elusive. In this study, we examine mRNA and protein expressions and DNA methylation of GAD1 in thymic epithelial tumors (TETs).
Method
In total, 95 thymic tumor samples (A; 9, AB; 11, B1; 19, B2; 21, B3; 14, carcinoma; 21) and 22 paired normal tissues were obtained from patients with histologically proven TET, who underwent surgery at the Tokushima University Hospital (Tokushima, Japan) between 1990 and 2016. The methylation status of thymic epithelial tumor samples was validated by pyrosequencing. The expression status was analyzed by quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC).
Result
The previous study (Oncogene 2015, 1–14) showed that the key locus responsible for GAD1 reactivation was mapped to DNA methylation-sensitive CTCF-binding site (CTCF-BS3) within the third intron of GAD1. We targeted this region for pyrosequencing, which confirmed that DNA methylation of GAD1 in TC was significantly higher than in thymoma (32.8% versus 4.0%, P<0.001). It revealed a high degree of both sensitivity and specificity for discriminating TCs and thymomas (AUC=0.936). There was no significant difference in the methylation rate between thymoma and normal thymus (P = 0.917); however, the DNA methylation rate in TC was higher than in normal thymus (P=0.015). qPCR revealed that GAD1 mRNA expression levels in TC were higher than in thymoma (qPCR; 2.03 vs 0.38, P < 0.001). IHC showed statically different GAD1 expression between TC and thymoma (93.75% vs 28.98%, P < 0.001). There was a slight positive correlation between the mRNA expression levels and methylation levels (Spearman’s rank correlation coefficient, ρ = 0.427); however, no differences of DNA methylation and expression of GAD1 was observed among subtype of thymoma according to WHO histologic classification.
Conclusion
TC had frequent DNA methylation of CTCF-binding site 3 in GAD1, and high levels of mRNA and protein of GAD1. GAD1 may resent an epigenetic therapeutic target in TC.
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MA20.03 - DNA Methylation of MT1A and NPTX2 Genes Predict Malignant Behavior of Thymic Epithelial Tumors (Now Available) (ID 3031)
11:30 - 13:00 | Presenting Author(s): Kyoka Muguruma | Author(s): Kazuya Kondo, Reina Kishibuchi, Mitsuhiro Tsuboi, Shiho Soejima, Bilguun Tegshee, Koichiro Kajiura, Yukikiyo Kawakami, Naoya Kawakita, Mitsuteru Yoshida, Hiromitsu Takizawa, Akira Tangoku
- Abstract
- Presentation
Background
Our previous studies showed that DNA methylation of cancer-related genes, such as DAP-K, p-16, MGMT, HPP1 was higher in thymic carcinoma (TC) than in thymoma (Lung Cancer 64:155-, 2009, 83:279-,2013). Genome-wide screening for aberrantly methylated CpG islands was performed in 7 TC samples and 8 type-B3 thymoma samples using HumanMethylation 450 K BeadChip (Illumina, Santa Clara, CA, USA) analysis. We identified 93 genes as commonly hypermethylated in TC comparing to B3 thymoma.We chose 2 candidate cancer-related genes; MT1A and NPTX2. MT1A which is an isozyme of metallothioneins is related to metabolism of trace elements, such as zinc, copper. DNA methylation of MT1A was higher in malignant melanoma than in normal melanocytes. NPTX2 has studied as synapse-related proteins. DNA methylation of NPTX2 was higher in some cancers than in normal tissues.
Method
In total, 48 thymic tumor samples (thymoma;31, carcinoma; 17) and 22 paired normal tissues were obtained from patients with histologically proven thymic epithelial tumor (TET), who underwent surgery at Tokushima University Hospital (Tokushima, Japan) between 1990 and 2016. The methylation status of TET samples was validated by pyrosequencing. The expression of mRNA in MT1A and NPTX2 genes was validated by RT-PCR (SYBR® Green method).
