The SWI/SNF chromatin remodeling complex is frequently inactivated by somatic mutations of its various components in various types of cancers, and also by aberrant DNA methylation. However, its ...somatic mutations and aberrant methylation in esophageal squamous cell carcinomas (ESCCs) have not been fully analyzed. In this study, we aimed to clarify in ESCC, what components of the SWI/SNF complex have somatic mutations and aberrant methylation, and when somatic mutations of the SWI/SNF complex occur. Deep sequencing of components of the SWI/SNF complex using a bench-top next generation sequencer revealed that eight of 92 ESCCs (8.7%) had 11 somatic mutations of 7 genes, ARID1A, ARID2, ATRX, PBRM1, SMARCA4, SMARCAL1, and SMARCC1. The SMARCA4 mutations were located in the Forkhead (85Ser>Leu) and SNF2 family N-terminal (882Glu>Lys) domains. The PBRM1 mutations were located in a bromodomain (80Asn>Ser) and an HMG-box domain (1,377Glu>Lys). For most mutations, their mutant allele frequency was 31-77% (mean 61%) of the fraction of cancer cells in the same samples, indicating that most of the cancer cells in individual ESCC samples had the SWI/SNF mutations on one allele, when present. In addition, a BeadChip array analysis revealed that a component of the SWI/SNF complex, ACTL6B, had aberrant methylation at its promoter CpG island in 18 of 52 ESCCs (34.6%). These results showed that genetic and epigenetic alterations of the SWI/SNF complex are present in ESCCs, and suggested that genetic alterations are induced at an early stage of esophageal squamous cell carcinogenesis.
Background
The area of nodal dissection should be modified by the location of the primary tumor in an individual patient. The purpose of this study was to evaluate the efficacy of lymph node ...dissection based on station by the location of the primary tumor based on a multi-institutional nationwide registry of esophageal cancer.
Methods
The study group comprised 1295 patients who underwent R0 resection and three-field esophagectomy. The Efficacy Index (EI) was calculated by multiplying the incidence of metastases to a station and the 5-year survival rate of patients with metastases to that station, by tumor location.
Results
There were 550 patients without nodal metastases and 745 patients with them. In patients with upper tumors, the EIs of recurrent nerve nodes, cervical paraesophageal nodes and supraclavicular nodes were highest. In patients with middle tumors, the EIs of recurrent nerve nodes, cardiac nodes and lesser curvature nodes were highest, and the EIs of supraclavicular nodes and cervical paraesophageal nodes were not negligible. In patients with lower tumors, the EIs of cardiac nodes, lesser curvature nodes and left gastric artery nodes were highest, and the EIs of recurrent nerve nodes were also high.
Conclusion
The EIs of certain node stations were different by location of the primary tumor. Node stations for dissection should be modified by the location of the primary tumor. For upper and middle esophageal tumors, the three-field approach is recommended. Dissection of the upper mediastinum is recommended for patients with lower esophageal tumors.
Contamination of normal cells is almost always present in tumor samples and affects their molecular analyses. DNA methylation, a stable epigenetic modification, is cell type-dependent, and different ...between cancer and normal cells. Here, we aimed to demonstrate that DNA methylation can be used to estimate the fraction of cancer cells in a tumor DNA sample, using esophageal squamous cell carcinoma (ESCC) as an example. First, by an Infinium HumanMethylation450 BeadChip array, we isolated three genomic regions (TFAP2B, ARHGEF4, and RAPGEFL1) i) highly methylated in four ESCC cell lines, ii) hardly methylated in a pooled sample of non-cancerous mucosae, a pooled sample of normal esophageal mucosae, and peripheral leukocytes, and iii) frequently methylated in 28 ESCCs (TFAP2B, 24/28; ARHGEF4, 20/28; and RAPGEFL1, 19/28). Second, using eight pairs of cancer and non-cancer cell samples prepared by laser capture microdissection, we confirmed that at least one of the three regions was almost completely methylated in ESCC cells, and all the three regions were almost completely unmethylated in non-cancer cells. We also confirmed that DNA copy number alterations of the three regions in 15 ESCC samples were rare, and did not affect the estimation of the fraction of cancer cells. Then, the fraction of cancer cells in a tumor DNA sample was defined as the highest methylation level of the three regions, and we confirmed a high correlation between the fraction assessed by the DNA methylation fraction marker and the fraction assessed by a pathologist (r=0.85; p<0.001). Finally, we observed that, by correction of the cancer cell content, CpG islands in promoter regions of tumor-suppressor genes were almost completely methylated. These results demonstrate that DNA methylation can be used to estimate the fraction of cancer cells in a tumor DNA sample.
