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This study aimed to evaluate the uptake of the clinical effectiveness of [S-methyl

Background Although diffusion-weighted magnetic resonance imaging (DWI) for detecting lymph node (LN) metastasis is reported to be a successful modality for primary malignant tumors, there are few studies relating to esophageal cancer. This study aimed to clarify the diagnostic performance of DWI for assessing LN metastasis compared with positron emission tomography (PET) in patients with esophageal squamous cell cancer (eSCC). Methods Seventy-six patients with histologically proven eSCC who underwent curative esophagectomy without neoadjuvant treatment were reviewed retrospectively. Harvested LNs were divided into 1229 node stations with 94 metastases. Diagnostic abilities and prognostic significance were compared. Results In a station-by-station evaluation, the sensitivity was higher in DWI than PET (67% vs. 32%, P P P = 0.048), as was PET-N status (HR 2.481; P = 0.033). Conclusions DWI, which depends on cancer cell volume followed by elevated intranodal density, is a non-invasive modality and showed higher sensitivity than PET. It has clinical impact in predicting postoperative survival for patients with eSCC alongside its diagnostic ability and has significant performance in clinical practice.

Phototheranostics represents a highly promising paradigm for cancer therapy, although selecting an appropriate optical imager and sensitizer for clinical use remains challenging.Liposomally formulated phospholipid-conjugated indocyanine green, denoted as LP-iDOPE, was developed as phototheranostic nanoparticle and its cancer imaging-mediated photodynamic reaction, defined as the immune response induced by photodynamic and photothermal effects, was evaluated with a near-infrared (NIR)-light emitting diode (LED) light irradiator.Using in vivo NIR fluorescence imaging, we demonstrated that LP-iDOPE was selectively delivered to tumor sites with high accumulation and a long half-life. Following low-intensity NIR-LED light irradiation on the tumor region of LP-iDOPE accumulated, effector CD8Our anti-cancer strategy based on tumor-specific LP-iDOPE accumulation and low-intensity NIR-LED light irradiation to the tumor regions, i.e., photodynamic reaction, represents a promising approach to noninvasive cancer therapy.

A multicenter phase 2 trial analysed chemoselection with docetaxel plus 5-fluorouracil and cisplatin (DCF) induction chemotherapy (ICT) and subsequent conversion surgery (CS) for locally advanced unresectable esophageal cancer. This study presents updated 3-year analyses to further characterize the impact of DCF-ICT followed by CS. Esophageal cancer patients with clinical T4 disease, unresectable supraclavicular lymph node metastasis, or both were eligible for this study. The treatment starts with DCF-ICT, followed by CS if the cancer is resectable, or by concurrent chemoradiation if it is not resectable. This updated analysis presents 3-year overall survival (OS), 3-year progression-free survival (PFS), and pattern of relapse. The median follow-up period for the patients surviving without death was 39.3 months. The estimated 1-year OS was 66.7%, and the lower limit of the 80% confidence interval (CI) was 54.6%. The estimated 3-year OS was 46.6% (95% CI 34.2–63.5%). The OS for the patients who underwent R0 resection (n = 19) was significantly longer than for those who did not (3-year OS: 71.4% vs. 30.1%). The estimated 1-year PFS was 50.6%, and the 3-year PFS was 39.6%. The PFS for R0 was significantly longer than for non-R0 (3-year PFS: 61.3% vs 25.0%). Recurrence or progression at the primary site was observed in 31% of the non-R0 group. The rate of distant metastasis did not differ significantly between the non-R0 and R0 groups (21% vs 16%). Long-term follow-up evaluation confirmed that DCF chemoselection aimed at CS is feasible and promising in terms of survival for patients with locally advanced esophageal cancer.

BACKGROUND/AIM Oral mucositis (OM) is one of the frequent adverse events experienced by patients receiving chemotherapy. Most diagnoses of OM are based on complaints from patients. The aim of this study was to develop a tool to diagnose OM accurately. MATERIALS AND METHODS A central review system (CRS) was created to allow judgment when the patient background is completely unknown. The primary endpoint was the rate of grade 2 or higher OM, and the secondary endpoint was the difference in grade between each institution's clinician judgement and that of the CRS. RESULTS In total, 53 patients were registered from four institutions. CRS successfully detected grade 2 or higher OM in 16 (30.2%) of the 53 patients. The detection rate of all grades of OM was 41.5% (22 of 53 patients) by each institution's clinician judgement and 84.9% (45 of 53 patients) by CRS judgement (p

Aim Evaluation of the therapeutic efficacy of carbon-ion radiation therapy for isolated lymph node recurrence following curative resection of esophageal cancer. Materials and methods Ten cases with lymph node recurrence after esophageal cancer surgery were treated with carbon-ion radiation therapy. A total of 48.0 Gy [relative biologic effectiveness (RBE)] was delivered over 3 weeks with a daily dose of 4.0 Gy (RBE). Results The median follow-up duration was 27.1 months (range=3-92.0 months) after carbon-ion radiation therapy. The local control rates at 2, 3 and 5 years were 92.4%. The overall survival rates at 2, 3 and 5 years were 70.0%, 58.3% and 21.9%. The median survival period was 45.3 months after carbon-ion radiation therapy. There were no toxicities of grade 3 or higher. Conclusion Carbon-ion radiation therapy may be a safe and effective treatment option for isolated lymph node recurrence after radical surgery for esophageal cancer.

