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Esophageal squamous cell carcinoma (ESCC) is one of the most fatal types of malignant tumors worldwide. Epitranscriptome, such as N6 -methyladenosine (m6 A) of mRNA, is an abundant post-transcriptional mRNA modification and has been recently implicated to play roles in several cancers, whereas the significance of m6 A modifications is virtually unknown in ESCC. Analysis of tissue microarray of the tumors in 177 ESCC patients showed that higher expression of m6 A demethylase ALKBH5 correlated with poor prognosis and that ALKBH5 was an independent prognostic factor of the survival of patients. There was no correlation between the other demethylase FTO and prognosis. siRNA knockdown of ALKBH5 but not FTO significantly suppressed proliferation and migration of human ESCC cells. ALKBH5 knockdown delayed progression of cell cycle and accumulated the cells to G0/G1 phase. Mechanistically, expression of CDKN1A (p21) was significantly up-regulated in ALKBH5-depleted cells, and m6 A modification and stability of CDKN1A mRNA were increased by ALKBH5 knockdown. Furthermore, depletion of ALKBH5 substantially suppressed tumor growth of ESCC cells subcutaneously transplanted in BALB/c nude mice. Collectively, we identify ALKBH5 as the first m6 A demethylase that accelerates cell cycle progression and promotes cell proliferation of ESCC cells, which is associated with poor prognosis of ESCC patients.

Poor oral health is an independent risk factor for upper aerodigestive tract cancers, including esophageal squamous cell carcinoma (ESCC). The pattern recognition receptor Toll-like receptor 4 (TLR4) recognizes lipopolysaccharide in the cell walls of Gram-negative periodontal pathogens associated with the development and progression of ESCC. It is, therefore, plausible that TLR4 plays a crucial role in the pathogenesis of ESCC. We used an ESCC tissue microarray to confirm expression of TLR4 in patients with ESCC and to determine whether TLR4 expression status correlates with the clinicopathological features of these patients or their prognosis after esophagectomy. We also tested whether the combined expression statuses of TLR4 and TLR3 better correlate with prognosis in these patients than either parameter alone. Clinical ESCC samples from all 177 patients tested showed expression of TLR4. Moreover, high TLR4 expression (3 + and 2 +) correlated with poorer 5-year overall survival after esophagectomy than lower TLR4 expression (1 +) (p = 0.0491). Patients showing high TLR4 expression tended to have a poorer prognosis whether treated with surgery alone or with surgery and adjuvant chemotherapy. Univariate and multivariate analyses showed TLR4 expression status to be an independent prognostic factor affecting 5-year overall survival. Patients exhibiting high TLR4 expression with low TLR3 expression had a much poorer prognosis than other patients (p =

Despite wide acknowledgement of the importance of sarcopenia and prognostic markers such as the neutrophil-to-lymphocyte ratio, the impact on cancer patient survival of the timing of sarcopenia’s emergence and its severity is not well understood, nor is the association between sarcopenia and prognostic markers. The aim of this study, therefore, was to investigate the effect of the severity and timing of changes in the psoas muscle index (PMI) on survival of advanced esophageal squamous cell carcinoma (ESCC) patients receiving neoadjuvant chemoradiotherapy (NACRT) plus esophagectomy and the association between PMI and known prognostic markers. Included in this study were 113 ESCC patients who underwent NACRT followed by esophagectomy. PMI and prognostic markers were measured at their initial visit, just before surgery (after NACRT), and 3 months postoperatively. All patients were classified into four groups according to the percent decrease in PMI after NACRT and after NACRT plus esophagectomy. Patients exhibiting a larger PMI decrease (≥20%) after NACRT plus esophagectomy had significantly poorer overall survival than those showing a smaller PMI decrease. Furthermore, multivariable analysis showed that a larger decrease in PMI after NACRT plus esophagectomy was a significant risk factor for overall (P

