Shigeo Haruki

YAP is a candidate oncogene for esophageal squamous-cell carcinoma

Yes-associated protein (YAP), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene located at chromosome 11q22. Since we previously reported amplification of 11q22 region in esophageal squamous cell carcinoma (ESCC), in this study we focused on the clinical significance and biological functions of YAP in this tumor. Frequent overexpression of YAP protein was observed in ESCC cells including those with a robust amplicon at position 11q22. Overexpression of the YAP protein was frequently detected in primary tumors of ESCC as well. Patients with YAP-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors, and YAP positivity was independently associated with a worse outcome in the multivariate analysis. Further analyses in cells in which YAP was either overexpressed or depleted confirmed that cell proliferation was promoted in a YAP isoform-independent but YAP expression level-dependent manner. YAP depletion inhibited cell proliferation mainly in the G(0)-G(1) phase and induced an increase in CDKN1A/p21 transcription but a decrease in BIRC5/survivin transcription. Our results indicate that YAP is a putative oncogene in ESCC and it represents a potential diagnostic and therapeutic target.

NEW ARGON PLASMA COAGULATION METHOD FOR SUPERFICIAL ESOPHAGEAL CARCINOMAS: ARGON PLASMA COAGULATION‐SUBEPITHELIAL ABLATION

Argon plasma coagulation (APC) has been introduced to the field of therapeutic endoscopy and is now widely used. A new ablation technique is herein proposed for the treatment of superficial esophageal carcinomas. According to this technique, after the initial ablation, we exfoliate the epithelium and then perform a second ablation (APC‐subepithelial ablation). APC is applied at a power/gas setting of 60 W and 2l min in the esophagus. The APC applicator is inserted through the working channel of the endoscope, and a transparent hood is then set at the tip of the endoscope. At first, lines are traced around the tumor. Next, the initial ablation is made in a uniform manner. A transparent hood is then attached to the ablated tumor and, thereafter, the epithelium is easily exfoliated. The muscularis mucosae are preserved. We next identify any remaining non‐uniform ablation areas and then a second ablation is made on those areas. To obtain a complete eradication of the mucosal and submucosal tissue, the endoscopic appearance of brownish subepithelial tissue following the secondary argon plasma irradiation after epithelial exfoliation with initial argon plasma irradiation is needed. The secondary ablation could thus safely ablate at the esophageal gland level. The procedure is minimally invasive and easy to apply. A total of 48 patients with superficial esophageal squamous cell carcinoma were treated between February 2000 and April 2006 (median follow up 46 months). One hundred and sixty one sessions were performed with no major complications (no bleeding, no perforation, and no stenosis). The technique is thus considered to be safe.

Argon plasma coagulation for local recurrence of squamous cell carcinoma of the esophagus after endoscopic mucosal resection: technique and outcome

BackgroundIt is difficult to undergo a second endoscopic mucosal resection (EMR) for local cancer recurrence because ulcer scars caused by the previous EMR are frequently located near the tumor. The main objective of this study was to evaluate whether argon plasma coagulation (APC) is an effective and safe modality for treating early esophageal cancer recurrence untreatable by EMR.MethodsWe reviewed the experience of this clinic in the administration of EMR for the treatment of mucosal esophageal cancer in 249 patients with 276 lesions (142, m1; 98, m2; 36, m3) between December 1989 and March 2005. A local recurrence of the disease after the EMR was detected in 24 cases (9.6%). Seventeen patients were treated with APC. An argon gas flow of 2 l/min was used at a power setting of 60 W. The follow-up period of the 17 patients ranged from 13 to 87 months (median, 68 months).ResultsThe depth of tumor invasion, estimated by endoscopy, was mucosal in all patients. Seventy-three sessions (mean, 4.3 sessions/person; range, 1–12 sessions) were performed. All lesions were easily irradiated. No serious complications such as bleeding, perforation, or stenosis occurred. Complete local control was achieved in 16 of the 17 patients, but the remaining patient required further surgery. Death occurred in 3 cases. Two patients died as a result of other disease, and 1 patient died of other carcinomas, but no patient died of esophageal carcinoma.ConclusionAPC is a safe and effective method for the treatment of local recurrence of squamous cell carcinoma of the esophagus after an EMR.