Phototheranostics represents a highly promising paradigm for cancer therapy, although selecting an appropriate optical imager for clinical use remains challenging. We evaluated the phototheranostic nanoparticle-related properties of liposomally formulated phospholipid-conjugated indocyanine green, denoted as LP-iDOPE, for cancer diagnosis and treatment using photobiomodulation with a near-infrared (NIR)-light emitting diode (LED) light irradiator. Using in vivo NIR fluorescence imaging, we demonstrated that LP-iDOPE was selectively delivered to tumor sites with high accumulation and a long half-life. Following NIR-LED light irradiation of the tumor region of LP-iDOPE accumulation, effector CD8+ T cells were activated at the secondary lymphoid organs, migrated, and subsequently released cytokines including interferon-γ and tumor necrosis factor-α, resulting in effective tumor regression. Our cancer immunotherapy strategy using LP-iDOPE as a phototheranostic nanoparticle and an NIR-LED light irradiator as a photobiomodulation device represents a promising approach to noninvasive cancer therapy.

Purpose Oral mucositis (OM) is one of the most uncomfortable adverse events experienced by cancer patients undergoing chemotherapy. Previous reports have revealed that the oral administration of an elemental diet (ED) may prevent OM. However, the incidence of OM has not been accurately determined by specialized diagnostic methods and the effects of an ED on OM remain unclear. We investigated the dose that could feasibly be administered and its effects with regard to the suppression of OM in esophageal cancer patients undergoing chemotherapy. Methods We performed a prospective multi-center feasibility study of the administration of an ED (160 g/day) with 2 cycles of docetaxel/cisplatin/5-FU (DCF) chemotherapy. We assessed compliance to the ED for 49 days and the incidence of OM according to the amount of the ED that was orally administered. The incidence of OM was graded by a dental specialist who was experienced in dental oncology using a central OM review system. Results Fourteen of 20 patients (70%) were able to complete the orally administered ED (160 g/day) during the course of chemotherapy. Three patients (15%) could not take the ED orally for 9, 14, and 21 days, respectively, while 1 patient (5%) took the ED orally at an average dose of 80 g/day for 35 days. The remaining 2 patients (10%) could not take the 80 g/day dose for 11 and 12 days, respectively. The incidence of grade ≥ 2 OM in the ED completion group (15.4%, 2 of 13 patients) was significantly lower than that in the non-completion group (66.7%, 4 of 6 patients) (p = 0.046). Conclusions An ED might be a one of the test treatment to reduce the incidence of OM in esophageal cancer patients treated with DCF and should be evaluated in further randomized study. Clinical trial The date of submission: Dec 08th, 2017. Electronic supplementary material The online version of this article (10.1007/s10388-018-0620-1) contains supplementary material, which is available to authorized users.

Overexpression of alternative splicing of far upstream element binding protein 1 (FUBP1) interacting repressor (FIR; poly(U) binding splicing factor 60 [PUF60]) and cyclin E were detected in esophageal squamous cell carcinomas (ESCC). Accordingly, the expression of FBW7 was examined by which cyclin E is degraded as a substrate via the proteasome system. Expectedly, FBW7 expression was decreased significantly in ESCC. Conversely, c-myc gene transcriptional repressor FIR (alias PUF60; U2AF-related protein) and its alternative splicing variant form (FIRΔexon2) were overexpressed in ESCC. Further, anticancer drugs (cis-diaminedichloroplatinum/cisplatin [CDDP] or 5-fluorouracil [5-FU]) and knockdown of FIR by small interfering RNA (siRNA) increased cyclin E while knockdown of FIRΔexon2 by siRNA decreased cyclin E expression in ESCC cell lines (TE1, TE2, and T.Tn) or cervical SCC cells (HeLa cells). Especially, knockdown of SAP155 (SF3b1), a splicing factor required for proper alternative splicing of FIR pre-mRNA, decreased cyclin E. Therefore, disturbed alternative splicing of FIR generated FIR/FIRΔexon2 with cyclin E overexpression in esophageal cancers, indicating that SAP155 siRNA potentially rescued FBW7 function by reducing expression of FIR and/or FIRΔexon2. Remarkably, Three-dimensional structure analysis revealed the hypothetical inhibitory mechanism of FBW7 function by FIR/FIRΔexon2, a novel mechanism of cyclin E overexpression by FIR/FIRΔexon2-FBW7 interaction was discussed. Clinically, elevated FIR expression potentially is an indicator of the number of lymph metastases and anti-FIR/FIRΔexon2 antibodies in sera as cancer diagnosis, indicating chemical inhibitors of FIR/FIRΔexon2-FBW7 interaction could be potential candidate drugs for cancer therapy. In conclusion, elevated cyclin E expression was, in part, induced owing to potential FIR/FIRΔexon2-FBW7 interaction in ESCC.

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). 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. 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). 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.

Esophageal squamous cell carcinoma (ESCC) is an intractable digestive organ cancer that has proven difficult to treat despite multidisciplinary therapy, and a new treatment strategy is demanded. Metformin is used for type 2 diabetes mellitus and its antitumor effects have been reported recently. Metformin exerts antitumor effects in various respects, such as inhibiting inflammation, tumor growth and epithelial-mesenchymal transition (EMT). However, few reports have described the efficacy of metformin on ESCC, and their findings have been controversial. We analyzed the antitumor effects of metformin and clarified its effects on anti-inflammation, growth suppression and EMT inhibition. Activation of nuclear factor kappa B (NF-κB), the major transcription factor induced by inflammation, was investigated by immunostaining. We found that localization of NF-κB in the nucleus was reduced after metformin treatment. This suggests that metformin inhibited the activation of NF-κB. Metformin inhibited tumor growth and induced apoptosis in ESCC cell lines. Associated with EMT, we examined cell motility by a wound healing assay and the epithelial marker E-cadherin expression of various ESCC cell lines by western blotting. Metformin inhibited cell motility and induced E-cadherin expression. In conclusion, metformin showed multiple antitumor effects such as growth suppression, invasion inhibition, and control of EMT by inhibiting NF-κB localization on ESCC. Further exploration of the marker of treatment efficacy and combination therapy could result in the possibility for novel treatment to use metformin on ESCC.

