Esophageal squamous cell carcinoma (ESCC) is the main prevalent histological type of esophageal cancer, predominantly constituting 90% of cases worldwide. Despite the development of multidisciplinary therapeutic approaches, its prognosis remains unfavorable. Recently, the development of monoclonal antibodies inhibiting programmed death 1 (PD‐1) or programmed death‐ligand 1 (PD‐L1) has led to marked therapeutic responses among multiple malignancies including ESCC. However, only a few patients achieved clinical benefits due to resistance. Therefore, precise and accurate predictive biomarkers should be identified for personalized immunotherapy in clinical settings. Because the tumor immune microenvironment can potentially influence the patient's response to immune checkpoint inhibitors, tumor immunity, such as PD‐L1 expression on tumors, tumor‐infiltrating lymphocytes, tumor‐associated macrophages, and myeloid‐derived suppressor cells, in ESCC should be further investigated. In this review, accumulated evidence regarding the tumor immune microenvironment and immune checkpoint inhibitors in ESCC are summarized.

BACKGROUND: The prognostic nutritional index is reportedly related to postoperative outcomes. OBJECTIVE: The aim of this study was to elucidate the clinical importance of the prognostic nutritional index in patients with colorectal cancer who were undergoing primary tumor resection. DESIGN: This is a retrospective study from a single institution. SETTINGS: This study was conducted at a colorectal surgery service in an academic teaching hospital. PATIENTS: The 556 patients with colorectal cancer who were undergoing surgery between March 2005 and August 2014 were eligible for this study. MAIN OUTCOME MEASURES: The preoperative prognostic nutritional index was calculated. Classification and regression tree analysis was performed to determine the prognostic nutritional index cutoff value. The associations of the prognostic nutritional index status with clinicopathological factors and postoperative outcomes were examined using univariate and multivariate analyses. RESULTS: Classification and regression tree analysis demonstrated that 45.5 was the optimal cutoff value. The low status (≤45.5) was correlated with older age, low BMI, low estimated glomerular filtration rate, CEA positivity, carbohydrate antigen 19-9 positivity, preoperative chemotherapy, tumors invading muscular or deeper layers, distant metastasis, poor differentiation, severe postoperative complications, tumor recurrence, and poor survival. In multivariate analysis, the low status was an independent risk factor for severe postoperative complications (OR = 2.06 [95% CI, 1.22–3.50]; p = 0.007) and low overall survival (HR =3.98 [95% CI, 2.38–6.89]; p < 0.001). LIMITATIONS: Our data set was collected retrospectively from a single institution. In addition, our study was only for preoperative prognostic nutritional index status, not considering the postoperative host status. CONCLUSIONS: The preoperative prognostic nutritional index predicts severe complications, recurrence, and poor prognosis in patients with colorectal cancer who are undergoing primary tumor resection. Investigation of the nutritional and immunologic statuses using the prognostic nutritional index could be a useful clinical approach.

To investigate the relationship between postoperative complications and long-term survival in patients with surgically resected esophageal squamous cell carcinoma (ESCC). Esophagectomy is the mainstay of curative treatment for ESCC; however, this complex procedure has high risks of postoperative morbidity and mortality. The impact of postoperative complications on long-term survival of such patients remains controversial. This retrospective single institution study included 502 consecutive patients who had undergone resection of ESCC. The Cox proportional hazard model was used to compute the hazard ratio (HR) for mortality. Postoperative complications (≥Clavien-Dindo classification grade 2) occurred in 217 patients (43%). Overall, postoperative complications did not affect long-term clinical outcomes of these patients. However, patients with pulmonary complications had worse overall survival than those without pulmonary complications [log rank P = 0.0002; univariate HR = 1.51, 95% confidence interval (CI) 1.20-1.88, P = 0.0006; multivariate HR = 1.60, 95% CI 1.05-2.38, P = 0.029]. The effect of pulmonary complications was not significantly modified by clinical or pathological features (P for all assessed interactions >0.05). In addition, postoperative chylothorax was also associated with poor overall survival (log rank P = 0.0021), whereas surgical site infection, recurrent nerve paralysis, cardiovascular complication, and anastomotic leakage were not. Postoperative pulmonary complications may be an independent predictor of poorer long-term survival in patients undergoing resection of ESCCs.

Cancer‐associated fibroblasts (CAFs) are reportedly involved in invasion and metastasis in several types of cancer, including gastric cancer (GC), through the stimulation of CXCL12/CXCR4 signaling. However, the mechanisms underlying these tumor‐promoting effects are not well understood, which limits the potential to develop therapeutic targets against CAF‐mediated CXCL12/CXCR4 signaling. CXCL12 expression was analyzed in resected GC tissues from 110 patients by immunohistochemistry (IHC). We established primary cultures of normal fibroblasts (NFs) and CAFs from the GC tissues and examined the functional differences between these primary fibroblasts using co‐culture assays with GC cell lines. We evaluated the efficacy of a CXCR4 antagonist (AMD3100) and a FAK inhibitor (PF‐573,228) on the invasive ability of GC cells. High CXCL12 expression levels were significantly associated with larger tumor size, increased tumor depth, lymphatic invasion and poor prognosis in GC. CXCL12/CXCR4 activation by CAFs mediated integrin β1 clustering at the cell surface and promoted the invasive ability of GC cells. Notably, AMD3100 was more efficient than PF‐573,228 at inhibiting GC cell invasion through the suppression of integrin β1/FAK signaling. These results suggest that CXCL12 derived from CAFs promotes GC cell invasion by enhancing the clustering of integrin β1 in GC cells, resulting in GC progression. Taken together, the inhibition of CXCL12/CXCR4 signaling in GC cells may be a promising therapeutic strategy against GC cell invasion.

Objectives: To examine the prognostic impact of the programmed death ligand 1 (PD-L1) expression, tumor-infiltrating lymphocyte (TIL) status, and their combination in esophageal cancer. Summary Background Data: PD-L1 has garnered much attention for its roles in tumor immunology and as an immune-based therapeutic target. To ensure a response to PD-L1 checkpoint inhibitor, a new framework based on PD-L1 expression and the presence or absence of TILs is required. Methods: Using a nonbiased database of 305 curatively resected esophageal cancers, we evaluated PD-L1 expression and TIL status (cluster of differentiation 8 (CD8) expression) by immunohistochemical analysis. The Cox proportional hazard model was used to compute the hazard ratio (HR) for mortality. Results: Compared with PD-L1 negative cases (n=252), PD-L1 positive cases (n = 53) showed significantly worse overall survival [log-rank P = 0.016; HR: 1.71; 95% confidence interval: 1.08–2.61; P = 0.024; multivariate HR: 1.69; 95% confidence interval: 1.05–2.67; P = 0.033]. TIL positivity was significantly correlated with longer overall survival (log-rank P < 0.0001) and high CD8 expression (P < 0.0001). A stratification based on PD-L1 expression and TIL status was also significantly associated with overall survival (log rank P < 0.0001). Conclusions: PD-L1 expression was associated with an unfavorable clinical outcome in esophageal cancer, supporting its role as a prognostic biomarker. In addition, the combination with TIL status enabled further classification patients according to clinical outcome. PD-L1 expression and TIL status may serve as predictive tissue biomarkers and can be used for patient selection in clinical trials of drugs targeting the PD-1/PD-L1 pathways.