Result
DNA methylation of MT1A gene was significantly higher in TC compared to thymoma (26.4% versus 9.5%, P<0.01). It revealed high degrees of sensitivity and specificity for discriminating TCs and thymomas (AUC=0.903). Although DNA methylation was significantly higher in TC than in normal thymus, there was no significant difference between DNA methylation of thymoma and normal thymus. No differences of MT1A DNA methylation was observed among subtype of thymoma according to WHO histologic classification. In MT1A gene, there was no correlation has observed between DNA methylation and mRNA expression.
On the other hand, NPTX2 gene was also significantly higher in TC compared to thymoma (38.0% vs 17.5%, P<0.01). It revealed high degrees of sensitivity and specificity for discriminating TCs and thymomas (AUC=0.765). Although DNA methylation was significantly higher in TC than in normal thymus, there was no significant difference between DNA methylation of thymoma and normal thymus. No differences of NPTX2 DNA methylation was observed among subtype of thymoma according to WHO histologic classification. There was no correlation has observed between DNA methylation and mRNA expression in all TETs, there was a reverse correlation in thymic carcinomas. The mean value of the frequency of the DNA methylation of was MT1A and NPTX2 divided into higher and lower level groups. A significant difference was observed in the relapse-free survival between the higher and lower level groups (p=0.015, p=0.042).
Conclusion
DNA methylation of MT1A and NPTX2 was significantly higher in TC compared to thymoma and normal thymus.
Epigenetic alteration may be related to progression and malignancy in TET.
In NPTX2 gene, there was a reverse correlation between DNA methylation and mRNA expression in thymic carcinomas. It may act as tumor suppressor gene.
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MA20.04 - Discussant - MA20.01, MA20.02, MA20.03 (Now Available) (ID 3801)
11:30 - 13:00 | Presenting Author(s): Nicolas Girard
- Abstract
- Presentation
Abstract not provided
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MA20.05 - Follow-Up Update of 2 Phase II Studies of Pembrolizumab in Thymic Carcinoma (Now Available) (ID 1120)
11:30 - 13:00 | Presenting Author(s): Guiseppe Giaccone | Author(s): Jinhyun Cho, Chul Kim, Myung-Ju Ahn
- Abstract
- Presentation
Background
Two phase II studies of pembrolizumab 200 mg every 3 weeks in advanced thymic carcinoma have recently been published (Giaccone et al. Lancet Oncol. 2018, study #1; Cho et al. JCO 2018, study #2). Both studies reported a response rate in about 20% of patients and a rate of autoimmune disorders that is higher than in other tumor types.
Method
This report provides a follow-up update of these 2 studies, with particular emphasis on duration of response, and occurrence of autoimmune disorders. Both studies included patients with thymic carcinoma who had progressed after at least one line of chemotherapy.
Result
In study #1 a total of 40 patients with advanced thymic carcinoma were treated, with a median follow up of 40.6 months. The response rate did not change (22.5%) compared to the original publication, however one patient who had developed myositis, myocarditis and myasthenia gravis (MG), continues to be in nearly complete response after only two cycles of pembrolizumab, 36 months from initiation of treatment. One patient who had developed myositis and hepatitis with unclear signs of MG developed overt MG symptoms several months after the interruption of therapy. No other new autoimmune disorders were observed (6/40 = 15%). Five patients completed 2 years of treatment according to protocol and 4 of them elected to continue treatment. Three patients who had been off therapy were rechallenged with pembrolizumab upon progression (one responded). Median duration of response was 38 months (from 22.4 in initial report), median PFS was 4.2 months (identical) and median survival was 25.8 months (24.9 in the initial report).
At completion of this study, an amendment was introduced to add epacadostat 10 mg BID to pembrolizumab in the same patient population. Four patients were treated before the study was closed after the results of a randomized trial of the combination in melanoma failed to meet its primary endpoint. No patient responded (2 stable and 2 progressions). One patient developed grade 2 myocarditis.