A 65-year-old man with cT1bN0M0 stage I middle thoracic esophageal cancer underwent subtotal esophagectomy and gastric tube reconstruction through the posterior mediastinal route after preoperative carbon-ion radiotherapy and chemotherapy in a clinical trial. Anastomotic leakage occurred, but it spontaneously improved. At six months after the operation, he was rehospitalized with a cough and dysphagia. An esophago-bronchiole fistula and stenosis of the gastric tube were observed. He first underwent stent placement in the gastric tube. Two weeks later, the syringeal epithelium was burned by argon plasma coagulation after stent removal. Endoscopic occlusion was then performed for the fistula with two guidewire-assisted silicone spigots. Two weeks later, he was discharged on an oral diet, and he has not developed recurrence of the fistula or cancer for three years. This is the first report of endoscopic occlusion with a guidewire-assisted silicone spigot through the esophagus.

This is a retrospective study to evaluate the prevention of complications of metallic stent placement in patients with unresectable advanced esophageal cancer. A total of 87 patients were treated with 4 types of metal stents in the esophagus over a period of 18 years. Stent placement was technically successful. The most common prior treatment was chemoradiotherapy. There were no significant differences in the rate of patients with no complications among the prior treatments. Approximately, 30% of patients had the most common chest pain in complications. Stent placement within one month after the completion of chemoradiotherapy should be avoided for the prevention of the chest pain. There was no significant difference in the rate of patients with no complications by lesion location. The rate of no complications was higher for the Niti-S stent than the Gianturco Z-stent or Ultraflex stent. Of note, no complications were noted for the Niti-S ultrathin stent at all. Among cases of stent-related death, the most common type of complication was respiratory disorder caused by the stent that seems to be thick and hard. Therefore, the stent with thin and flexible characteristics like the Niti-S ultrathin stent will solve the various problems of esophageal stent placement.

Objective: ZNF750, an epidermal differentiation regulator, has been suggested to act as a tumor suppressor of esophageal squamous cell carcinoma (ESCC). Although a correlation between the epidermal differentiation gene and resistance to chemoradiotherapy (CRT) has been posited, no data regarding the ZNF750 status in ESCC have been reported. The aim of the present study was to evaluate the relationship between ZNF750 expression and response to CRT in ESCC. Methods: Eighty-seven patients who had been pathologically diagnosed with ESCC were evaluated in the present study. All patients underwent neoadjuvant CRT, followed by curative esophagectomy. The expression of ZNF750 in pretreatment biopsy samples was immunohistochemically investigated and compared to the histopathological effectiveness of CRT in surgical specimens. Results: High expression of ZNF750 was closely correlated with good sensitivity to CRT (p = 0.016). A univariate analysis showed that high/intermediate expression of ZNF750 was a significant predictive factor for good sensitivity to CRT (p = 0.006). High/intermediate expression of ZNF750 (30% or more) remained an independent predictive factor for sensitivity to CRT in a multivariate analysis (p = 0.033). Conclusions: ZNF750 expression predicts sensitivity to CRT and can be a biomarker that reliably predicts the response of ESCC to CRT.

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). 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. 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. 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 standard treatment for locally advanced unresectable squamous cell carcinoma (SCC) of the oesophagus is chemoradiation with cisplatin and 5-fluorouracil (CF-RT). This multicentre phase II trial assessed the safety and efficacy of chemoselection with docetaxel plus cisplatin and 5-fluorouracil (DCF) induction chemotherapy (ICT) and subsequent conversion surgery (CS) for initially unresectable locally advanced SCC of the oesophagus. Methods: Patients with clinical T4 and/or unresectable supraclavicular lymph node metastasis were eligible. Treatment started with three cycles of DCF-ICT, followed by CS if resectable, or by CF-RT if unresectable. The resectability was re-evaluated at 30–40 Gy of CF-RT, followed by CS if resectable, or by completion of 60 Gy of CF-RT. If resectable after CF-RT, CS was performed. The primary end point was 1-year overall survival (OS). Results: From April 2013 to July 2014, 48 patients were enrolled. CS was performed in 41.7% (n=20), including DCF-CS (n=18), DCF-CF-RT40Gy-CS (n=1), and DCF-CF-RT60Gy-CS (n=1). R0 resection was confirmed in 19 patients (39.6%). Grade ⩾3 postoperative complications included one event each of recurrent laryngeal nerve palsy, lung infection, wound infection, pulmonary fistula, and dysphagia; but no serious postoperative complications were observed in patients undergoing CS. Clinical complete response after CF-RT was confirmed in 4 patients (8.3%). The estimated 1-year OS was 67.9% and lower limit of 80% confidence interval was 59.7%. There was one treatment-related death in patient receiving DCF-CF-RT60Gy. Conclusions: Chemoselection with DCF-ICT followed by CS as a multidisciplinary treatment strategy showed promising signs of tolerability and efficacy in patients with locally advanced unresectable SCC of the oesophagus.

