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Objectives Tumor-infiltrating lymphocytes (TILs) have long been recognized as playing an important role in tumor immune microenvironment. Lately, the Immunoscore (IS) has been proposed as a new method of quantifying the number of TILs in association with patient survival in several cancer types. Methods In 300 preoperatively untreated esophageal cancer (EC) patients who underwent curative resection at two different institutes, immunohistochemical staining using CD3 and CD8 antibodies was performed to evaluate IS, as objectively scored by auto-counted TILs in the tumor core and invasive margin. In addition, in pre-neoadjuvant chemotherapy (pre-NAC) endoscopic biopsies of a different cohort of 146 EC patients who received NAC, CD3 and CD8 were immunostained to evaluate TIL density. Results In all cases, the IS-high (score 3-4) group tended to have better survival (5-year overall survival [OS] of the IS-high vs low group: 77.6 vs 65.8%, P = 0.0722) than the IS-low (score 1-2) group. This trend was more remarkable in cStage II-IV patients (70.2 vs 54.5%, P = 0.0208) and multivariate analysis of OS further identified IS (hazard ratio 2.07, P = 0.0043) to be an independent prognostic variable. In preNAC biopsies, NAC-responders had higher densities than non-responders of both CD3+ (P = 0.0106) and CD8+ cells (P = 0.0729) and, particularly CD3+ cell density was found to be an independent prognostic factor (hazard ratio 1.75, P = 0.0169). Conclusions The IS signature in surgical specimens and TIL density in preNAC-biopsies could be predictive markers of clinical outcomes in EC patients.

OBJECTIVE To evaluate pathological response to NAC in metastatic LNs, and assess its clinical prognostic significance in patients with EC. SUMMARY OF BACKGROUND DATA The pathological response to preoperative treatment is commonly evaluated in the PT. However, LN metastases strongly correlate with systemic micro-metastases. Thus, pathological evaluation of LN response could more accurately predict prognosis in EC patients undergoing NAC before surgery. METHODS We enrolled 371 consecutive patients who underwent triplet NAC followed by surgery for EC between January 2010 and December 2016. Pathological LN regression grade was defined by the proportion of viable tumor area within the whole tumor bed area for all metastatic LNs: grade I, >50%; II, 10%-50%; III

The aim of the study was to determine the optimal extent of lymph node dissection for the 2 histological types of esophagogastric junction (EGJ) tumors based on the incidence of metastasis in a prospective nationwide multicenter study.Because most previous studies were retrospective, the optimal surgical procedure for EGJ tumors has not been standardized.Patients with cT2-T4 adenocarcinoma or squamous cell carcinoma located within 2.0 cm of the EGJ were enrolled before surgery. Surgeons dissected all lymph nodes prespecified in the protocol, using either the abdominal transhiatal or right transthoracic approach. The primary endpoint was the metastasis rate of each lymph node. Lymph nodes were classified according to metastasis rate, as follows: category-1 (strongly recommended for dissection), rate more than 10%; category-2 (weakly recommended for dissection), rate from 5% to 10%; and category-3 (not recommended for dissection), rate less than 5%.Between 2014 and 2017, 1065 patients with EGJ tumor were screened, and 371 were enrolled. Among 358 patients who underwent surgical resection, category-1 nodes included abdominal stations 1, 2, 3, 7, 9, and 11p, whereas category-2 nodes included abdominal stations 8a, 19, and lower mediastinal station 110. If esophageal involvement exceeded 2.0 cm, station 110 was assigned to category-1. Among 98 patients who had either adenocarcinoma with esophageal involvement over 3.0 cm or squamous cell carcinoma, there were no category-1 nodes in the upper/middle mediastinal field, whereas category-2 nodes included upper mediastinal station 106recR and middle mediastinal station 108. When esophageal involvement exceeded 4.0 cm, station 106recR was assigned to category-1.The study accurately identified the distribution of lymph node metastases from EGJ tumors and the optimal extent of subsequent lymph node dissection.

OBJECTIVE The aim of this study was to evaluate primary tumor (PT) and lymph node (LN) responses to neoadjuvant chemotherapy (NACT) for predicting long-term survival in patients with metastatic esophageal cancer (EC). BACKGROUND In evaluating NACT responses in patients with EC, imaging modalities typically target the PT in the esophagus, which is unmeasurable. Targeting measurable organs, like positive LNs, might provide more accurate assessments. METHODS We enrolled 251 patients with EC and clinically positive LNs that underwent curative resections, after triplet NACT. The percent reduction of PT area was measured with bidimensional computed tomography. The LN response was defined as the percent reduction of the sum of the short diameters in all positive LNs. RESULTS NACT reduced PTs and LNs by (median, range) 58.0% (38.1-94.9) and 34.5% (46.2-68.2), respectively. Based on the receiver-operating characteristic analyses for predicting a histological response and a 10% stepwise cutoff analyses of recurrence-free survival (RFS), responder/nonresponder cutoff values were ≥60% for PT area reductions and ≥30% for LN size reductions. 39.6% of patients showed discordant PT and LN responses. Compared with PT-responders, LN-responders had significantly less advanced pN (P < 0.0001) and pM (P = 0.015) in addition to less advanced pT (P < 0.0001) and better histological responses (P < 0.0001), and closer correlations to lymphatic, distant metastases and dissemination. A multivariate analysis of RFS identified 2 independent prognostic factors: the LN response [hazard ratio (HR) = 2.51, 95% confidence interval (CI) = 1.63-3.95, P < 0.0001] and the pN (HR = 2.72, 95% CI = 1.44-5.64, P = 0.0016), but not the PT response. CONCLUSIONS The LN response to NACT predicted long-term survival more precisely than the PT response in patients with metastatic EC.