In study #2 a total of 26 patients with advanced thymic carcinoma were included, with a median follow up of 33.4 months. The response rate (19.2%) did not change, and no other autoimmune disorder appeared since the initial publication (5/26 = 19%). Median duration of response (9.7 months), median PFS (6.1 months) and median survival (14.5 months) did not change compared to the initial publication. No additional autoimmune disorders were documented compared to the original publication. A total of 5 patients received 2 years of pembrolizumab according to protocol; no patient continued beyond 2 years or was retreated upon progression with pembrolizumab.
Conclusion
These two studies confirm definite activity of pembrolizumab in advanced thymic carcinoma. Recently pembrolizumab was included in the NCCN guidelines for thymic carcinoma. No additional autoimmune disorders were noted after discontinuation of pembrolizumab. There are significant differences in duration of response and overall survival in the 2 studies and potential factors are being investigated. In study #1 pembrolizumab was continued beyond 2 years in several patients and rechallenge was an available option.
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MA20.06 - Neutrophil to Lymphocyte Ratio Is an Independent Prognostic Predictor in Thymoma (Now Available) (ID 1637)
11:30 - 13:00 | Presenting Author(s): Paulo De Sousa | Author(s): Filippo Tommaso Gallina, Alessandro Paolo Tamburrini, Maria Nizami, Chukwuemeka Igwe, Khalid Amer, Eric Lim, Vincenzo Ambrogi
- Abstract
- Presentation
Background
Thymoma is the most common primary neoplasm of the anterior mediastinum in adults and conventional prognostic factors include Masaoka Stage, WHO histology and completeness of resection. Little is known of preoperative peripheral neutrophil-to-lymphocyte ratio (NLR) as an independent additional discriminator of prognosis.
Method
We performed an international multicentre retrospective cohort study (UK Health Research Reference 19/HRA/0440 and EU internal approval reference xxxxxx). We included patients who underwent complete resection for thymoma and data was acquired through patient medical records with follow up data obtained through national database and hospital records. NLR calculated on pre-operation bloods results.
Result
From July 1987 to December 2017, 433 patients underwent surgery for thymoma. The majority were male 228(53%) with a mean age (SD) of 55(15) years. The surgical approach was sternotomy in 335 patients (77%), thoracotomy in 23(5%) and VATS in 75(17%). The WHO classification was type A 63(15%), AB 126(29%), B1 98(23%), B2 55(13%) and B3 86(20%) patients. The Masaoka-Koga stage was I in 135(33%) II in 194(47%), III in 54 (13%) and IV in 31(7%) patients.
Median (IQR) follow-up time was 86 (30 to 152) months with a 5 and 10-year survival of 88% and 79% respectively. The median NLR was 2.1 (1.5 to 3.1), when split into three groups (NLR < 1.4, NLR between 1.4 and 2.3 and NLR > 2.3), higher NLR was associated with poorer survival (log rank P<0.001) that persisted on Cox regression after adjustment for WHO grade and Masaoka stage with a HR of 1.69 (95% CI 1.20 to 2.39; P=0.002).
Conclusion
Pre-operative NLR is a simple, low cost biomarker that can stratify risk of death independent to WHO grade and Masaoka stage in patients undergoing surgery for thymoma.
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MA20.07 - Thymomectomy and Total Thymectomy or Simple Thymomectomy for Early Stage Thymoma Without Myasthenia Gravis: An ESTS Thymic Working Group Study (Now Available) (ID 1683)
11:30 - 13:00 | Presenting Author(s): Francesco Guerrera | Author(s): Claudia Filippini, luca Voltolini, Francesco Londero, Pierre-Emmanuel Falcoz, Giorgio Lo Iacono, Charalambos Zisis, Paolo Mendogni, Laureano Molins, Nicola Martucci, Gaetano Rocco, Alper Toker, Matthias Esch, Clemens Aigner, Ivan Bravio, Sara Mantovani, Bernhard Moser, Nuria M Novoa, Bram Verdonck, Bert Du Pont, Miguel Congregado, Luca Ampollini, Pascal Alexandre Thomas, Enrico Ruffini
- Abstract
- Presentation
Background
Resection of thymic tumors has traditionally included removal of the tumor and the thymus gland (thymothymomectomy). Nevertheless, in recent years, some authors questioned the need to remove the thymus gland in non-MG thymomas, suggesting that resection of the tumor (simple-thymomectomy) is enough from an oncological point of view in Stage I (TNM stage classification) thymoma patients. The aim of our study was to compare short- and long-term outcome of thymothymomectomy vs. simple-thymomectomy using European Society of Thoracic Surgeons (ESTS) Thymic Database.
