Mitsuhiro Tsuboi

Frequent silencing of the candidate tumor suppressor TRIM58 by promoter methylation in early-stage lung adenocarcinoma

In this study, we aimed to identify novel drivers that would be epigenetically altered through aberrant methylation in early-stage lung adenocarcinoma (LADC), regardless of the presence or absence of tobacco smoking-induced epigenetic field defects. Through genome-wide screening for aberrantly methylated CpG islands (CGIs) in 12 clinically uniform, stage-I LADC cases affecting six non-smokers and six smokers, we identified candidate tumor-suppressor genes (TSGs) inactivated by hypermethylation. Through systematic expression analyses of those candidates in panels of additional tumor samples and cell lines treated or not treated with 5-aza-deoxycitidine followed by validation analyses of cancer-specific silencing by CGI hypermethylation using a public database, we identified TRIM58 as the most prominent candidate for TSG. TRIM58 was robustly silenced by hypermethylation even in early-stage primary LADC, and the restoration of TRIM58 expression in LADC cell lines inhibited cell growth in vitro and in vivo in anchorage-dependent and -independent manners. Our findings suggest that aberrant inactivation of TRIM58 consequent to CGI hypermethylation might stimulate the early carcinogenesis of LADC regardless of smoking status; furthermore, TRIM58 methylation might be a possible early diagnostic and epigenetic therapeutic target in LADC.

Demonstration of the skip metastasis pathway for N2 non-small cell lung cancer.

FIGURE 1. Intraoperative endoscopic findings. A, A 2-mL dose of indocyanin needle. B, White-light mode showing injected indocyanine green. C, Indocyan From the Department of Thoracic, Endocrine Surgery and Oncology, Institute of Health Bioscience, The University of Tokushima Graduate School, Tokushima, Japan. Disclosures: Authors have nothing to disclose with regard to commercial support. Received for publication Aug 14, 2013; revisions received Dec 8, 2013; accepted for publication Dec 13, 2013; available ahead of print Feb 8, 2014. Address for reprints: Hiromitsu Takizawa, MD, Department of Thoracic, Endocrine Surgery and Oncology, Institute of Health Bioscience, The University of Tokushima Graduate School, 3-18-15, Kuramotocho, Tokushima 770-8503, Japan (E-mail: h-takizawa@mbf.ocn.ne.jp). J Thorac Cardiovasc Surg 2014;147:e50-2 0022-5223/

A feasibility study of postoperative adjuvant chemotherapy with fluoropyrimidine S‐1 in patients with stage II‐IIIA non‐small cell lung cancer

36.00 Copyright 2014 by The American Association for Thoracic Surgery http://dx.doi.org/10.1016/j.jtcvs.2013.12.058

Mediastinal Parathyroidectomy Using a Cervical Approach Under a Pneumomediastinum

BACKGROUND Adjuvant chemotherapy with uracil tegafur (UFT) improved survival among patients with completely resected stage I lung adenocarcinoma. S-1, an oral dihydropyrimidine dehydrogenase (DPD)-inhibitory 5-fluorouracil, is a more potent DPD inhibitor than UFT;therefore, we hypothesized that postoperative adjuvant chemotherapy with S-1 would be effective for advanced non-small cell lung cancer (NSCLC). We conducted a feasibility study of S-1 as postoperative adjuvant chemotherapy in patients with curatively resected pathological stage bold I back 10 bold I and bold I back 10 bold I back 20 bold I A NSCLC. METHODS Adjuvant chemotherapy consisted of 9 courses (4-week administration, 2-week withdrawal) of S-1 at 80-120 mg/body per day. Twenty-four patients with completely resected NSCLC were enrolled in this study from November 2007 through December 2010. The primary endpoint was the rate of completion of the scheduled adjuvant chemotherapy. The secondary endpoints were safety, overall survival, and relapse-free survival. RESULTS Five patients were censored because of disease recurrence. The planned 9 courses of S-1 were administered to completion in 8 patients. Twelve patients completed more than 70% of the planned courses. Grade 3 adverse reactions, such as elevated total bilirubin (4.2%) and pneumonitis (4.2%), were observed, but there were no Grade 4 adverse reactions. Patients who completed more than 70% of the 9 courses demonstrated better overall survival than those who completed less than 70%. CONCLUSION Postoperative administration of S-1 may be possible with few severe adverse events as adjuvant chemotherapy for patients with curatively resected pathological stage bold I back 10 bold I -bold I back 10 bold I back 20 bold I A NSCLC. J. Med. Invest. 65:90-95, February, 2018.