Background We performed endoscopic ultrasound real-time tissue elastography to more accurately diagnose lymph node metastasis of esophageal cancer. The aim of this study was to evaluate the ability of EUS elastography to distinguish benign from malignant lymph nodes in esophageal cancer patients. Methods The present study had two steps. As the first step (study 1), we developed diagnostic criteria for metastatic lymph nodes using elastography and verified the validity of the criteria. Three hundred and twenty-two lymph nodes from 35 patients treated by surgical resection were included in the study. As the second step (study 2), we preoperatively examined the lymph nodes of esophageal cancer patients with EUS elastography and compared its diagnostic performance with that of the conventional B-mode EUS images. A total of 115 lymph nodes from 31 patients were included. Results In study 1, lymph nodes were considered malignant if 50 % or more of the node appeared blue, or if the peripheral part of the lesion was blue and the central part was red/yellow/green. The sensitivity and specificity of the elastography were 79.7 and 97.6 % with an accuracy of 93.8 %, which was significantly higher than the values for conventional B-mode imaging. In study 2, the sensitivity and specificity of the EUS elastography were 91.2 and 94.5 % with an accuracy of 93.9 %, which was also significantly higher than the values for conventional B-mode EUS imaging. Conclusions The present study demonstrated that EUS elastography is useful for diagnosing lymph node metastasis of esophageal cancer.

Expression of genes is controlled by histone modification, histone acetylation and methylation, but abnormalities of these modifications have been observed in carcinogenesis and cancer development. The effect of the lysine-specific histone demethylase 1 (LSD1) inhibitor, a demethylating enzyme of histones, is thought to be caused by controlling the expression of genes. The aim of the present study is to elucidate the efficacies of the LSD1 inhibitor on the gene expression of esophageal cancer cell lines using chromatin immunoprecipitation (ChIP)-Seq. A comprehensive analysis of gene expression changes in esophageal squamous cell carcinoma (ESCC) cell lines induced by the LSD1 inhibitor NCL1 was clarified via analysis using microarray. In addition, ChIP-seq analysis was conducted using a SimpleChIP plus Enzymatic Chromatin IP kit. NCL1 strongly suppressed the proliferation of T.Tn and TE2 cells, which are ESCC cell lines, and further induced apoptosis. According to the combinatory analysis of ChIP-seq and microarray, 17 genes were upregulated, and 16 genes were downregulated in both cell lines. The comprehensive gene expression study performed in the present study is considered to be useful for analyzing the mechanism of the antitumor effect of the LSD1 inhibitor in patients with ESCC.

Objective: ZNF750, a transcriptional regulator of epidermal differentiation, has been identified as a tumor suppressor in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to investigate the clinical and prognostic significance of ZNF750 expression and to evaluate the effect of ZNF750 knockdown on cell proliferation, migration, and invasion in ESCC. Methods: A total of 124 patients with ESCC who underwent curative esophagectomy were evaluated in this study. The expression of ZNF750 in surgical specimens was immunohistochemically assessed and used in the analysis of clinicopathological features and overall survival (OS). The molecular role of ZNF750 was investigated by ZNF750 knockdown using small interfering RNA (siRNA) in ESCC cell lines. Results: Low ZNF750 expression had a significant correlation with positive lymph node metastasis (p = 0.028). Furthermore, there was a significant relationship between low expression of ZNF750 in ESCC and a poor OS, and a multivariate analysis showed that low ZNF750 expression was an independent prognostic factor (p = 0.020). The cell growth, migration, and invasion were significantly increased by downregulation of ZNF750. Conclusions: The low expression of ZNF750 was significantly associated with a poor prognosis, and ZNF750 expression may, therefore, be a reliable prognostic biomarker in ESCC.

In patients with obstructive esophageal cancer (OEC) with stenosis of the tract to the stomach, the percutaneous endoscopic gastrostomy (PEG) procedure cannot be performed if the endoscope is unable to pass through to the stomach. Our aim was to describe the safety and utility of the gradual tube dilation method (GTD) before PEG in cases of OEC. This study enrolled 38 consecutive patients. If an ultrathin transnasal endoscope (UTNE) could successfully reach the stomach through the esophageal stenosis, then PEG was performed without using the GTD. If even the UTNE could not be passed to the stomach, PEG was performed after the GTD. The GTD shows the method that gradually increases the size from an 8 Fr to 16 Fr nasogastric tube which passed through the obstruction before performing PEG. We conducted a retrospective review of all patients who received the GTD. The complications were examined from the first UTNE to the completion of PEG. Seventeen of 38 patients received the GTD. All 17 patients successfully underwent the PEG procedures. The intubation period was 9.8 ± 3.4 days. The mean number of replacements was 2.5. Regarding complications, only three of the 17 patients experienced a sore throat. No significant differences were found in the PEG procedure times between the patients with the GTD and those without the GTD (P = 0.360). If patients with progressive esophageal cancer, such as OEC, need to undergo PEG, then the GTD is considered to be a useful modality for dilating the stenosis simply and safely.

A male patient in his early seventies complained of swallowing difficulty and back pain. Esophagogastroscopy was performed and the patient was diagnosed as squamous cell carcinoma in the middle and lower part of the esophagus with a longitudinal submucosal elevation of 15 cm and S2 stage of gastric ulcer infected by Helicobacter pylori. Multiple lymph node swelling was detected not only in the mediastinum but also in the neck and the para-aortic area by CT scanning. The clinical stage was T3 N4 M0 Stage IVa. Systemic chemotherapy was applied first and the curative effectiveness was SD based on the RECIST criteria. PET revealed accumulation of FDG in the esophageal and stomach wall. These lesions were suspected to be HP-infected esophageal cancer, and Helicobacter pylori elimination was performed. After HP eradication, the tumor of the esophagus, submucosal elevation of esophagus, and gastric ulcer was markedly shrunk. Multiple lymph node swelling was definitely shrunk based on CT. Overall the early esophageal cancer remained. Endoscopic submucosal dissection (ESD) was performed. The pathological diagnosis was Type 0-IIc, pT1b(SM2), ly1, v2, pHM0, pVM0. After ESD, he indicated febrile neutropenia, was diagnosed as myelodysplastic syndrome (MDS) during the follow-up period and chose best supportive care (BSC).