Method
We investigated 1131 patients with thymic epithelial tumors included in the ESTS-Thymic Database. Three-hundred twenty-four clinical stage I (cT1N0M0, according to the 8th edition of the UICC/AJCC TNM stage classification) without Myasthenia Gravis (non-MG) thymoma cases were evaluated from 23 contributing centers (2000-2017), of which 300 (93%) thymothymomectomy and 24 (7%) simple-thymomectomy. Surgical upstaging was evaluated. In pathological stage I, we compared the completeness of resection, the rate of complications, the 30-day mortality, the overall survival and the disease-free survival (DFS).
Result
Overall, we observed an upstaging to stage III in 10 (3%) patients. We did not observe any significant difference between the two techniques in terms of the completeness of resection, the rate of complications and the 30-day mortality. The 5-year overall survival rate was 94% in the thymothymomectomy group and 56% in the simple-thymomectomy group (Figure 1 - P= 0.0004). The 5-year DFS was 95% in the thymothymomectomy group and 82% in the simple-thymomectomy group (Figure 1 -P= 0.013).
Conclusion
Patients affected by stage I TNM non-MG thymoma submitted to thymothymomectomy presented a significantly better DFS and overall survival than those submitted to simple-thymomectomy. Thymothymomectomy should be considered the procedure of choice in Stage I TNM non-MG thymomas, also considering the not negligible rate of pathological upstaging.
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MA20.08 - Discussant - MA20.05, MA20.06, MA20.07 (Now Available) (ID 3802)
11:30 - 13:00 | Presenting Author(s): Meinoshin Okumura
- Abstract
- Presentation
Abstract not provided
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MA20.09 - Breast Implant Associated Anaplastic Large Cell Lymphoma: Outcomes of a Newly-Recognized Malignancy of the Thoracic Wall (Now Available) (ID 2746)
11:30 - 13:00 | Presenting Author(s): Mark Warren Clemens | Author(s): Roberto N. Miranda
- Abstract
- Presentation
Background
In 2016, the World Health Organization provisionally classified breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) as a novel lymphoma and the National Comprehensive Cancer Network (NCCN) established evidence-based consensus guidelines for the diagnosis and surgical management of the disease. BIA-ALCL progresses locally as a solid tumor, invading the chest wall and mediastinum and leading to respiratory compromise in advanced cases. Local disease is treated surgically while aggressive disease involving regional lymph nodes and metastasis are currently managed with systemic chemotherapy, most commonly CHOP regimens (cyclophosphamide, vincristine, doxorubicin and prednisone). The goal of this study is to evaluate the efficacy of different therapies in the treatment of BIA-ALCL with chest wall invasion.
Method
A prospective study of all institutional cases from 2013 to 2018 was performed for patients with advanced disease (Stage IIA-III) locally invasive into the chest wall. Pathologic findings, treatments, and outcomes were reviewed.
Result
Eighteen consecutive patients were identified with BIA-ALCL Stage IIA-III. The median and mean follow-up times were 42 and 27 months, respectively (range, 6 to 226 months). Patients who underwent a complete en bloc resection had better OS (P = .022) and EFS (P = .014) than did patients who received partial resection, systemic chemotherapy, or radiation therapy. Perioperative complications included one pneumothorax. Two disease recurrences (7.8%) were noted at an average of 5 months from surgery. All patients eventually achieved complete remission (100%). The median overall survival (OS) time after diagnosis was 13 years, and the OS rate was 94% and 90% at 3 and 5 years, respectively. Patients presenting with chest wall invasion demonstrated significantly longer time from diagnosis to definitive surgery (21 versus 8 months, P = 0.039). Partial tumor resection resulted in disease hyperprogression in two cases.