Simple Summary This study aimed to clarify the efficacy of neoadjuvant chemoradiotherapy (NACRT) followed by esophagectomy with three-field lymph node (LN) dissection for clinical Stage III patients and for clinical Stage IVB patients with supraclavicular LN metastasis as the only distant metastatic factor. We observed that NACRT followed by esophagectomy with three-field lymph node dissection is feasible and offers the potential for long-term survival of these patients. It is also suggested that supraclavicular LNs should be treated as regional LNs at least in patients with upper and middle thoracic esophageal squamous cell carcinoma (ESCC). Abstract Background: Neoadjuvant chemoradiotherapy (NACRT) followed by esophagectomy is now the standard treatment for patients with resectable advanced thoracic esophageal squamous cell carcinoma (ESCC) worldwide. However, the efficacy of NACRT followed by esophagectomy with three-field lymph node dissection for clinical Stage III patients and for clinical Stage IVB patients with supraclavicular LN metastasis has not yet been determined. Methods: Between 2008 and 2018, 94 ESCC patients diagnosed as clinical Stage III and 18 patients diagnosed as clinical Stage IVB with supraclavicular LN metastasis as the only distant metastatic factor were treated with NACRT followed by esophagectomy with extended lymph node dissection at Akita University Hospital. Long-term survival and the patterns of recurrence in these 112 patients were analyzed. Results: The median follow-up period of censored cases was 60 months. The five-year OS and DSS rates among the clinical Stage III patients were 57.6% and 66.6%, respectively. The five-year OS and DSS rates among the clinical Stage IVB patients were 41.3% and 51.6%, respectively. The most frequent recurrence pattern was distant metastasis (69.2%) in the Stage III patients and LN metastasis (75.0%) in the Stage IVB patients. Conclusion: NACRT followed by esophagectomy with three-field LN dissection is feasible and offers the potential for long-term survival of clinical Stage III ESCC patients and even clinical Stage IVB patients with supraclavicular LN metastasis as the only distant metastatic factor. At least in patients with upper and middle thoracic ESCC, treating supraclavicular LNs as regional LNs seems to be appropriate.

Background/aim The platelet distribution width (PDW) and serum C-reactive protein (CRP) levels are known to be predictive of prognosis in various malignancies. Our aim was to determine whether combining PDW and serum CRP levels produces a prognostic indicator for esophageal cancer (EC) patients. Patients and methods A total of 168 EC patients who underwent neoadjuvant therapy prior to esophagectomy were included in this study. Results We defined a combined PDW and CRP (CPC) score as follows: patients with both low pretherapeutic PDW (≤12.4 fl) and high postoperative serum CRP levels (≥0.5 mg/dl) were assigned a score of 2, while patients with one or neither of those were assigned a score of 1 or 0. A multivariable analysis showed that the CPC score was a significant risk factor for overall (p=0.006) and recurrence-free (p=0.004) survival. Conclusion The CPC score is a strong prognostic indicator in EC patients.

Esophageal squamous cell carcinoma (ESCC) is one of the most fatal types of malignant tumors worldwide. Epitranscriptome, such as N

Background Preoperative clinical diagnosis of lymph node (LN) metastasis and subsequent pathological diagnosis are often not in agreement. Detection of false-negative LNs is essential in selecting an optimal treatment strategy, and most importantly, the presence of false-negative LN is itself a significant prognostic indicator. Therefore, at present, there is an urgent need to establish more accurate and individualized evaluation methods for LN metastasis. Methods Of 213 cN0 patients who underwent curative esophagectomy without preoperative neoadjuvant treatment, 60 (28%) had LN metastasis diagnosed pathologically. There were 129 false-negative LNs, of which 85 were detectable by preoperative computed tomography (CT). We retrospectively investigated the distribution, frequency, and characteristics of pathologically positive nodes in patients with clinically N0 esophageal cancer. Results The paracardial region was the most frequent region of false-negative LNs, accounting for 26% (22 LNs) of the total incidence. False-negative LNs distributed widely from the neck to the abdomen in patients with a primary tumor in the middle thoracic esophagus. In patients with a primary tumor in the lower thoracic esophagus, four false-negative LNs were detected in the superior mediastinum. When the short-axis diameter, shape, and attenuation patterns of the LNs were used as criteria for metastasis diagnosis, they were insufficient for an accurate diagnosis. However, false-negative LNs in the most frequently occurring sites are characterized by smaller short-axis, suggesting that accurate diagnosis cannot be made unless the diagnostic criteria for the short-axis are reduced in addition to shape and attenuation. Conclusions Although restrictive to the most frequent regions of false-negative LNs occur, reducing size criterion and consideration of their shape and attenuation may contribute to improved diagnosis.

