Retrospective Study of Selective Submandibular Neck Dissection versus Radical Neck Dissection for N0 or N1 Necks in Level I Patients with Oral Squamous Cell Carcinoma

Objective. To evaluate the efficacy of selective submandibular neck dissection (SMND) in patients with oral squamous cell carcinoma (OSCC) with or without nodal metastasis. Patients. From a total of 384 patients with untreated OSCC who underwent radical excision, we identified 229 with clinically N0 necks and 68 with clinically N1 necks in level I. Main Outcome Measures. The Kaplan-Meier 5-year regional control and 5-year disease specific survival (DSS) were compared for SMND, radical neck dissection (RND), and modified radical neck dissection (MRND). Results. In clinically node-negative necks, the regional control rates were 85.2% with SMND and 83.3% with MRND (P = 0.89), and 5-year DSS rates were 86.5% and 87.0%, respectively, (P = 0.94). In clinically N1 necks, the regional control rates were 81.3% with SMND and 83.0% with RND (P = 0.72), and the DSS rates were 81.3% and 80.0%, respectively, (P = 0.94). Type of neck dissection was not significantly associated with regional control or DSS on either univariate or multivariate analysis using Cox's proportional hazard model. Conclusions. SMND can be effectively applied in elective and therapeutic management to patients with OSCC that are clinically assessed as N0 or N1 to level I of the neck

Clinical Study Retrospective Study of Selective Submandibular Neck Dissection versus Radical Neck Dissection for N0 or N1 Necks in Level I Patients with Oral Squamous Cell Carcinoma

Objective. To evaluate the efficacy of selective submandibular neck dissection (SMND) in patients with oral squamous cell carcinoma (OSCC) with or without nodal metastasis. Patients. From a total of 384 patients with untreated OSCC who underwent radical excision, we identified 229 with clinically N0 necks and 68 with clinically N1 necks in level I. Main Outcome Measures. The Kaplan-Meier 5-year regional control and 5-year disease specific survival (DSS) were compared for SMND, radical neck dissection (RND), and modified radical neck dissection (MRND). Results. In clinically node-negative necks, the regional control rates were 85.2% with SMND and 83.3% with MRND (P = 0.89), and 5-year DSS rates were 86.5% and 87.0%, respectively, (P = 0.94). In clinically N1 necks, the regional control rates were 81.3% with SMND and 83.0% with RND (P = 0.72), and the DSS rates were 81.3% and 80.0%, respectively, (P = 0.94). Type of neck dissection was not significantly associated with regional control or DSS on either univariate or multivariate analysis using Cox's proportional hazard model. Conclusions. SMND can be effectively applied in elective and therapeutic management to patients with OSCC that are clinically assessed as N0 or N1 to level I of the neck