Objective
There is no consensus concerning whether the residual stomach should be preserved after esophagectomy for thoracic esophageal cancer patients with previous distal or segmental gastrectomy. ...The purpose of this retrospective study was to assess the efficacy of preserving the residual stomach after esophagectomy in patients with previous gastrectomy.
Methods
Between 2000 and 2015, 45 consecutive thoracic esophageal cancer patients with previous distal or segmental gastrectomy underwent esophagectomy followed by colon reconstruction. Patients were assigned to two groups according to how the residual stomach was treated (preservation group,
n
= 11; resection group,
n
= 34). We compared surgical outcomes and alterations of nutrition status, including the skeletal muscle area, between the two groups. In addition, we investigated the distribution of abdominal lymph node metastases in the resection group.
Results
Operative time and blood loss tended to be lower in the preservation group compared to the resection group. However, the difference did not reach statistical significance. The rate of patients decreasing skeletal muscle area after surgery was significantly higher in the resection group (88% vs 50%,
P
= 0.03). There were no patients with metastatic abdominal lymph nodes when the previous gastrectomy had been performed for gastric cancer and the esophageal cancer was located at the upper or middle esophagus in the resection group.
Conclusions
Preservation of the residual stomach after esophagectomy in esophageal cancer patients with previous gastrectomy may influence the postoperative nutrition status and can be selectively approved.
Few driver genes have been well established in esophageal squamous cell carcinoma (ESCC). Identification of the genomic aberrations that contribute to changes in gene expression profiles can be used ...to predict driver genes.
We searched for driver genes in ESCC by integrative analysis of gene expression microarray profiles and copy number data. To narrow down candidate genes, we performed survival analysis on expression data and tested the genetic vulnerability of each genes using public RNAi screening data. We confirmed the results by performing RNAi experiments and evaluating the clinical relevance of candidate genes in an independent ESCC cohort.
We found 10 significantly recurrent copy number alterations accompanying gene expression changes, including loci 11q13.2, 7p11.2, 3q26.33, and 17q12, which harbored CCND1, EGFR, SOX2, and ERBB2, respectively. Analysis of survival data and RNAi screening data suggested that GRB7, located on 17q12, was a driver gene in ESCC. In ESCC cell lines harboring 17q12 amplification, knockdown of GRB7 reduced the proliferation, migration, and invasion capacities of cells. Moreover, siRNA targeting GRB7 had a synergistic inhibitory effect when combined with trastuzumab, an anti-ERBB2 antibody. Survival analysis of the independent cohort also showed that high GRB7 expression was associated with poor prognosis in ESCC.
Our integrative analysis provided important insights into ESCC pathogenesis. We identified GRB7 as a novel ESCC driver gene and potential new therapeutic target.
Introduction
Laparoscopic bariatric surgery (BS) is not readily performed in Japan. To facilitate safe initial access to the abdominal cavity, we insert an optical viewing trocar at a unique site in ...the left upper quadrant (LUQ). Herein, we describe the technique, its advantages, and outcomes.
Materials and Surgical Technique
Briefly, the optical trocar is inserted just below the left subcostal margin, 8 cm from the midline. On insertion, layers of the abdominal wall are visualized on the monitor. Depending on the angle of insertion, five, seven, or eight layers are seen.