The incidence of anastomotic leakage after esophagectomy remains around 10%. It was previously reported that PDSII rapidly loses tensile strength at pH 1.0 and pH 8.5. By contrast, LACLON degradation is reportedly insensitive to pH. We therefore compared LACLON with PDSII for esophago-gastric conduit, layer-to-layer, handsewn anastomosis. Between January 2016 and January 2020, 90 patients who received posterior mediastinal gastric conduit reconstruction with layer-to-layer handsewn anastomosis (51 using PDSII and 39 using LACLON) at Akita University Hospital were enrolled. The incidence of anastomotic leakage was significantly lower in the LACLON (2.6%, 1/39 patients) than PDSII group (15.7%, 8/51 patients) (p = 0.0268). Multivariable logistic analysis showed the risk of anastomotic leakage was significantly greater with PDSII than LACLON (odds ratio 11.01; 95% CI 1.326–277.64; p = 0.024). The percentages of time the pH was higher than 8 on the gastric conduit side of the anastomosis were 3.1%, 5.7%, 20.9% and 80.5%, respectively, in the four most recent patients. The present study showed that pH at the anastomosis soon after esophagectomy tends to be alkaline rather than acidic, which raises the possibility that this alkalinity facilitates the deterioration of surgical sutures including PDSII.

To establish whether Sphingosine-1-phosphate (S1P) and sphingosine kinase 1 (SphK1) contribute to lymph node metastasis in esophageal squamous cell carcinoma.Immunohistochemical analysis of SphK1 expression was performed using a tissue microarray containing 177 thoracic squamous cell esophageal cancer specimens resected at surgery, to investigate the association between intratumoral SphK1 expression and lymph node metastasis. Serum S1P levels and intratumoral SphK1 mRNA and protein expression were also evaluated in mice with vs. mice without lymph node metastasis in a murine lymph node metastasis model.Among 177 esophageal cancer patients, 127 (72%) were defined as being SphK1-positive. In univariate and multivariate analyses, SphK1 expression status was a significant factor contributing to lymph node metastasis and poorer 5-year overall survival. In the murine lymph node metastasis model, there was no difference in tumor volume or weight between the lymph node metastasis-negative and lymph node metastasis-positive groups. However, levels of SphK1 mRNA and protein and serum S1P levels were all much higher in the metastasis-positive group.S1P/SphK1 may be novel targets for inhibiting lymph node metastasis in esophageal squamous cell carcinoma, and may provide the basis for a therapeutic strategy to suppress lymph node metastasis.

Background/aim The potential advantages of robot-assisted thoracoscopic esophagectomy (RATE) have yet to be verified. This study focused on the degree of lymph node dissection around the left recurrent laryngeal nerve (RLN). Patients and methods A total of 21 consecutive patients who received RATE (RATE group) and 38 who received conventional thoracoscopic esophagectomy (TE) (TE group), both with extended lymphadenectomy, for thoracic squamous cell esophageal carcinoma, were enrolled in this study. We compared the numbers of lymph nodes dissected from the mediastinum, especially around the left RLN. Results The median number of lymph nodes dissected from around the left RLN was 6 in the RATE group and 4 in the TE group, and the ratio of the dissected lymph nodes around the left RLN to all lymph nodes was significantly higher in the RATE group (p=0.048). Conclusion Our findings indicate that a robot-assisted surgical system enables for more extensive dissection of lymph nodes around the left RLN.