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. 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. 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. 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.

Esophageal cancer is thought to be the most malignant neoplasm due to its biological aggressiveness. The most effective treatment modality for esophageal cancer, particularly T4 esophageal cancer, is chemoradiotherapy (CRT). Some T4 patients show long-term survival after receiving CRT, suggesting that even T4 esophageal cancer can be cured with this modality. Although surgery is performed after CRT in some T4 cases, its prognostic benefit is controversial. In this paper, we review the status of CRT and conversion surgery as well as the development of new regimens and discuss the future prospects of CRT in the treatment of T4 esophageal cancer in Japan.

The aim of this study was to clarify the importance of microRNA‑375 (miR‑375) expression in patients with esophageal squamous cell carcinoma (ESCC) and to examine the in vivo antitumor effects of miR‑375 in a model of ESCC using a non‑viral delivery system. We estimated the miR‑375 and LDHB and AEG‑1/MTDH mRNA expression of the ESCC tumors from 85 patients. The correlation between the miR‑375 expression and clinicopathological features, including the prognosis, were evaluated. The presence of high miR‑375 expression was associated with lymphatic vessel invasion, while a low expression of miR‑375 significantly correlated with a poor prognosis for the 85 ESCC patients. We also found that there was a significant inverse correlation between the expression of miR‑375 and that of LDHB. Before the examination of miR‑375 in the in vivo assay, we confirmed that atelocollagen prolonged the accumulation of miRNA by using fluorescently‑labeled miRNA and an in vivo imaging system. We injected the miR‑375/atelocollagen complex or a control‑miRNA/atelocollagen complex into mice bearing TE2 and T.Tn xenografts via subcutaneous (s.c.) injections. The growth of both the TE2 and T.Tn tumors in the miR‑375 groups was significantly suppressed compared with that in the control‑miRNA groups. In addition, The LDHB mRNA expression of TE2 xenografts was significantly downregulated after miR‑375 treatment. In conclusion, it might be possible for the level of miR‑375 expression to be a utilized as a prognostic indicator for ESCC patients. The administration of miR‑375 using a non‑viral delivery might represent a powerful new treatment for ESCC.

Short gastric vessel division (SGVD) has been performed as a part of fundoplication for achalasia. However, whether or not SGVD is necessary is still unknown. Forty-six patients with achalasia who underwent a laparoscopic surgery with or without SGVD were analyzed. A questionnaire was administered to assess the postoperative improvement. Regarding improvement of dysphagia and postoperative reflux, there were no significant differences between SGVD (+) group and SGVD (−) group (P = 0.588 and P = 0.686, respectively). Nineteen patients (95%) in the SGVD (+) group and 24 (92%) in the SGVD (−) group answered that the surgery was satisfactory (P = 0.756). In the SGVD (+) group, the pre- and postsurgical body weight increase was +7.3%. In the SGVD (−) group, it was 8.2%. There was no significant difference of body weight increase between the 2 groups (P = 0.354). SGVD is not always required in laparoscopic surgery for achalasia.

The aim of this study was to assess whether modulated electro-hyperthermia (mEHT) can induce an abscopal effect and thereby enhance the antitumor effects of immunotherapy. We used an intratumoral dendritic cell (DC) injection and mEHT to treat C3H/He mice inoculated with squamous cell carcinoma SCCVII cells in the left leg, and we assessed the whole body antitumor effects. Tumors were examined every two or three days in order to assess growth inhibition. The tumor-draining lymph nodes were removed to enable flow cytometric analysis of CD3+ and CD8+ cells, whereas immunohistochemistry was used to assess CD8, S100 and Foxp3 expression in the tumors. Additionally, GP96 expression in the tumors from the different treatment groups was measured. In the control group, the mean tumor volume was larger than that in other groups. These results indicated that the combination therapy of an intratumoral DC injection and mEHT evoked systemic antitumor activity. A larger number of CD3+ and CD8+ cells were detected by flow cytometric analysis in the DC plus mEHT treatment group. Tumor tissue immunostaining showed that CD8 and S100 were more strongly expressed in the DC plus mEHT treatment group, although Foxp3 expression was much higher in the control group. The GP96 gene expression level in the mEHT group was significantly different from the expression level in the control group. An abscopal effect may be induced by mEHT, and the effect of immunotherapy with DCs was strongly enhanced by the overexpression of GP96. GP96 is thought to be one of the molecules explaining the abscopal effect. Direct intratumoral administration of DCs and mEHT may be a feasible future treatment strategy.