Conclusion
BIA-ALCL with chest wall invasion may be a consequence of a delay in diagnosis or treatment. Complete en bloc surgical excision is essential for curative treatment of BIA-ALCL. Patients who receive textured surface breast implants need to be advised of the risk of developing BIA-ALCL, as well as the common presenting symptoms, such as a mass or delayed onset (>1 year) of effusion. When treated appropriately and in a timely fashion, BIA-ALCL has an excellent prognosis. Future research is warranted to determine modifiable risk factors and stratification of at-risk populations.
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MA20.10 - Long-Term Prognostic Factors After Minimally Invasive Esophagectomy (MIE) for Esophageal Cancer (Now Available) (ID 2956)
11:30 - 13:00 | Presenting Author(s): Yu-Han Huang | Author(s): Pei-Wen Yang, Ke-Cheng Chen, Pei-Ming Huang, Jang-Ming Lee
- Abstract
- Presentation
Background
MIE has been demonstrated to associate a better peri-operative outcome to treat esophageal cancer as compared to that done by open surgery. However, the long-term clinical impact of MIE and its prognostic factors still requires further clarification.
Method
In current study, we evaluated the survival results and the factors influencing the prognosis of patients with esophageal cancer who received total minimally invasive esophagectomy using thoracoscopic and laparoscopic esophagectomy and esophageal reconstruction.
Result
A total of 483 patients were included in the study with 179 and 304 receiving Ivor Lewis and McKeown MIE respectively. Neoadjuvant chemoradiation was administered to 379 (78 %) of the patients. The overall and disease progression-free survival curves of all the patients were constructed with five-year survival rates of 48.3% and 40.3% respectively. Multivariate analysis revealed that pathological tumor stage was a significant factor for prognosis after surgery both in the patients treated with and without neoadjuvant CCRT (P< 0.05). Of the patients with patholoigical stage I or ypStage I esopahgeal cancer after CCRT, overall survival was significantly improved with the increased number of dissected lymph nodes (P=0.022).
Conclusion
The survival of patients with esophageal cancer undergoing MIE was influenced by their tumor staging, irrespective the use of neoadjuvant CCRT. Of these patients with stage I and ypStage I disease, improved survival can be facilitated with increased number of dissected lymph nodes during MIE.
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MA20.11 - Surgical Treatment for Metastatic Lung Tumors from Sarcomas of Soft Tissue and Bone (Now Available) (ID 2391)
11:30 - 13:00 | Presenting Author(s): Hiromasa Yamamoto | Author(s): Kei Namba, Haruchika Yamamoto, Tomohiro Toji, Junichi Soh, Kazuhiko Shien, Ken Suzawa, Takeshi Kurosaki, Shinji Ohtani, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Katsuhito Takahashi, Toshiyuki Kunisada, Takahiro Oto, Shinichi Toyooka
- Abstract
- Presentation
Background
Sarcoma is one of the refractory malignant tumors and often develops pulmonary metastasis. The purpose of this study was to evaluate the impact of surgical resection for metastatic lung tumors from sarcomas of soft tissue and bone retrospectively.
Method
Between 2006 and 2015, we had a total of 158 patients with metastatic lung tumors from soft-tissue and bone sarcomas who underwent pulmonary metastasectomy for the first time. In total, 265 surgical procedures were performed in Okayama University Hospital in this period. We analyzed the age, sex, site of primary lesion, histology, extent of primary tumors at the initial diagnosis, extent of pulmonary metastases at the first pulmonary metastasectomy, presence or absence of local recurrence and/or extrapulmonary metastases with or before pulmonary metastases, operative procedures, size of the largest lesions resected, maximum number of the resected tumors, postoperative complications, and the prognosis at the end of 2018.