Background Loss of skeletal muscle is predictive of a poor prognosis in patients with various malignant lesions. Our aim was to determine whether changes in skeletal muscle after neo-adjuvant therapy (NAT) predict prognosis in patients with esophageal squamous cell carcinoma (ESCC) undergoing esophagectomy. Patients and methods The cross-sectional areas of the psoas muscles were measured on computed tomographic images collected at the initial visit, preoperatively and postoperatively in 84 patients. The psoas muscle index (PMI) was calculated by normalizing the cross-sectional areas to the patients' heights. Results Low PMI at the initial visit was not associated with a poor prognosis. The majority of patients showed decreased PMI after NAT and surgery. The group in which the post-NAT PMI decreased had poorer overall survival than group without PMI decrease (p=0.025). Conclusion Decreased PMI correlates well with a poor prognosis in patients with ESCC. Changes in PMI over a period of time may have greater sensitivity when evaluating prognosis than the PMI at any single time point.

Aim We investigated the safety of adding Japanese-style extended 3-field lymphadenectomy in patients treated with neoadjuvant chemoradiotherapy (NACRT) for thoracic esophageal squamous cell carcinoma (TESCC). Furthermore, the efficacy of NACRT, as shown by the pathological and metabolic responses were determined. Patients and methods One hundred consecutive patients with cStage II-IV TESSC were enrolled. We analyzed the adverse events related to NACRT and surgical complications following surgery. Pathological responses to NACRT and the association between pCR and [18F]-fluorodeoxyglucose positron-emission tomography (FDG-PET) evaluation were investigated. Results Adding Japanese-style extended 3-field lymph node dissection after NACRT did not increase serious surgical complications. Seventy-four percent of patients experienced grade 2-3 pathological response, with 25% achieving pCR. There was a significant relationship between the change from positive to negative findings on FDG-PET/CT and pCR. Conclusion Transthoracic esophagectomy with Japanese-style extended 3-field lymph node dissection after NACRT is a safe and powerful treatment.

Aim We investigated which is the stronger predictor, pathological response or metabolic response, for survival outcome in patients treated with neoadjuvant chemoradiotherapy (NACRT) plus esophagectomy for thoracic esophageal squamous cell carcinoma (TESCC). Patients and methods Fifty consecutive patients with cStage IIB-IV TESCC were enrolled. We analyzed the pathological response and metabolic response (fractional decrease in tumor maximum standardized uptake value) to NACRT. Independent prognostic factors predictive of 3-year survival were investigated using univariate and multivariate analyses. Results Among the 50 patients, 10 (20%) showed a pathological complete response (in both tumor and lymph nodes) and 36 (72%) showed grade 2-3 pathological response. Univariate analysis showed that age, gender, cT stage, pathological response and metabolic response to be significant prognostic factors. A subsequent multivariate analysis confirmed metabolic response and gender to be significant prognostic factors. Conclusion Metabolic response for NACRT was an independent prognostic factor and a more powerful predictor of survival compared to pathological response.

Background We evaluated that metabolic response using [18F]-Fluorodeoxyglucose positron-emission tomography/computed tomography (PET/CT) predicts survival outcome in patients treated with neoadjuvant chemoradiotherapy (NACRT) plus esophagectomy for thoracic esophageal squamous cell carcinoma (TESCC). Methods Fifty consecutive Japanese patients with cStage IIB-IV TESCC, treated at our hospital between April 2009 and January 2014, were enrolled. We analyzed the metabolic response (fractional decrease in tumor maximum standardized uptake value) to NACRT. Independent prognostic factors predictive of 3-year survival were investigated using univariate and multivariate analysis. Results The study participants included 41 (82%) males and 9 (18%) females, with an age of 62.5 (rage 43–74) years. All 42 patients examined were found to be positive for tumors on FDG-PET/CT before treatment. After NACRT, 28% (10/36) of patients had changed from positive to negative for tumor on FDG-PET/CT. Seventy-one percent (30/42) of patients were positive for lymph node involvement on FDG-PET/CT before treatment. After NACRT, 81% (22/27) of patients previously positive for lymph node involvement were negative on FDG-PET/CT. The median fractional decrease in tumor SUVmax was 75% (range = 19–90%). We found that there was a significant correlation between a decrease in FDG-PET/CT and recurrence. Consistent with those findings, univariate and multivariate analysis taking into consideration age, gender, cT, cN, cM, adverse events, interval between NACRT and surgery, number of dissected LNs, pT, pN, pCR, pathological response, and fractional decrease in tumor SUVmax showed that fractional decrease in tumor SUVmax of Conclusion Metabolic response as a decrease in SUVmax of ≥ 75% was an independent prognostic factor for 3-year overall survival in multivariate analysis and associated with recurrence. On the other hand, cT, cN, pT, pN, pCR were not associated with survival outcome or recurrence. Disclosure All authors have declared no conflicts of interest.