Among patients with T4 thoracic esophageal squamous cell carcinoma (TESCC), it is unclear whether the outcomes of late responders who undergo high-dose chemoradiotherapy (CRT) followed by salvage esophagectomy differs from those of early responders who undergo low-dose CRT followed by esophagectomy. A total of 153 patients with T4 TESCC were treated with CRT. The first evaluation was performed after 40 Gy of CRT for downstaging. Of these, 28 patients could be downstaged, and underwent subsequent surgery (early responders). For the remaining patients, additional CRT was administered, and patients were re-evaluated after treatment and underwent salvage surgery. In total, 40 patients (early + late responders) were analyzed. The primary tumors exhibited a grade 3 response in six (21.4 %) of the early responders and two (16.7 %) of the late responders (p = 1.000). The rate of residual tumor in the primary tumor was 80 % (32/40 patients). The proportions of resected lymph nodes and positive metastatic nodes were similar between early and late responders (p = 0.406 and p = 0.859, respectively). The 5-year overall survival rates among the early and late responders were 25.9 and 36.5 %, respectively, and the median survival times were 24.8 and 24.3 months (p = 0.925), respectively. The 5-year cause-specific survival rates in the early and late responder groups were 61.5 and 72.9 % (p = 0.425), respectively. The outcomes of both early and late responders to CRT were similar, and salvage surgery for T4 TESCC outweighs the risks in patients with T4 TESCC.

Gastrointestinal stromal tumors (GISTs) rarely arise in the esophagus, where carcinoma is the most common malignant neoplasm and leiomyoma is the most common benign tumor. Because of their rarity, the clinical course and treatment of esophageal GISTs are poorly understood. These lesions are generally thought to carry a poor prognosis, making the differential diagnosis of other common mesenchymal neoplasms essential, for both prognostic and therapeutic reasons. We report a case of successfully resected giant esophageal GIST, thought to be the largest resected GIST reported in Japan. The patient was a 65-year-old woman, in whom upper gastrointestinal endoscopy found a 180-mm submucosal tumor in the lower thoracic esophagus, extending just below the aortic arch. We diagnosed esophageal GIST, and the patient underwent middle and lower esophagectomy via left thoracotomy, followed by gastric tube reconstruction. The tumor was resected completely. Histopathological and immunohistochemical staining confirmed that the tumor was a high-risk lesion, and treatment with imatinib was initiated. Computed tomography showed liver metastasis 5 months later, but the patient is doing well 24 months after surgery.

Cyclooxygenase-2 (COX-2) is a key enzyme of prostaglandin (PG) synthesis that has been demonstrated to be overexpressed in several types of cancers. The function of COX-2 in tumor progression has been recently elucidated. In tumors in which COX-2 is overexpressed, the antitumor effects are suppressed. We examined the effects of celecoxib, a COX-2 inhibitor, in enhancing the antitumor effects of chemotherapy and radiotherapy for esophageal squamous cell carcinoma (ESCC) by reducing the COX-2 activity. We used the human esophageal squamous cell lines TE2 and T.Tn treated with celecoxib and 5-FU/radiation, after which cell viability assays were performed. Changes in the expressions of dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT) mRNA and PGE2 were also measured. In addition, apoptotic changes, and the invasion and migration activity in both the celecoxib and 5-FU treated cells were evaluated. The experiments showed that T.Tn and TE2 proliferation was strongly inhibited by the combination of 5-FU/radiation and the COX-2 inhibitor. Inhibiting the COX-2 activity induced a reduction in PGE2 levels in TE2/T.Tn cells. Following treatment with the COX-2 inhibitor and 5-FU, the OPRT expression was upregulated and the DPD expression was downregulated in the resistant cells. In addition, the combination treatment with the COX-2 inhibitor and 5-FU markedly inhibited both the cell invasion and migration activity. Therefore, COX-2 inhibitors can be useful enhancers of antitumor drugs and radiotherapy for ESCC.

Objective: The aim of this study was to identify alternative compounds to the tumor suppressor miR-375 using the connectivity map (CMAP) and to validate the antitumor effects of the identified drugs in esophageal squamous cell carcinoma (ESCC). Methods: Gene profiling of miR-375-treated TE2 and T.Tn cells was applied in order to search the CMAP database. Among the compounds identified using the CMAP, we focused on 8 drugs [(-)-epigallocatechin-3-gallate, metformin, rosiglitazone among others], excluding 2 drugs among the top 10 compounds. We evaluated whether these compounds possess tumor-suppressive functions in ESCC. Results: A cytotoxicity assay showed that the sensitivity of TE2 and T.Tn cells treated with the 8 compounds was evaluated based on IC50 values of 42.9 µM to 3.8 mM. A cell cycle analysis revealed that the percentage of TE2 and T.Tn cells incubated with 6 compounds in the G0/G1 phase or the G2/M phase increased by approximately 40-80%. A TUNEL assay showed that the percentages of apoptotic cells treated with almost all compounds were significantly increased (p < 0.05) compared with the control cells. Conclusion: The CMAP database is a useful tool for identifying compounds affecting the same molecular pathways, particularly products that are difficult to apply via practical approaches, such as microRNAs.

Postoperative anastomotic leaks and subsequent mediastinal abscess are serious complications. The purpose of this study was to assess the efficacy of naso-esophageal extraluminal drainage after thoracic esophagectomy with gastric conduit reconstruction using a posterior mediastinal route. About 50 of 365 patients (13.7%) with esophageal cancer and postoperative anastomotic leak after curative esophagectomy was investigated. Beginning in June 2009, naso-esophageal extraluminal drainage by inserting a naso-esophageal aspiration tube into the abscess cavity when percutaneous abscess drainage was introduced which was ineffective or technically impossible. Twenty-five patients underwent naso-esophageal extraluminal drainage concomitantly with enteral nutrition. Twenty-one (84%) patients had major leaks, one (4%) minor leak and three (12%) had endoscopically proven conduit necrosis. None of the naso-esophageal extraluminal drainage cases (100%) required reintervention or reoperation and all experienced complete cure (100%) during hospitalization. Endoscopic balloon dilatation was performed for four patients after discharge because of anastomotic stricture. Patients with leaks were divided into two groups: current group (n = 32), treated after June 2009, and preceding group (n = 18), treated prior to the introduction of naso-esophageal extraluminal drainage. Significantly more patients in the preceding group suffered respiratory failure (28% vs. 61%, p = 0.024), and higher reoperation rate (0% vs. 17%, p = 0.042) and hospital mortality (0% vs. 22%, p = 0.013). In the current group, 31 (97%) patients experienced complete cure during hospitalization. Naso-esophageal extraluminal drainage and concomitant enteral nutritional support are less invasive, and effective and powerful methods to treat even major leakage after esophagectomy. These methods may be an alternative management to improve mortality for patients with esophageal cancer.