Result
Average number of resected tumors per intervention was 4.0 (range 1-19). These sarcoma patients consisted of 36 males and 122 females, and their average age was 53.7 years (range 14-88 years). Leiomyosarcoma was the most common histological subtype (n = 92, 58.2%) and uterus was the most common location of the primary disease (n = 71, 44.9%). Operative procedures were composed of 202 partial resections, 35 segmentectomies with or without partial resections, 26 lobectomies with or without partial resections, 1 pneumonectomy, and 1 basal segmental auto-transplantation after pneumonectomy. The postoperative complications were limited, showing that pulmonary metastasectomies for sarcomas are acceptable. Overall 3-year survival after the first pulmonary metastasectomy was 50.6%. In univariate analysis, the survival was significantly better for the group with disease-free interval of more than 2 years from the date of the initial treatment for primary disease until the date of diagnosis for the first pulmonary metastasis, the one who underwent pulmonary resections three times or more, and the one in which size of the largest resected lesion was 20 mm or less. Those factors significant in univariate analysis were all significant in multivariate analysis.
Conclusion
Surgical resections for metastatic lung tumors from sarcomas of soft tissue and bone were performed without major complications, indicating the acceptable feasibility. If disease-free interval is more than 2 years and the size of the largest resected lesion is less than 20 mm, patients may maximally benefit from pulmonary resection. In order to increase the opportunities of pulmonary resections, we should preserve the lung parenchyma as much as possible when performing pulmonary metatstasectomy, resulting in the better survival.
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MA20.12 - Discussant - MA20.09, MA20.10, MA20.11 (Now Available) (ID 3803)
11:30 - 13:00 | Presenting Author(s): Scott Swanson
- Abstract
- Presentation
Abstract not provided
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Author of
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MA20 - Thymic Tumors: From Molecular to Clinical Results and New Challenges in Other Rare Thoracic Tumors (ID 149)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Thymoma/Other Thoracic Malignancies
- Presentations: 2
- Now Available
- Moderators:Kazuya Kondo, Edith Michelle Marom
- Coordinates: 9/10/2019, 11:30 - 13:00, San Francisco (2009)
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MA20.02 - GAD1 Expression and Its Methylation Become Indicators of Malignant Behavior in Thymic Epithelial Tumor (Now Available) (ID 2370)
11:30 - 13:00 | Author(s): Kazuya Kondo
- Abstract
- Presentation
Background
Genome-wide screening for aberrantly methylated CpG islands was performed in 7 thymic carcinoma (TC) samples and 8 type-B3 thymoma samples using HumanMethylation450 K BeadChip (Illumina, Santa Clara, CA, USA) analysis. We identified 93 genes as commonly hypermethylated in TC comparing to type-B3 thymoma. GAD1 （glutamic acid decarboxylase 1） was one of the most significant hypermethylated genes in TC. GAD1 catalyzes the production ofγ-aminobutyric acid (GABA). Some recent reports showed that GAD1 expression is significantly increased in neoplastic tissues. However, the underlying mechanism of elevated GAD1 remains elusive. In this study, we examine mRNA and protein expressions and DNA methylation of GAD1 in thymic epithelial tumors (TETs).
Method
In total, 95 thymic tumor samples (A; 9, AB; 11, B1; 19, B2; 21, B3; 14, carcinoma; 21) and 22 paired normal tissues were obtained from patients with histologically proven TET, who underwent surgery at the Tokushima University Hospital (Tokushima, Japan) between 1990 and 2016. The methylation status of thymic epithelial tumor samples was validated by pyrosequencing. The expression status was analyzed by quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC).