Autofluorescence for the diagnosis of visceral pleural invasion in non-small-cell lung cancer

Video-assisted thoracoscopic surgery (VATS) and robotic surgery are minimally invasive surgeries for mediastinal parathyroid adenomas. However, a transthoracic approach is often difficult in the cervicothoracic transition area because of the limited visual field. We report a novel minimally invasive surgery for an ectopic parathyroid adenoma in the middle mediastinum using a cervical approach under a pneumomediastinum.

Frequent silencing of RASSF1A by DNA methylation in thymic neuroendocrine tumours

OBJECTIVES This study was conducted to evaluate the accuracy of autofluorescence as a mode of diagnosis for visceral pleural invasion of non-small-cell lung cancer compared with white-light by means of clinical questions to several thoracic surgeons. METHODS Eight independent thoracic surgeons evaluated visceral pleural invasion in 25 cases of non-small-cell lung cancer attached to the visceral pleura on lung windows of preoperative computed tomography images. At the first study meeting to evaluate the accuracy of visceral pleural invasion diagnosis using conventional white-light images, the surgeons diagnosed visceral pleural invasion based on information in preoperative computed tomography images, histological types and videos recorded with white-light mode using a thoracoscope. At the second study meeting to evaluate the accuracy of visceral pleural invasion diagnosis using autofluorescence, the same surgeons diagnosed visceral pleural invasion based on information in 2 videos recorded in white-light mode and in autofluorescence mode using the thoracoscope. RESULTS The overall average sensitivity, specificity and accuracy of visceral pleural invasion diagnosis by white-light versus autofluorescence mode were 64.6% vs 83.3%, 53.9% vs 73.7% and 56.5% vs 76.0%, respectively. CONCLUSIONS The sensitivity, specificity and accuracy of visceral pleural invasion diagnosis was improved through the additional use of the autofluorescence mode compared with the white-light mode alone.

Surgical treatment of locally advanced papillary thyroid carcinoma after response to lenvatinib: A case report

OBJECTIVES Aberrant methylation of promoter CpG islands (CGIs) of tumour suppressor genes is a common epigenetic mechanism underlying cancer pathogenesis. The methylation patterns of thymic tumours have not been studied in detail since such tumours are rare. Herein, we sought to identify genes that could serve as epigenetic targets for thymic neuroendocrine tumour (NET) therapy. MATERIALS AND METHODS Genome-wide screening for aberrantly methylated CGIs was performed in three NET samples, seven thymic carcinoma (TC) samples, and eight type-B3 thymoma samples. The methylation status of thymic epithelial tumours (TETs) samples was validated by pyrosequencing in a larger cohort. The expression status was analysed by quantitative polymerase chain reaction (PCR) and immunohistochemistry. RESULTS We identified a CGI on a novel gene, RASSF1A, which was strongly hypermethylated in NET, but not in thymic carcinoma or B3 thymoma. RASSF1A was identified as a candidate gene statistically and bibliographically, as it showed frequent CGI hypermethylation in NET by genome-wide screening. Pyrosequencing confirmed significant hypermethylation of a RASSF1A CGI in NET. Low-grade NET tissue was more strongly methylated than high-grade NET. Quantitative PCR and immunohistochemical staining revealed that RASSF1A mRNA and protein expression levels were negatively regulated by DNA methylation. CONCLUSIONS RASSF1A is a tumour suppressor gene epigenetically dysregulated in NET. Aberrant methylation of RASSF1A has been reported in various tumours, but this is the first report of RASSF1A hypermethylation in TETs. RASSF1A may represent an epigenetic therapeutic target in thymic NET.

P1.05-14 Autofluorescence Mode of Thoracoscope Improves Visceral Pleural Invasion Diagnosis in Non-Small Cell Lung Cancer

Highlights • There is no established neoadjuvant therapy for advanced DTC.• We report the case of a locally advanced DTC that was invaded the trachea, the muscular layer of the esophagus, and the right internal jugular vein.• After response to lenvatinib, the tumor was resected.