Postoperative anastomotic leaks and subsequent mediastinal abscess are serious complications. The purpose of this study was to assess the efficacy of naso-esophageal extraluminal drainage after thoracic esophagectomy with gastric conduit reconstruction using a posterior mediastinal route. About 50 of 365 patients (13.7%) with esophageal cancer and postoperative anastomotic leak after curative esophagectomy was investigated. Beginning in June 2009, naso-esophageal extraluminal drainage by inserting a naso-esophageal aspiration tube into the abscess cavity when percutaneous abscess drainage was introduced which was ineffective or technically impossible. Twenty-five patients underwent naso-esophageal extraluminal drainage concomitantly with enteral nutrition. Twenty-one (84%) patients had major leaks, one (4%) minor leak and three (12%) had endoscopically proven conduit necrosis. None of the naso-esophageal extraluminal drainage cases (100%) required reintervention or reoperation and all experienced complete cure (100%) during hospitalization. Endoscopic balloon dilatation was performed for four patients after discharge because of anastomotic stricture. Patients with leaks were divided into two groups: current group (n = 32), treated after June 2009, and preceding group (n = 18), treated prior to the introduction of naso-esophageal extraluminal drainage. Significantly more patients in the preceding group suffered respiratory failure (28% vs. 61%, p = 0.024), and higher reoperation rate (0% vs. 17%, p = 0.042) and hospital mortality (0% vs. 22%, p = 0.013). In the current group, 31 (97%) patients experienced complete cure during hospitalization. Naso-esophageal extraluminal drainage and concomitant enteral nutritional support are less invasive, and effective and powerful methods to treat even major leakage after esophagectomy. These methods may be an alternative management to improve mortality for patients with esophageal cancer.

Background A multicenter phase II trial revealed that docetaxel plus 5-fluorouracil and cisplatin (DCF) induction chemotherapy (IC) and subsequent conversion surgery (CS) was tolerable and effective in patients with locally advanced unresectable esophageal cancer (LAUEC) (Br J Cancer 2016;115:1328–1334). Here, we report updated 3-year analyses to further characterize the impact of DCF-IC followed by CS. Methods Esophageal cancer patients with clinical T4 disease and/or unresectable supraclavicular lymph node metastasis were eligible. The treatment starts with 3 cycles of DCF-IC, followed by CS if resectable, or by concurrent radiation plus chemotherapy with 5-fluorouracil and cisplatin (CF-RT) if not resectable. This updated analysis represents 3-year overall survival (OS), 3-year progression free survival (PFS), location of relapse, and subsequent therapy. Results As of October 11, 2017, 25 patients were dead. The median follow-up period in patients surviving without death was 39.3 months (95%CI: 38.7 - 41.7months). The estimated 1-year OS was 66.7% and lower limit of 95% confidence interval was 54.6%. The estimated 3-year OS was 46.6% (95% CI; 34.2 - 63.5%). The OS for patients who underwent R0 resection (n = 19) was significantly longer than those who did not undergo R0 resection (3-year OS: 71.4% vs. 30.1%). The estimated 1-year PFS was 50.6% (95%CI: 38.1 - 67.3%) and the estimated 3-year PFS was 39.6% (95%CI: 27.7 - 56.6%). The PFS for patients who underwent R0 resection (n = 19) was significantly longer than those who did not undergo R0 resection (3-year PFS: 61.3% vs. 25%). The recurrence or progression in primary site was observed in 31% of non R0 group. There was no significant difference in the rates of distant metastasis between the two groups (non R0 group vs. R0 group; 21% vs. 16%). The subsequent therapy after protocol therapy included chemotherapy (n = 18), radiotherapy (n = 11), and surgery (n = 5). Conclusion This longer follow up of DCF-IC followed by CS strategy for patients with LAUEC revealed promising OS and PFS. Based on this phase 2 trial, JCOG1510, a prospective randomized controlled trial to compare chemoselection with DCF-IC followed by CS versus CF-RT as a standard treatment is in preparation for LAUEC. Disclosure All authors have declared no conflicts of interest.

Background: FSCN1 and matrix metalloproteinase 14 (MMP14) are both invadopodia-related proteins. We herein elucidate the tumourigenicity of these proteins and identify novel therapeutic agents in esophageal squamous cell carcinoma (ESCC). Methods: FSCN1 and MMP14 were evaluated by immunohistochemistry and quantitative PCR, and microRNA (miR)-133a was also evaluated by PCR in surgical ESCC specimens. The roles of FSCN1, MMP14 and miR-133a were established in ESCC cells. Results: The expression of FSCN1 or MMP14 was an independent poor prognostic factor according to a multivariate analysis of immunohistochemistry, and their co-expression correlated with the poorest overall survival (OS) out of all the examined factors. Additionally, their mRNAs significantly correlated and both inversely correlated with miR-133a in surgical specimens. Transfection of a miR-133a mimic decreased the mRNA and protein levels of both FSCN1 and MMP14 in ESCC cells. The knockdown of FSCN1 or MMP14 and transfection of a miR-133a mimic inhibited the proliferation and invasion of ESCC cells. Patients with a lower miR-133a expression have a significantly poorer OS than those with a higher expression. Conclusion: The combined expression of FSCN1 and MMP14 is associated with a poor prognosis, and miR-133a, which regulates their mRNAs, can serve as a strong tumour suppressor of ESCC.

