No previous reports on lymph-node metastasis (LNM) from superficial squamous cell carcinoma of the esophagus have proposed definite criteria for additional treatment after endoscopic mucosal ...resection (EMR). We investigated the association between histopathological factors and LNM in 464 consecutive patients with superficial squamous cell carcinoma of the esophagus who had undergone a radical esophagectomy with lymph-node dissection (14 ‘M1' lesions: intraepithelial tumors, 36 ‘M2' lesions: tumors invading the lamina propria, 50 ‘M3' lesions: tumors in contact with or invading the muscularis mucosa, 32 ‘SM1' lesions: tumors invading the most superficial 1/3 of the submucosa and 332 ‘SM2/3' lesions: tumors invading deeper than SM1 level). Histopathological factors including invasion depth, size, lymphatic invasion (LY), venous invasion, tumor differentiation, growth pattern, degree of nuclear atypia and histological grade were assessed for their association with LNM in 82 M3 or SM1 lesions to determine which patients need additional treatment after EMR. LNM was found in 0.0, 5.6, 18.0, 53.1 and 53.9% of the M1, M2, M3, SM1 and SM2/3 lesions, respectively. A univariate analysis showed that each of the following histopathological factors had a significant influence on LNM: invasion depth (M3 vs SM1), LY, venous invasion and histological grade. Invasion depth and LY were significantly associated with LNM in a multivariate analysis. Four out of 38 patients (10.3%) with M3 lesions without LY had LNM, whereas five out of 12 patients (41.7%) with M3 lesions and LY had LNM. Only patients with M1/2 lesions are good candidates for EMR. Invading the muscularis mucosa (M3) is a high-risk condition for LNM the same as submucosal invasion, but M3 lesions without LY can be followed up after EMR without any additional treatment.
Background
The number of long-term survivors after allogeneic hematopoietic stem cell transplantation (HSCT) has increased recently. Esophageal squamous cell carcinoma occurs at a particularly high ...incidence as a secondary cancer after HSCT. However, standard treatment for these patients has not been established yet. The objectives of this study were to investigate outcomes of esophagectomy for esophageal carcinoma developed in HSCT patients, and to provide the appropriate perioperative management.
Methods
Ten HSCT patients underwent esophagectomy for esophageal squamous cell carcinoma between December 2007 and September 2017 at the National Cancer Center Hospital. The surgical outcomes and long-term prognosis of these patients were reviewed retrospectively.
Results
In the former group, 5 of the 7 patients (71.4%) developed pneumonia after esophagectomy, with two of them requiring intubation because of respiratory failure. None of the three patients of the latter group, who received broad-spectrum antibiotics for more than 7 days after the surgery, developed any postoperative complications. The estimated survival probability of these patients at 5 years after the surgery was 53.3%.
Conclusions
HSCT patients have an extremely high risk of developing pneumonia after esophagectomy, and the condition can easily become serious. Therefore, broad-spectrum antibiotics should be administered prophylactically to prevent severe pneumonia during the perioperative period in these patients.
Multiple cancers frequently occur in the upper digestive tract. One possible explanation is that specific bacterial infection stimulates the normal epithelium to initiate inflammation and/or promotes ...carcinogenesis. This study was undertaken to determine which bacterial species is predominantly associated with esophageal cancer. We examined the bacterial diversity in this type of cancer and in the saliva from healthy people by using a culture‐independent molecular method. Here we report the preferential and frequent infection of the oral periodontopathic spirochete Treponema denticola (T. denticola), Streptococcus mitis (S. mitis), and Streptococus anginosus (S. anginosus) in esophageal cancer from different regions of the world, and we also describe the induction of inflammatory cytokines by infection of S. anginosus and S. mitis. Our present data suggest that these three bacteria could have significant roles in the carcinogenic process of many cases of esophageal cancer by causing inflammation and by promoting the carcinogenic process, and that eradication of these three bacteria may decrease the risk of recurrence.
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors. Although improvement in both surgical techniques and neoadjuvant chemotherapy has been achieved, the 5‐year ...survival rate of locally advanced tumors was, at best, still 55%. Therefore, elucidation of mechanisms of the malignancy is eagerly awaited. Epithelial‐mesenchymal transition (EMT) by transforming growth factor‐β (TGF‐β) has been reported to have critical biological roles for cancer cell stemness, whereas little is known about it in ESCC. In the current study, a transcriptional factor SIX1 was found to be aberrantly expressed in ESCCs. SIX1 cDNA transfection induced overexpression of transforming growth factors (TGFB1 and TGFB2) and its receptor (TGFBR2). Cell invasion was reduced by SIX1 knockdown and was increased in stable SIX1‐transfectants. Furthermore, the SIX1‐transfectants highly expressed tumor basal cell markers such as NGFR, SOX2, ALDH1A1, and PDPN. Although mock‐transfectants had only a 20% PDPN‐high population, SIX1‐transfectants had 60–70%. In two sets of 42 and 85 ESCC patients receiving surgery alone or neoadjuvant chemoradiotherapy followed by surgery, the cases with high SIX1 mRNA and protein expression level significantly showed a poor prognosis compared with those with low levels. These SIX1 high cases also expressed the above basal cell markers, but suppressed the differentiation markers. Finally, TGF‐β signaling blockade suppressed ESCC cell growth in association with the reduction of PDPN‐positive tumor basal cell population. The present results suggest that SIX1 accelerates self‐renewal of tumor basal cells, resulting in a poor prognosis for ESCC patients.
