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Background: Proton-based, definitive chemoradiotherapy (P-CRT) for esophageal squamous cell carcinoma (ESCC) previously showed comparable survival outcomes with the surgery-based therapy, i.e., neoadjuvant chemotherapy followed by esophagectomy (NAC-S), in a single-institutional study. This study aimed to validate this message in a Japanese multicenter study., Methods: Eleven Japanese esophageal cancer specialty hospitals have participated. A total of 518 cases with clinical Stage I-IVA ESCC between 2010 and 2019, including 168 P-CRT and 350 NAC-S patients, were enrolled and long-term outcomes were evaluated. Propensity-score weighting analyses with overlap weighting for confounding adjustment were used., Results: The 3-year overall survival (OS) of the P-CRT group was equivalent to the NAC-S group (74.8% vs. 72.7%, hazard ratio [HR]: 0.87, 95% confidence interval [CI]: 0.61-1.25). Although, the 3-year P-CRT group progression-free survival (PFS) was inferior to the NAC-S group (51.4% vs. 59.6%, HR 1.39, 95% CI 1.04-1.85), the progression P-CRT group cases showed better survival than the NAC-S group (HR 0.58, 95% CI 0.38-0.88), largely because of salvage surgery or endoscopic submucosal dissection for local progression. The survival advantage of P-CRT over NAC-S was more pronounced in the cT1-2 (HR 0.61, 95% CI 0.29-1.26) and cStage I-II (HR 0.50, 95% CI 0.24-1.07) subgroups, although this trend was not evident in other populations, such as cT3-4 and cStage III-IVA., Conclusions: Proton-based CRT for ESCC showed equivalent OS to surgery-based therapy. Especially for patients with cT1-2 and cStage I-II disease, proton-based CRT has the potential to serve as a first-line treatment., (© 2024. The Author(s), under exclusive licence to The Author(s) under exclusive licence to The Japan Esophageal Society.)

Purpose: The gut microbiome plays an important role in cancer pathogenesis and therapy. Some studies have reported that specific bacteria in tumor tissues may contribute to the prognosis and treatment of esophageal squamous cell carcinoma (ESCC). However, there is limited evidence that the gut microbiome is associated with ESCC. This study assessed the utility of the gut microbiome as a predictive marker of the therapeutic effect in patients with ESCC undergoing chemo-radiotherapy (CRT)., Patients and Methods: Fecal samples were collected from 51 patients with ESCC who had never undergone treatment between April 2021 and May 2022 in the Department of Frontier Surgery, Chiba University. The gut microbiome was analyzed using 16S metagenomics sequencing. The association between the gut microbiome composition and stage according to the TNM classification (American Joint Committee on Cancer 7.0) and CRT response according to the RECIST criteria was evaluated., Results: The relative abundance of Fusobacteriaceae was enriched in cStage III-IVb group. Among the 27 patients who received CRT, the relative abundance of Lactobacillaceae was enriched in those with a partial and complete response. Lactobacillaceae also did not correlate with any clinical data, but the high Lactobacillales group had a higher LMR (P = 0.032) and lower PLR (P = 0.045) than in the low Lactobacillales group., Conclusions: In conclusion, we found that the relative abundance of Lactobacillaceae was enriched in patients with a partial or complete response among CRT those with ESCC, thus suggesting that the relative abundance of Lactobacillaceae can predict the effect of CRT., (© 2023. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: Esophageal squamous cell carcinoma (ESCC) is a malignant cancer with a poor prognosis. Chemoradiotherapy is one of the most important strategies for patients with locally advanced unresectable ESCC; however, its therapeutic effect is unsatisfactory. Tumor-initiating cells (TICs) have been reported to be resistant to conventional chemotherapy and radiotherapy so far. Therefore, we aimed to develop a treatment strategy targeting TICs in ESCC to improve radiosensitivity., Methods: First, we validated aldehyde dehydrogenase 1 (ALDH1) as a TIC marker and investigated its ability to mediate resistance in human ESCC cell lines using flow cytometry, Western blotting, and functional analyses. Then, we focused on disulfiram (DSF), an aldehyde dehydrogenase inhibitor, used to treat alcohol use disorder. We investigated the effect of DSF and copper (II) D-gluconate (Cu) on the radiosensitivity of ESCC in xenograft mouse models., Results: ALDH1-positive cells showed an