Background/aim Programmed death-1 ligand 1 (PD-L1) induces apoptosis of tumor-reactive T-cells, that enables tumors to evade immune defense and thus furthers their growth. Our aim was to determine whether PD-L1 expression status correlates with prognosis in patients with advanced thoracic esophageal squamous cell carcinoma. Patients and methods The PD-L1 expression status of 177 patients treated with esophagectomy without preoperative therapy was evaluated immunohistochemically using tissue microarray. We then statistically analyzed the relationships between PD-L1 expression status and clinicopathological features and survival. Results In patients undergoing surgery alone, PD-L1 expression was significantly positivity associated with a better prognosis. By contrast, there were no significant correlations between PD-L1 expression and clinicopathological features or outcomes in patients treated with surgery plus postoperative adjuvant chemotherapy. Conclusion PD-L1 positivity in advanced thoracic esophageal squamous cell carcinoma may be predictive of a positive prognosis in patients treated without adjuvant chemotherapy.

Highlights • Three cases of postoperative chylothorax were successfully diagnosed or cured by intranodal lipiodol lymphangiography. • It is a minimally invasive and easily performed procedure and we recommend an early performance of this procedure. • A therapeutic strategy for postoperative chylothorax is proposed., Introduction Ultrasound-guided intranodal lipiodol lymphangiography (LAG) from the groin is a recently introduced technique for diagnosing and treating postoperative chylothorax. The benefits of this technique include reduced technical difficulty and shorter procedure duration, as compared to traditional pedal LAG. Although these benefits may eventually increase utilization of intranodal LAG, reports are still few. Presentation of cases Herein, we report three cases of post-esophagectomy chylothorax in whom ultrasound-guided intranodal lipiodol LAG from the groin were successfully performed with no complications. Leak points were clearly identified in the three cases. Cure was obtained in one case by the LAG only. Surgical ligations were performed after LAG in two cases and cures were achieved. Discussion If LAG successfully cured chylothorax, chest drain output would decrease dramatically and the leaked lipiodol could be confirmed near the leak point in plain computerized tomography (CT) in the following 1-2 days. But if LAG failed to cure, chest drain output would be unchanged and the leaked lipiodol would be found diffusing in the surrounding. Conclusion Ultrasound-guided intranodal lipiodol LAG from the groin is a minimally invasive and easily performed procedure with high diagnostic and therapeutic value for postoperative chylothorax. If LAG failed to cure, conservative management is often insufficient and surgical ligation should be performed as soon as possible.

Background: Poor oral health is a risk factor for causing upper aerodigestive tract tumors, including esophageal cancer. Our aim was to determine the periodontitis rate in our cohort of esophageal cancer patients. We also analyzed whether preoperative dental examination and care reduces the likelihood of severe pneumonia after esophagectomy. Study Design: Between 2003 and 2014, 529 esophageal cancer patients received esophagectomy at Akita University Hospital. We studied 232 patients who had preoperative dental examinations and care (dental care group) retrospectively and assessed the severity of their periodontitis. The dental care group was compared to 297 patients who did not have preoperative dental care (control group) with respect to the incidence of severe pneumonia after esophagectomy. Results: Ninety-one patients (39.2%) in the dental care group were diagnosed with slight periodontitis and 69 (29.7%) were diagnosed with severe periodontitis. Among all the patients, 69 patients (13.0%) were diagnosed with grade 3B postoperative severe pneumonia. The dental care group had a significantly lower incidence of severe pneumonia than the control group. Moreover, multivariable logistic regression analysis revealed that anastomotic leakage, preoperative dental care, gender and %VC were correlated significantly with the occurrence of postoperative severe pneumonia. Conclusion: Preoperative dental examination and care by a dentist are essential to reduce the likelihood of postoperative severe pneumonia in esophageal cancer patients.