Discussion
In assessing our initial entry technique, used in 21 obese patients undergoing laparoscopic sleeve gastrectomy, we found median insertion time to be 25 seconds. There were no related complications. In nearly all (20/21) patients, the abdominal wall was visualized as seven layers: subcutaneous fat, anterior rectus sheath, rectus abdominis muscle, posterior rectus sheath, transverse abdominis muscle, transversalis fascia, and peritoneum. Understanding the layers of the abdominal wall visualized during optical trocar insertion in the LUQ will provide for safe and rapid initial entry in patients undergoing laparoscopic BS and can further the widespread acceptance of laparoscopic BS.
Background Recent improvements in the survival of patients after esophagectomy have led to an increasing occurrence of gastric tube cancer (GTC). Removal of the reconstructed gastric tube, however, ...can lead to high morbidity and mortality. Objective To assess the feasibility and effectiveness of endoscopic submucosal dissection (ESD) for GTC. Design Retrospective study. Setting National Cancer Center Hospital, Tokyo, Japan. Patients We investigated patients with GTC after esophagectomy undergoing ESD from 1998 to 2011. Intervention ESD. Main Outcome Measurements Patient characteristics, endoscopic findings, technical results, histopathology including curability and Helicobacter pylori gastritis, and long-term outcomes. Results There were 51 consecutive patients with 79 lesions including 38 lesions (48%) meeting the absolute indication, 31 (39%) satisfying the expanded indications, and 10 (13%) falling outside such indications. The median procedure time was 90 minutes. There were 73 en bloc resections (92%), 59 en bloc resections with tumor-free margins (R0 resections, 75%), and 51 curative resections (65%) based on the Japanese Gastric Cancer Association criteria. Fifty patients (98%) were assessed as H pylori gastritis positive. Adverse events included 3 perforations (3.8%) during ESD and 2 delayed perforations (2.5%) without any emergency surgery and 3 delayed bleeding (3.8%). Local recurrence was detected in 4 patients (7.8%), and metachronous GTCs were identified in 18 patients (35%). Five patients (10%) died of GTC including 3 metachronous lesions. The 5-year overall survival rate was 68.4%, and the disease-specific survival rate was 86.7% with 100% for curative and 72.7% for non-curative patients during a median follow-up period of 3.8 years (range, 0-12.1 years). Limitation Single-center retrospective study. Conclusions ESD for GTC was feasible and effective for curative patients; however, long-term outcomes for non-curative patients were less satisfactory.
Definitive chemoradiotherapy (CRT) is a less invasive therapy for esophageal squamous cell carcinoma (ESCC). Five-year survival rate of locally advanced ESCC patients by definitive CRT were 37%. We ...previously reported that tumor-specific cytotoxic T-lymphocyte (CTL) activation signatures were preferentially found in long-term survivors. However, it is unknown whether the CTL activation is actually driven by CRT. We compared gene expression profiles among pre- and post-treatment biopsy specimens of 30 ESCC patients and 121 pre-treatment ESCC biopsy specimens. In the complete response (CR) cases, 999 overexpressed genes including at least 234 tumor-specific CTL-activation associated genes such as IFNG, PRF1, and GZMB, were found in post-treatment biopsy specimens. Clustering analysis using expression profiles of these 234 genes allowed us to distinguish the immune-activated cases, designating them as I-type, from other cases. However, despite the better CR rate in the I-type, overall survival was not significantly better in both these 30 cases and another 121 cases. Further comparative study identified a series of epithelial to mesenchymal transition-related genes overexpressed in the early relapse cases. Importantly, the clinical outcome of CDH2-negative cases in the I-type was significantly better than that of the CDH2-positive cases in the I-type. Furthermore, NK cells, which were activated by neutrophils-producing S100A8/S100A9, and CTLs were suggested to cooperatively enhance the effect of CRT in the CDH2-negative I-type. These results suggested that CTL gene activation may provide a prognostic advantage in ESCCs with epithelial characteristics.
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