upregulation of SOX2 and Nanog, exhibiting much stronger tumor-initiating properties than ALDH1-negative cells. Furthermore, inhibition of ALDH1 attenuated the tumor-initiating properties of ESCC cell lines. Our results also showed that ALDH1-positive cells were resistant to chemotherapy and radiotherapy, and the inhibition of ALDH1 led to the mitigation of therapeutic resistance. Our in vitro and in vivo studies revealed that the DSF/Cu complex could radiosensitize ALDH1-positive ESCC cells and downregulate the phosphoinositide 3-kinase/Akt pathway., Conclusion: ALDH1 inhibition by the DSF/Cu complex enhances the radiosensitivity of TICs in ESCC. The drug repositioning approach using disulfiram is a potential treatment option to overcome radioresistance in patients with locally advanced ESCC., (© 2022. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: With the aging of society and increasingly longer of life expectancy, elderly patients with esophageal cancer are more commonly encountered. This study aimed to identify the risk factors for operative mortality after esophagectomy in elderly patients., Methods: We used data from the National Clinical Database of Japan. After cleaning the data, 10,633 records obtained from 861 hospitals were analyzed. A risk model for operative mortality was developed using risk factors from the entire study population. Then, odds ratios (OR) were compared between age categories using this risk model., Results: In this study, 1959 (18.4%) patients were ≥ 75 years (defined as "elderly" in this study). Eighteen variables, including T4b, N2-N3, and M1 in the TNM classification, were included in the risk model for operative mortality. The ORs increased in age categories < 65, 65-74, and ≥ 75 years for N2-N3 (1.172, 1.200, and 1.588, respectively), and M1 (2.189, 3.164, and 4.430, respectively). Based on these results, we also focused on residual tumors, which are caused by extensive tumor development. The operative mortality in the elderly group with residual tumors increased to more than twice than that in the non-elderly groups (15.9 vs. 5.5 or 6.5%) and was much higher than that in elderly patients without residual tumors (15.9 vs. 4.6%)., Conclusion: We should carefully select the treatment for elderly patients with highly advanced tumors, which result in N2-N3 and M1, to avoid unfavorable short-term outcomes. In addition, R0 resection is important in preventing operative mortality among elderly patients., (© 2022. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: Recent progress of large-scale international studies has provided comprehensive catalogs of somatic mutations in cancers. Additionally, it has become evident that allelic imbalance in the abundance of somatic mutations between DNA and RNA were pervasive in various types of cancer. However, the allelic imbalance of the abundance of somatic mutations in esophageal squamous cell carcinoma (ESCC) has not been fully analyzed., Methods: We performed exome sequencing for 25 Japanese patients with ESCC to detect a comprehensive catalog of somatic mutations in ESCC. Additionally, we performed mRNA sequencing to evaluate the allelic imbalance of the identified somatic mutations at the transcriptional level by comparing the mutant allele frequencies between RNA and DNA., Results: The exome sequencing showed that TP53 and ZNF750 were significantly mutated genes. The expression levels of TP53 and ZNF750 were different depending on the mutation status. In almost all the tumors with missense mutations in TP53 and ZNF750, the mutant allele frequencies were higher in the RNA sequencing than those in the exome sequencing, indicating that the mutant alleles were preferentially expressed. By examining the allelic imbalances for all the identified missense mutations, we demonstrated that genes showing preferential expressions of the mutant alleles were involved in the pathways including cell cycle, cell death, and chromatin modification., Conclusions: The results of this study suggest that the allelic imbalance of the abundance of somatic mutations plays important roles in the initiation and progression of ESCC by modulating cancer-related biological pathways., (© 2021. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: Neoadjuvant chemotherapy (NAC) followed by esophagectomy can improve the prognosis of locally advanced esophageal cancer (LAEC). However, LAEC reportedly recurred in 17-21% of patients within 6 months post surgery. Thus, current treatment strategies may be inadequate for LAECs with poor prognosis. Preoperative identification of patients with poor prognosis might aid in modification of treatment strategies. This study aimed to evaluate the usefulness of the maximum standardized uptake value change rate (ΔSUV max ) in predicting treatment effects on the primary lesion, prognosis, and LAEC recurrence., Methods: This study involved 220 esophageal cancer patients who underwent esophagectomy after NAC at three facilities in Japan. The optimal cut-off point for ΔSUV max in predicting tumor regression grade (TRG) was calculated and used to assess the correlation between ΔSUV max and postoperative survival., Results: The optimal cut-off point for ΔSUV max was 0.5. The 5-year overall survival rate in patients with ΔSUV max  ≥ 0.5 was significantly higher than that in patients with ΔSUV max  < 0.5 (71.5% vs. 50.5%, P = 0.001). Multivariate analysis identified ΔSUV max (hazards ratio, 0.496; P = 0.004) as an independent prognostic factor. Among 199 patients evaluated for recurrence, 24 (12.1%) showed recurrence within 6 months post surgery. Univariate analysis revealed ΔSUV max as the only predictor for early recurrence (odds ratio, 0.222; P = 0.004)., Conclusion: ΔSUV max before and after NAC is clinically useful as it could help predict TRG, survival outcome, and early recurrence within 6 months post esophagectomy and is easily obtainable in general clinical practice. We believe that it may also help determine suitable treatment strategies for LAEC., (© 2021. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: Intravoxel incoherent motion MRI (IVIM-MRI) can quantify micro-perfusion at the capillary level in the tissue. The purpose of this study is to measure tumor perfusion using IVIM-MRI, and evaluate its value as a biomarker to predict prognosis in esophageal squamous cell carcinoma (ESCC) patients., Methods: 109 ESCC patients (93 men and 16 women; median age: 72) who underwent IVIM-MRI prior to treatment between February 2018 and August 2020 were retrospectively investigated. Both mean apparent diffusion coefficient (ADC) value and mean perfusion-related parameter (PP) value of the primary tumor were measured using three b values of 0, 400, and 1000 s/mm 2 based on the IVIM model. We analyzed associations of these parameters with clinical stage and disease-specific survival (DSS)., Results: Lower ADC and PP values of the tumor were significantly associated with the higher clinical T stage (p < 0.0001, p < 0.0001, respectively). In Kaplan-Meier analyses, patients with lower PP value tumors (< 18.94, median) had significantly worse DSS (p < 0.0001), while tumor ADC value did not show a significant correlation with DSS. In a multivariate analysis, PP value of the tumor was an independent prognostic factor for DSS (p = 0.0027)., Conclusions: Quantification of tumor perfusion using IVIM-MRI can be a non-invasive prognostic biomarker of ESCC, reflecting clinical stage and survival., (© 2021. The Japan Esophageal Society.)

It has been said that "thoracoscopy suppresses the occurrence of pneumonia in comparison to thoracotomy", but does it reflect real clinical practice? To resolve this clinical question, we compared the results of randomized controlled trials (RCTs) and retrospective cohort studies from limited institutes (CLIs) in which a large number of high-volume centers were the main participants to those of retrospective cohort studies based on nationwide databases (CNDs) in which both high-volume centers and low-volume hospitals participated. A systematic review and meta-analysis were conducted to compare the short-term outcomes of thoracoscopic to open esophagectomy for esophageal cancer in the three above-mentioned research formats. In total, 43 studies with 21,057 patients, which included 1 RCT with 115 patients, 38 CLIs with 6,126 patients and 4 CNDs with 14,816 patients, were selected. Pneumonia was one of the most important complications. Although significant superiority in thoracoscopic esophagectomy was observed in RCTs (p = 0.005) and CLIs (p = 0.003), no such difference was seen in findings using nationwide databases (p = 0.69). In conclusion, unlike RCTs and CLIs, CNDs did not show the superiority of thoracoscopic surgery in terms of post-operative pneumonia. RCTs and CLIs were predominantly performed by high-volume hospitals, while CNDs were often performed by low-volume hospitals. In actual clinical practice including various types of hospitals, the superiority of thoracoscopic over open esophagectomy regarding the incidence of pneumonia may, therefore, decrease., (© 2021. The Japan Esophageal Society.)