Result
The previous study (Oncogene 2015, 1–14) showed that the key locus responsible for GAD1 reactivation was mapped to DNA methylation-sensitive CTCF-binding site (CTCF-BS3) within the third intron of GAD1. We targeted this region for pyrosequencing, which confirmed that DNA methylation of GAD1 in TC was significantly higher than in thymoma (32.8% versus 4.0%, P<0.001). It revealed a high degree of both sensitivity and specificity for discriminating TCs and thymomas (AUC=0.936). There was no significant difference in the methylation rate between thymoma and normal thymus (P = 0.917); however, the DNA methylation rate in TC was higher than in normal thymus (P=0.015). qPCR revealed that GAD1 mRNA expression levels in TC were higher than in thymoma (qPCR; 2.03 vs 0.38, P < 0.001). IHC showed statically different GAD1 expression between TC and thymoma (93.75% vs 28.98%, P < 0.001). There was a slight positive correlation between the mRNA expression levels and methylation levels (Spearman’s rank correlation coefficient, ρ = 0.427); however, no differences of DNA methylation and expression of GAD1 was observed among subtype of thymoma according to WHO histologic classification.
Conclusion
TC had frequent DNA methylation of CTCF-binding site 3 in GAD1, and high levels of mRNA and protein of GAD1. GAD1 may resent an epigenetic therapeutic target in TC.
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MA20.03 - DNA Methylation of MT1A and NPTX2 Genes Predict Malignant Behavior of Thymic Epithelial Tumors (Now Available) (ID 3031)
11:30 - 13:00 | Author(s): Kazuya Kondo
- Abstract
- Presentation
Background
Our previous studies showed that DNA methylation of cancer-related genes, such as DAP-K, p-16, MGMT, HPP1 was higher in thymic carcinoma (TC) than in thymoma (Lung Cancer 64:155-, 2009, 83:279-,2013). Genome-wide screening for aberrantly methylated CpG islands was performed in 7 TC samples and 8 type-B3 thymoma samples using HumanMethylation 450 K BeadChip (Illumina, Santa Clara, CA, USA) analysis. We identified 93 genes as commonly hypermethylated in TC comparing to B3 thymoma.We chose 2 candidate cancer-related genes; MT1A and NPTX2. MT1A which is an isozyme of metallothioneins is related to metabolism of trace elements, such as zinc, copper. DNA methylation of MT1A was higher in malignant melanoma than in normal melanocytes. NPTX2 has studied as synapse-related proteins. DNA methylation of NPTX2 was higher in some cancers than in normal tissues.
Method
In total, 48 thymic tumor samples (thymoma;31, carcinoma; 17) and 22 paired normal tissues were obtained from patients with histologically proven thymic epithelial tumor (TET), who underwent surgery at Tokushima University Hospital (Tokushima, Japan) between 1990 and 2016. The methylation status of TET samples was validated by pyrosequencing. The expression of mRNA in MT1A and NPTX2 genes was validated by RT-PCR (SYBR® Green method).
Result
DNA methylation of MT1A gene was significantly higher in TC compared to thymoma (26.4% versus 9.5%, P<0.01). It revealed high degrees of sensitivity and specificity for discriminating TCs and thymomas (AUC=0.903). Although DNA methylation was significantly higher in TC than in normal thymus, there was no significant difference between DNA methylation of thymoma and normal thymus. No differences of MT1A DNA methylation was observed among subtype of thymoma according to WHO histologic classification. In MT1A gene, there was no correlation has observed between DNA methylation and mRNA expression.
On the other hand, NPTX2 gene was also significantly higher in TC compared to thymoma (38.0% vs 17.5%, P<0.01). It revealed high degrees of sensitivity and specificity for discriminating TCs and thymomas (AUC=0.765). Although DNA methylation was significantly higher in TC than in normal thymus, there was no significant difference between DNA methylation of thymoma and normal thymus. No differences of NPTX2 DNA methylation was observed among subtype of thymoma according to WHO histologic classification. There was no correlation has observed between DNA methylation and mRNA expression in all TETs, there was a reverse correlation in thymic carcinomas. The mean value of the frequency of the DNA methylation of was MT1A and NPTX2 divided into higher and lower level groups. A significant difference was observed in the relapse-free survival between the higher and lower level groups (p=0.015, p=0.042).