Abstract 3071: Frequent silencing of protocadherin 17, a candidate tumour suppressor for esophageal squamous-cell carcinoma

Protocadherins are a subfamily of the cadherin superfamily, but little is known about their functions. We identified a homozygous loss of protocadherin 17 (PCDH17) in the course of a program to screen a panel of esophageal squamous-cell carcinoma (ESCC) cell lines for genomic copy-number aberrations. PCDH17 mRNA was expressed in normal esophageal tissue but not in the majority of ESCC cell lines without a homozygous deletion of this gene, and restored in gene-silenced ESCC cells after treatment with 5-aza-2′-deoxycytidine. The DNA methylation status of the PCDH17 CpG-island correlated inversely with the PCDH17 expression, and a putative methylation-target region showed promoter activity. The methylation of the PCDH17 promoter was also associated with the silencing of gene expression in primary ESCC at least partly. Among primary ESCC cases, the silencing of PCDH17 protein expression was associated with a poorer differentiation status of ESCC cells, and possibly with prognosis in a subset of this tumour. Restoration of PCDH17 expression in ESCC cells reduced cell proliferation and migration/invasion. These results suggest that silencing of PCDH17 expression through hypermethylation of the promoter or other mechanisms leads to loss of its tumour-suppressive activity, which may be a factor in the carcinogenesis of at least some ESCCs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3071.

P69 A pilot trial of Docetaxel plus Pedaplatin in Cisplatin-pretreated esophageal cancer

patients. The aim of the study was the assessment of the impact of therapeutic strategy with a combined modality treatment on the status of regional lymph nodes in patients with squamous cell carcinoma (SSC) of the esophagus. Methods: Between 2001 and 2004, in a prospective randomized controlled multicenter (4 institutions) trial (SCSR 6PO5C01320), 84 stage II and III patients (75M/9K; median age 56, range 42–76) with SCC of the thoracic esophagus were randomly assigned to one of the following therapeutic arms: surgery alone (SURG) – 30 pts, chemotherapy followed by surgery (CHTH+SURG) – 23 pts and chemoradiotherapy followed by surgery (CHRTH+SURG) – 31 pts. The 21-day combination chemotherapy regimen consisted of a continuous infusion of cisplatin (20mg/m/day) and 5-fluorouracil (300mg/m/day). The patients who underwent chemoradiotherapy received concomitant fractionated radiation to a total dose of 30Gy. After 3 week interval transthoracic esophagectomy with 2-field extended lymph node dissection was carried out in all the patients. Lymph node involvment rate, number of metastatic nodes and positive nodes ratio (positive/harvested) were analysed in particular therapeutic arms. A statistical analysis was conducted with the computer statistical package STATISTICA v. 6.0 (StatSoft). A P value lower than 0.05 was considered as significant. Results: The median number of harvested lymph nodes was 23.7±9.6 for all patients and 27.8±11, 22.5±10.1 and 22.5±8.5, for particular therapeutic arms CHTH+SURG, CHRTH+SURG and SURG, respectively (P=0.2283). Metastatic nodes were found in 63.9% of all patients and in 46.7, 41.2 and 86.2% of patients treated with CHTH+SURG, CHRTH+SURG and SURG, respectively (P=0.0027). The median number of metastatic nodes was 2.6±3.1 for all patients and 1.3±2.6, 1.3±2.4 and 3.8±3.3 for CHTH+SURG, CHRTH+SURG and SURG, respectively (P=0.0013). The median positive nodes ratio was 0.12±0.06 for all patients and 0.05±0.10, 0.05±0.09 and 0.18±0.17 for CHTH+SURG, CHRTH+SURG and SURG, respectively (P=0.0018). Conclusion: Neoadiuvant treatment in patients with SCC of the esophagus significantly decreases the number and ratio of positive lymph nodes and thus it might result in potentially better local clearance of resection surgery.