Background: The purpose of this study was to investigate whether histogram analysis of an apparent diffusion coefficient (ADC) can serve as a prognostic biomarker for esophageal squamous cell carcinoma (ESCC)., Methods: This retrospective study enrolled 116 patients with ESCC who received curative surgery from 2006 to 2015 (including 70 patients who received neoadjuvant chemotherapy). Diffusion-weighted magnetic resonance imaging (DWI) was performed prior to treatment. The ADC maps were generated by DWIs at b = 0 and 1000 (s/mm 2 ), and analyzed to obtain ADC histogram-derived parameters (mean ADC, kurtosis, and skewness) of the primary tumor. Associations of these parameters with pathological features were analyzed, and Cox regression and Kaplan-Meier analyses were performed to compare these parameters with recurrence-free survival (RFS) and disease-specific survival (DSS)., Results: Kurtosis was significantly higher in tumors with lymphatic invasion (p = 0.005) with respect to the associations with pathological features. In univariate Cox regression analysis, tumor depth, lymph node status, mean ADC, and kurtosis were significantly correlated with RFS (p = 0.047, p < 0.001, p = 0.037, and p < 0.001, respectively), while lymph node status and kurtosis were also correlated with DSS (p = 0.002 and p = 0.017, respectively). Furthermore, multivariate analysis demonstrated that kurtosis was the independent prognostic factor for both RFS and DSS (p < 0.001 and p = 0.015, respectively). In Kaplan-Meier analysis, patients with higher kurtosis tumors (> 3.24) showed a significantly worse RFS and DFS (p < 0.001 and p = 0.006, respectively)., Conclusions: Histogram analysis of ADC may serve as a useful biomarker for ESCC, reflecting pathological features and prognosis.

Background: Postoperative docetaxel plus S-1 (DS) chemotherapy is expected to be the standard therapeutic strategy for pStage III gastric cancer based on the results of the JACCRO GC-07 study. Neoadjuvant chemotherapy (NAC) is thought to have several advantages over adjuvant settings., Objective: This study aimed to compare the efficacies of NAC DS and the surgery-first strategy for advanced gastric cancer patients with D2 gastrectomy., Methods: This was a retrospective, single-institution observational study. Of 171 patients with locally advanced (cStage IIB or III) gastric cancer who underwent curative D2 gastrectomy and received NAC DS and/or S-1 adjuvant chemotherapy between 2011 and 2017, 76 (after propensity score matching for 132 patients who met the eligibility criteria) were enrolled in this study. The 3-year progression-free survival (PFS) rate was used to directly compare efficacies between NAC DS patients and surgery-first patients., Results: The 3-year PFS rates for the NAC DS group were significantly higher than those for the surgery-first group (80.0 vs. 58.7; p = 0.037), and the progression hazard ratio of the NAC DS group compared with the surgery-first group was 0.394 (95% confidence interval 0.159-0.978; p = 0.045)., Conclusions: The NAC DS group showed a high 3-year PFS compared with the surgery-first group, with standard S-1 postoperative chemotherapy or observation. NAC DS can be expected to be beneficial as the standard therapy for advanced gastric cancer and should be adopted for the test arm of a randomized controlled phase III trial.