Conclusion
DNA methylation of MT1A and NPTX2 was significantly higher in TC compared to thymoma and normal thymus.
Epigenetic alteration may be related to progression and malignancy in TET.
In NPTX2 gene, there was a reverse correlation between DNA methylation and mRNA expression in thymic carcinomas. It may act as tumor suppressor gene.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-22 - Chromate Exposure Induces DNA Hypermethylation of the Mismatch Repair Gene MLH1 in Lung Cancer (Now Available) (ID 2156)
10:15 - 18:15 | Presenting Author(s): Kazuya Kondo
- Abstract
Background
Hexavalent chromium is recognized as a human carcinogen. To elucidate the role of chromate on carcinogenesis, we have investigated molecular features of LC from chromate workers (chromate LC). Chromate LC frequently had the microsatellite instability (MSI), and that the MSI was associated with repression of MLH1, which is one of the essential DNA mismatch repair (MMR) proteins. In the present study, we investigated methylation status of the promoter region of MLH1 determined quantitatively by bisulfite-pyrosequencing in the paired tumorous/ non-tumorous sample sets of chromate and non-chromate LCs. Moreover, we analyzed three DNA double-strand break (DSB) repair genes (MRE11, RAD50, and DNA-PKcs) as possible targets of MSI by fragment length polymorphism analysis.
Method
Thirty-two lung tumor samples were obtained from chromate workers with LC during surgery or at autopsy at 5 hospitals between August 1975 and October 1997. Thirty-one tumors were obtained from LC patients without chromate exposure during surgery at Tokushima University Hospital as a control group (non-chromate LC).
DNA was extracted and bisulfite conversion of DNA was conducted using the EpiTect Bisulfite Kit (QIAGEN). PCR primers and sequencing primer for quantification of methylation level in region -209 nucleotides (nt) to -181 nt from the transcription start site in the MLH1. Pyrosequencing of 5 CpG sites in MLH1 was performed with sequencing primers using a PyroMark 24 Pyrosequencing System, version 2.0.6 (QIAGEN). Regions encompassing mononucleotide repeated sequences of genes were amplified using nested-PCR procedure. Fragments were separated by automated capillary electrophoresis in an ABI Prism 3130/3130xl Genetic Analyzer (Applied Biosystems) and electropherograms were analyzed using the GeneMapper software (Applied Biosystems).
Result
The mean methylation level of tumorous tissue was 21.1±15.7% and was significantly higher than that of non-tumorous tissue, 10.9±9.4% (P = 0.004) in chromate LC. In non-chromate LC, there was no significant difference between tumorous and non-tumorous tissues: 3.9±5.1% in tumorous tissue versus 4.9±4.1% in non-tumorous tissue. The mean methylation level of tumorous tissues was significantly higher in chromate LC than in non-chromate LC (P < 0.001). The mean methylation level of non-tumorous tissues tended to be higher in the chromate LC than in non-chromate LC (P = 0.062). There was a significant positive correlation between the methylation level and chromate exposure period in tumorous tissue of chromate LC (r = 0.481, P = 0.017). The methylation level was significantly higher in LCs with reduced expression of MLH1 than in LCs with normal expression of MLH1(P = 0.019). The incidence of mutations at mononucleotide repeats was observed in 50.0% of chromate LC and 28.6% of non-chromate LC in MRE11, and 17.4% of chromate LC and 0.0% of non-chromate LC in RAD50, and in 53.8% of chromate LC and 46.2% of non-chromate LC in DNA-PKcs. The incidence of mutation of mononucleotide tended to be higher in chromate LC than in non-chromate LC in MRE11. In RAD50, the mutation was significantly higher frequency in chromate LC than in non-chromate LC.
Conclusion
These results suggest that chromate exposure might induce MLH1 hypermethylation in LC, which is possible cause of carcinogenesis.