TGF‐β signaling blockade suppressed ESCC cell growth in association with the reduction of PDPN‐positive tumor basal cell population. The present results suggest that SIX1 accelerates self‐renewal of tumor basal cells, resulting in a poor prognosis for ESCC patients.
Background
Although esophagectomy is the standard treatment for resectable esophageal cancer, chemoradiotherapy or radiotherapy alone is also selected for some cases. However, there have been very ...few detailed studies conducted on a large scale on the efficacy of these treatments in Japan.
Methods
Of the patients enrolled in the Comprehensive Registry of Esophageal Cancer in Japan by the Japan Esophageal Society for the 2015–2017 surveys (patients treated between 2009 and 2011), the data of 388 patients treated by definitive radiotherapy alone (RTx) and 1964 patients treated by definitive chemoradiotherapy (CRTx) were analyzed.
Results
The median age of the patients was 78 years in the RTx group and 69 years in the CRTx group; thus, the proportion of elderly patients was significantly higher in the RTx group than in the CRTx group (
p
< 0.0001). With regard to the rates of treatment by the two modalities according to the depth of invasion, extent of lymph node metastasis, and disease stage, the treatment rate by CRTx increased more significantly than that by RTx as the disease progressed (
p
< 0.0001). With regard to the distribution of the total irradiation dose, 11.4% and 2.3% of patients in the RTx and CRTx groups, respectively, received a dose of 67 Gy or more; thus, the RTx group received significantly higher total irradiation doses (
p
< 0.0001). In the RTx group, the 5-year overall survival rate was 23.2%, and the rates in patients with cStage 0–I, II, III, and IV disease were 41.8%,18.5%, 9.3%, and 13.9%, respectively. In the patients of the RTx group showing complete response (CR), the 5-year overall survival rate was 46.6% and the rates in patients with cStage 0–I, II, III, and IV disease were 54.8%, 39.6%, 32.4%, and 38.9%, respectively. In the CRTx group, the 5-year overall survival rate was 30.6% and the rates in patients with cStage 0–I, II, III, and IV disease were 57.8%, 47.8%, 23.4%, and 13.0%, respectively. In the patients of the CRTx group showing CR, the 5-year overall survival rate was 59.2% and the rates in patients with cStage 0–I, II, III, and IV disease were 67.9%, 59.5%, 56.5%, and 39.6%, respectively.
Conclusion
This study revealed the current status of treatment of esophageal cancer in Japan, and we think that we have been able to establish the grounds for explaining to patients with esophageal cancer and their families the treatment decisions made for them in daily clinical practice.
Definitive chemoradiotherapy (dCRT) is the major treatment for esophageal squamous cell carcinoma (ESCC), and prediction of the response to dCRT is important so as not to miss an opportunity to cure ...an ESCC. Nevertheless, few validated markers are available. Here, we aimed to identify a highly reproducible marker using multi-layer omics analysis. 117 ESCC samples from 67 responders and 50 non-responders were divided into screening, validation, and re-validation sets. In the screening cohort (n = 41), somatic mutations in 114 genes showed no association with dCRT response. Genome-wide DNA methylation analysis using Infinium HumanMethylation450 BeadChip array identified four genic regions significantly associated with dCRT response. Among them, FGF5 methylation was validated to be associated with dCRT response (n = 34; P = 0.001), and further re-validated (n = 42; P = 0.020) by bisulfite-pyrosequencing. The sensitivity and specificity in the combined validation and re-validation sets (n = 76) were 45% and 90%, respectively, by using the cut-off value established in the screening set, and FGF5 methylation had predictive power independent from clinicopathological parameters. In ESCC cell lines, FGF5 promoter methylation repressed its expression. FGF5 expression was induced by cisplatin (CDDP) treatment in three unmethylated cell lines, but not in two methylated cell lines. Exogenous FGF5 overexpression in a cell line with its methylation conferred resistance to CDDP. In non-cancerous esophageal tissues, FGF5 was not expressed, and its methylation was present in a small fraction of cells. These results showed that FGF5 methylation is a validated marker for ESCC sensitivity to dCRT.
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.
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