Background: We determined the serum concentrations of Programmed cell death-1 (PD-1) and its ligands (PD-L1 and PD-L2) in patients with esophageal squamous cell carcinoma (ESCC)., Methods: Blood samples were collected from 85 patients with histologically proved ESCC. Serum levels of PD-1, PD-L1, and PD-L2 were measured using enzyme linked immunosorbent assays. Correlations between serum PD-1, PD-L1, and PD-L2 concentration and tumor depth, number of lymph node metastases, organ metastasis status, or disease stage were assessed and five-year survival rates according to clinicopathological characteristics were calculated., Results: The concentration of PD-1 was not differed according to tumor progression. On the other hand, the average concentration of PD-L1 in patients with T3/T4 disease was 15.6 (12.2-18.3) pg/mL (25-75%), and this was significantly higher than that in patients with Tis/T1/T2 disease (p = 0.020). Similarly, PD-L1 levels were significantly higher in patients with positive lymph nodes than in cases with negative lymph node involvement (p = 0.006) and were higher in patients with organ metastasis (p = 0.123) and in more advanced stage (p = 0.006). Similar tendency was observed regarding PD-L2 concentrations. PD-L2 concentration was higher in T3, T4 cases (p = 0.008), in LN positive cases (p = 0.032), and in more advanced stage (p = 0.024)., Conclusion: Our data showed that a concentration of PD-L1 in peripheral blood was high in advanced cancer and high concentration of PD-L1 predicted disease progression and also poor survival in patients with ESCC.

Background: The expression of Fos-related antigen 1 (Fra-1) affects tumor progression, migration, and invasion. In this study, we identified the genes regulated by Fra-1 in esophageal squamous cell carcinoma (ESCC)., Methods: We constructed Fra-1 knockdown models via the transfection of small interfering RNA (siRNA) into ESCC cell lines (TE10, TE11). The expression levels of the genes in the knockdown models were analyzed using a microarray and a Biobase Upstream Analysis, while the expression levels of the candidate genes in the primary tumors of surgical specimens obtained from ESCC patients were determined using real-time polymerase chain reaction (PCR) and immunohistochemical staining. The clinicopathological features were then analyzed., Results: The Biobase Upstream Analysis showed the high-mobility-group protein-1 (HMGA1) to be a significant gene regulated by Fra-1. Actual binding of Fra-1 to the promotor region of HMGA1 was revealed in subsequent chromatin immunoprecipitation PCR experiments. Patients with a positive HMGA1 expression had a poor prognosis, and a multivariate analysis demonstrated a positive HMGA1 expression to be a significant independent prognostic factor., Conclusion: HMGA1 is regulated by Fra-1 in ESCC, and the HMGA1 expression is significantly associated with a poor prognosis in ESCC patients. Downregulation of the HMGA1 expression may become a practical treatment strategy against ESCC in the future.

Background: The expression of genes can be influenced by the balance of histone acetylation and/or histone demethylation, with an imbalance of these processes possibly observed in many cancers. The histone demethylase LSD1 inhibitor activity is associated with selective transcriptional regulation and alterations in the gene expression. However, the exact mechanisms underlying the antitumor effects of LSD1 inhibitors are not fully understood., Methods: The antitumor effects of NCL1, an LSD1 inhibitor, in esophageal squamous cell cancer (ESCC) cell lines were evaluated. A comprehensive analysis of the changes in the gene expression in ESCC cell lines induced by NCL1 was carried out using a microarray analysis. A loss-of-function assay using a siRNA analysis was performed to examine the oncogenic function of the gene., Results: NCL1 strongly inhibited the cell growth of T.Tn and TE2 ESCC cells and induced apoptosis. According to the microarray analysis, 81 genes in the T.Tn cells and 149 genes in the TE2 cells were up- or down-regulated 2-fold or more by NCL1 exposure. Among these genes, 27 were contained in both cell lines and exhibited similar expression patterns. PHLDB2, one of the genes down-regulated by NCL1, was overexpressed in the ESCC tumor tissues. Moreover, a high expression level of PHLDB2 was found to be significantly correlated with poor prognosis., Conclusions: The present observations of the comprehensive analysis of the gene expression levels provide insight into the mechanisms underlying the antitumor effects of LSD1 inhibitors in ESCC patients.