口腔癌におけるBrachyury発現と上皮間葉移行の関与 : 予後因子としての応用の可能性

要旨 緒言 材料と方法 考察 総括 謝辞 引用文献Made available in DSpace on 2012-06-07T07:14:09Z (GMT). No. of bitstreams: 1 dent554.pdf: 1878188 bytes, checksum: 005209acd04fbd4599095bb7e834bbe9 (MD5) Previous issue date: 2012-03-27歯学府_歯学癌浸潤・転移は治療を困難にする最も重要な因子である。転移には細胞生物学的にダイナミックな細胞特性の変化と多段階の過程を経ることが知られており、近年、その過程における上皮間葉移行（epithelial-mesenchymal transition:EMT）の関与が数多く報告されている。さらにT-box転写因子のひとつであるBrachyuryがEMTを誘導することが報告された。しかし、臨床検体を用いてBrachyury発現とEMTの関連を検討した報告は、これまでに口腔癌を含むすべての癌種において見られない。そこで本研究では、腺様嚢胞癌と扁平上皮癌の未治療生検組織を用いて、EMTおよびBrachyury発現と臨床的背景因子との関連、Brachyury発現とEMTの関連について検討した。 1．腺様嚢胞癌におけるBrachyury発現とEMTの関与 腺様嚢胞癌（AdCC）21例の未治療生検組織におけるBrachyury、E-cadherin、Vimentinの発現様式を免疫組織化学的に検索した。それぞれのタンパク質の陽性率はBrachyury:100％（21/21例）、E-cadherin:90.5％（19/21例）、Vimentin:90.5%（19/21例）と症例の分布に偏りがあったため、VimentinおよびBrachyury発現と臨床的背景因子との関連、Brachyury発現とEMTとの関連は検討できなかった。また、E-cadherin発現と臨床的背景因子との関連も認められなかった。患者の10年生存率および無病生存率についてKaplan-Meier法にて検討を行ったところ、Vimentin発現とは相関が認められなかったが、E-cadherin発現およびEMTと生存率に相関が認められた（p<0.001,p=0.001）。Brachyury発現には陰性症例がなく相関の検討が出来なかった。 2．扁平上皮癌におけるBrachyury発現とEMTの関与 扁平上皮癌（SCC）152例の未治療生検組織におけるBrachyury、E-cadherin、Vimentinの発現様式を免疫組織化学的に検索した。それぞれのタンパク質の陽性率はBrachyury:71.1％（108/152例）、E-cadherin:68.4％（104/152例）Vimentin:18.4%（28/152例）であった。臨床的背景因子のうちE-cadherin発現と関連を認めたものは、リンパ節転移、遠隔転移、腫瘍の分化度、腫瘍の浸潤様式（いずれもp<0.05）であり、Vimentin発現はリンパ節転移、遠隔転移、腫瘍の浸潤様式（いずれもp<0.05）と関連が認められた。Brachyury発現と関連を認めたものは、腫瘍の大きさ（T分類）、リンパ節転移、腫瘍の分化度、腫瘍の浸潤様式（いずれもp<0.05）であった。E-cadherinの発現低下とVimentinの発現をEMTと定義し、Brachyury発現とEMTの関連を検討したところ、Brachyury発現様式とVimentinの発現およびEMTに関連が認められた（p=0.002,p=0.035）。検索したBrachyury、E-cadherin、Vimentinの分子のうちどれが最もリンパ節転移、遠隔転移と相関するかロジスティック回帰分析を用いて検索したところ、単変量解析において、リンパ節転移はすべての分子と相関し、特にBrachyury発現（p=0.001, オッズ比4.390）と最も強く相関していた。遠隔転移はBrachyury発現との相関は認められず、E-cadherin発現（p=0.001,オッズ比0.113）と最も強く相関した。5年生存率、無病生存率についてKaplan-Meier法にて検討を行ったところ、Brachyury、E-cadherin、Vimentinの発現はすべて強い相関が認められた。AdCCは症例数が尐なく統計学的な解析が困難であったが、SCCと比較したBrachyury陽性率の高さはAdCCの高転移性を示す可能性があると考えられる。以上より、口腔癌におけるBrachyury発現とEMTの関与が示され、口腔癌特にSCCの予後因子として臨床応用が可能であると考えられた

The T-box transcription factor Brachyury regulates epithelial–mesenchymal transition in association with cancer stem-like cells in adenoid cystic carcinoma cells

Abstract Background The high frequencies of recurrence and distant metastasis of adenoid cystic carcinoma (AdCC) emphasize the need to better understand the biological factors associated with these outcomes. To analyze the mechanisms of AdCC metastasis, we established the green fluorescence protein (GFP)-transfected subline ACCS-GFP from the AdCC parental cell line and the metastatic ACCS-M GFP line from an in vivo metastasis model. Methods Using these cell lines, we investigated the involvement of the epithelial–mesenchymal transition (EMT) and cancer stem cell (CSCs) in AdCC metastasis by real-time RT-PCR for EMT related genes and stem cell markers. Characteristics of CSCs were also analyzed by sphere-forming ability and tumorigenicity. Short hairpin RNA (shRNA) silencing of target gene was also performed. Results ACCS-M GFP demonstrated characteristics of EMT and additionally displayed sphere-forming ability and high expression of EMT-related genes (Snail, Twist1, Twist2, Slug, zinc finger E-box binding homeobox 1 and 2 [Zeb1 and Zeb2], glycogen synthase kinase 3 beta [Gsk3β and transforming growth factor beta 2 [Tgf-β2]), stem cell markers (Nodal, Lefty, Oct-4, Pax6, Rex1, and Nanog), and differentiation markers (sex determining region Y [Sox2], Brachyury, and alpha fetoprotein [Afp]). These observations suggest that ACCS-M GFP shows the characteristics of CSCs and CSCs may be involved in the EMT of AdCC. Surprisingly, shRNA silencing of the T-box transcription factor Brachyury (also a differentiation marker) resulted in downregulation of the EMT and stem cell markers. In addition, sphere-forming ability, EMT characteristics, and tumorigenicity were simultaneously lost. Brachyury expression in clinical samples of AdCC was extremely high and closely related to EMT. This finding suggests that regulation of EMT by Brachyury in clinical AdCC may parallel that observed in vitro in this study. Conclusions The use of a single cell line is a limitation of this study. However, parallel data from in vitro and clinical samples suggest the possibility that EMT is directly linked to CSCs and that Brachyury is a regulator of EMT and CSCs.</p