Objectives To investigate the residual pattern of esophageal cancer in the esophageal wall after neoadjuvant chemotherapy (NAC) and its clinical significance. Background NAC is a standard treatment for locally advanced esophageal cancer; however, residual tumor patterns in resected specimens after NAC and their clinico-pathological characteristics remain unknown. Methods One hundred twenty consecutive patients with cT3 or deeper esophageal cancer underwent curative esophagectomy after NAC and achieved grade 2 histological responses between 2000 and 2016. Hematoxylin-eosin staining of residual tumor sections revealed 4 remnant categories: Type 1: shallow, Type 2: central, Type 3: deep, and Type 4: diffuse. We examined associations between these Types and clinico-pathological factors, including prognosis. Results Forty-five (38%) specimens had no residual tumor cells in the mucosal layer. The adventitia layer displayed the lowest residual tumor cell frequency (18%) among all layers. Types 1, 2, 3, and 4 residual tumor patterns were found in 49 (41%), 33 (28%), 9 (8%), and 29 (24%) patients, respectively. Type 4 showed the maximum standard uptake value after NAC; Types 3 and 4 had higher ratios of venous invasion than Type 1 or 2. Patients with Type 3 or 4 more frequently developed pleural dissemination or distant metastasis than patients with Type 1 or 2. Survival was similar among the 4 Types. Conclusions After NAC for locally advanced esophageal cancer, the shallow residual tumor pattern was most common, but approximately 40% of specimens showed no tumor cells in the mucosal layer. Deep and diffuse remnant patterns were associated with high risks of pleural dissemination and distant metastasis.

A prospective randomized phase II trial was conducted to evaluate the efficacy of ghrelin administration in reducing systemic inflammatory response syndrome (SIRS) duration after esophagectomy.Esophagectomy for esophageal cancer is highly invasive and leads to prolonged SIRS duration and postoperative complications. Ghrelin has multiple effects, including anti-inflammatory effects.Forty patients undergoing esophagectomy were randomly assigned to either the ghrelin group (n = 20), which received continuous infusion of ghrelin (0.5 μg/kg/h) for 5 days, or the placebo group (n = 20), which received pure saline for 5 days. The primary endpoint was SIRS duration. The secondary endpoints were the incidence of postoperative complications, time of a negative nitrogen balance, changes in body weight and composition, and levels of inflammatory markers, including C-reactive protein (CRP) and interleukin-6 (IL-6).The ghrelin group had a shorter SIRS duration and lower CRP and IL-6 levels than did the placebo group. The incidence of pulmonary complications was lower in the ghrelin group than in the placebo group, whereas other complications did not differ between the groups. Although time of the negative nitrogen balance was shorter in the ghrelin group than in the placebo group, changes in total body weight and lean body weight did not differ significantly.Postoperative ghrelin administration was effective for inhibiting inflammatory mediators and improving the postoperative clinical course of patients with esophageal cancer.

To examine the clinical implications of supraclavicular (SC) lymph node (LN) metastasis in patients with esophageal squamous cell carcinoma (ESCC) who receive neoadjuvant chemotherapy, followed by surgery.Indications for surgery for esophageal cancer often do not include cases with SCLN metastasis because the latter is considered distant metastasis. However, neaodjuvant therapy may change the clinical importance of SCLN metastasis.In 323 patients with ESCC who underwent neoadjuvant chemotherapy, the correlations between SCLN metastasis and clinicopathological factors including survival were examined.The incidence of SCLN metastasis was 17.6% before therapy and 14.6% after therapy. In patients with SCLN metastasis at baseline, the incidence of posttherapy SCLN metastasis was significantly lower in major responders to chemotherapy than in minor responders. The total number of metastatic LNs was significantly higher in patients with posttherapy SCLN metastasis than in patients with metastatic LN but no SCLN (10.9 vs 3.9; P ≤ 0.001). Survival was shorter in patients with SCLN metastasis than in those with metastatic LN without SCLN (3-year overall survival rate; 20.1% vs 45.7%; P = 0.003). However, there was no significant difference in survival between patients with SCLN metastasis before but not after therapy and patients without SCLN metastasis before and after chemotherapy (3-year overall survival rate; 64.9% vs 58.2%; P = 0.2071).This study showed that SCLN metastasis in ESCC reflects the number of metastatic LNs. SCLN metastasis should not be considered as contraindication to curative surgery in multimodal treatment of ESCC because preoperative treatment can change SC nodal status.