A 67-year-old male was referred to our hospital after being diagnosed with esophageal squamous cell carcinoma of the middle thoracic esophagus. The clinical stage was T1b(sm)N4M1 cStage IVb, so he was admitted to our hospital for systemic chemotherapy. He had sustained fever and a dry cough. Chest computed tomography showed the presence of irregular shadows, and unidentified respiratory insufficiency had progressed. A transbronchial lung biopsy revealed a pulmonary artery tumor embolus of esophageal squamous cell carcinoma. He developed DIC and died of respiratory failure on the 19th hospital day. The postmortem autopsy detected pulmonary tumor thrombotic microangiopathy accompanied by esophageal squamous cell carcinoma.

An epiphrenic diverticulum is a pulsion pseudodiverticulum of the distal esophagus that is frequently associated with esophageal motility disorders. Therefore, a simple diverticulectomy leads to a poor outcome. High-resolution impedance manometry (HRIM), introduced recently, enables easier evaluation of both esophageal pressure and bolus transit dynamics. We report the case of a 40-year-old female diagnosed with an epiphrenic diverticulum with hypertensive lower esophageal sphincter pressure by use of HRIM. She underwent a laparoscopic transhiatal diverticulectomy with a long myotomy and Dor’s fundoplication and was discharged with no complications. Four weeks after the operation, HRIM was performed again, and showed no accumulation of water in the esophagus and improvement of bolus transit. We herein report the usefulness of HRIM for evaluation of esophageal motility disorders for patients with an epiphrenic diverticulum.

The purpose of this research is to determine the correlation between IGFBP-4/IGF-I expression and the clinical status of esophageal squamous cell carcinoma (ESCC). Immunohistochemical staining for IGFBP-4 and IGF-I was performed in 61 clinical samples. The correlation between IGFBP-4/IGF-I staining and clinicopathological features was examined statistically. In addition, we compared the mRNA expression levels of IGFBP-4 and IGF-I between ESCC cancer tissues and the normal esophageal epithelium using a quantitative real-time RT-PCR. According to the results of immunohistochemical staining, IGFBP-4 expression in the region of normal epithelial cells showed an increase of 52.5 % compared to expression in the tumor cells. There was no statistically significant correlation between IGFBP-4/IGF-I and clinicopathological features. The correlation between IGF-I and IGFBP-4 was not significant either. RT-PCR assay showed IGF-I expression in ESCC tissue has a tendency to be higher than that of normal esophageal epithelium. On the other hand, IGFBP-4 expression levels in cancer tissue were lower in comparison with normal epithelium. These results were not significant. There were the differences of IGFBP-4 expression between the region of ESCC and the region of normal epithelium cells. One suggested possibility is that IGF-independent action of IGFBP-4 might have taken part in these results. We need further exploratory experiments to elucidate the details of the actual function of IGFBP-4 expression in ESCC.

Background: Recent studies have demonstrated that microRNAs (miRNAs) are stably detectable in blood and can serve as useful biomarkers for cancer. Methods: We performed an miRNA array using serum samples obtained from oesophageal squamous cell carcinoma (ESCC) patients or healthy controls. MiR-1246 was the most markedly elevated in ESCC patients. Therefore, miR-1246 was selected as a candidate for further analysis. The serum miR-1246 level in 46 healthy controls and 101 ESCC patients was evaluated and compared among various clinicopathological characteristics. MiR-1246 expressions in tissue, exosomal, and cellular samples were also examined. Results: Serum miR-1246 alone yielded an receiver-operating characteristic curve area of 0.754, with 71.3% sensitivity and 73.9% specificity for distinguishing ESCC patients from healthy controls. Serum miR-1246 was significantly correlated with the TNM stage and showed to be the strongest independent risk factor for poor survival (HR, 4.032; P=0.017). Unlike the tendency shown in previous reports, miR-1246 was not upregulated in ESCC tissue samples. Furthermore, exosomal miR-1246 did not reflect the abundance in the cell of origin. Conclusion: These data support our contention that serum miR-1246 has strong potential as a novel diagnostic and prognostic biomarker in ESCC, and its releasing mechanism is selective and independent of tissue miRNA abundance.

We have rationally designed and synthesized a novel near-infrared (NIR) photoactivating probe, designated by iDOPE, in which an indocyanine green (ICG) fluorophore is covalently conjugated with a phospholipid moiety, 1,2-dioleoyl- sn -glycero-3-phosphoethanolamine (DOPE), to incorporate into liposome bilayers. NIR irradiation showed that iDOPE retained the optical and fluorescence properties of ICG and demonstrated photoactivator characteristics: fluorescence emission at around 820 nm in a solvent, singlet oxygen production, and concentration-dependent heat generation. Additionally, iDOPE was incorporated into liposome bilayers and maintained stable liposomally formulated iDOPE (LP-iDOPE) over 1 week under physiological conditions. We also observed the tumor-specific biodistribution of LP-iDOPE of in vivo xenografts. These findings suggest that LP-iDOPE might be a promising tool for NIR optical imaging, photodynamic therapy, and photothermal therapy.