Evaluating the prognostic significance of tumor-infiltrating lymphocytes in solid tumor: practice of a standardized method from the International Immuno-Oncology Biomarkers Working Group.

PURPOSE: Tumor-infiltrating lymphocytes (TILs) become increasingly relevant to tumor progression. This study aims to evaluate (a) methods of TILs assessment and (b) their prognostic significance in gastric cancer (GC). METHODS: The percentage of stromal TILs (psTIL) was reported semi-quantitatively by H&E evaluation. Herein, we screened two independent cohorts of breast cancer (n=240) and GC (n=481) for psTIL characterization. Correlations between psTIL and clinic-pathological features, as well as overall survival (OS) were further explored. Additionally, the prediction role of psTIL in GC was evaluated by receiver operating characteristic curve (ROC) analysis. RESULTS: TILs could be demonstrably distinguished from other stromal areas and surrounding tumor nests according to the assessment method. More importantly, it is reproducible, easily to determine, and quickly performed. In GC, a two-grade scale for psTIL was appropriate to be divided into low and high subgroups by using the median value of 10% as the threshold. High psTIL was correlated with no serosa invasion, earlier TNM stage and better survival state (P<0.05 for all), and identified as a favorable prognostic factor both by univariate (HR: 0.734, P=0.047) and multivariate analyses (HR: 0.722, P=0.030). A beneficial OS of high psTIL was found in a linear manner with increasing TILs infiltrates associated with improved survival by Kaplan-Meier survival curve (P=0.030) and ROC analysis (AUC: 0.432, P=0.012). CONCLUSION: TILs provide a reproducible method for assessment that can potentially be used to guide management. The parameter psTIL could be served as an independent, favorable prognostic factor of GC.

The prognosis role of AJCC/UICC 8th edition staging system in gastric cancer, a retrospective analysis.

OBJECTIVE: The present study was designed to investigate whether AJCC/UICC 8th edition staging system precisely differentiated patients with different prognosis of gastric cancer (GC). METHODS: There were 540 GC cases included in this study. Stratification was done according to the 7th and 8th AJCC/UICC tumor-node-metastasis (TNM) staging systems. Detailed comparison was conducted between two editions in terms of the sub-classification of pN3 stage, redefinitions of stage III, homogeneity, discrimination power, predictive accuracy, and complexity. RESULTS: Compared to the 7th edition, the 8th TNM staging system performed better by incorporating pN3a and pN3b into the final stage of GC (P<0.001), had better stage grouping homogeneity (P<0.001), prognostic value (area under the curve, AUC-value was 0.809), and comparable discrimination power. CONCLUSIONS: AJCC 8th TNM staging system showed improved efficiency in GC prognosis.

Distribution pattern of tumor associated macrophages predicts the prognosis of gastric cancer.

PURPOSE: As mayor biomarkers in tumor microenvironment (TME), tumor associated macrophages (TAMs) of gastric cancer (GC) still needs further studies in terms of the number and distribution pattern. METHODS: Herein, tissue microarrays (TMA) incorporating 494 GC surgical samples in duplicate were stained for TAMs infiltration analysis. TAMs number was counted according to the locations, including infiltrating macrophages in cancer nest (MC), in invasive front (MF) and in stroma (MS). Correlations between TAMs number, distribution pattern and clinic-pathological features and survival analyses were performed. RESULTS: Infiltrating macrophages number in GC tissues was much higher than that in peritumoral tissues. TAMs number was not significantly correlated with the overall survival (OS). TAMs distribution pattern could be categorized into MC or MF/MS dominant pattern, and correlated with histological grade (P =0.001). The median OS of MF/MS dominant pattern (22.1, 95%CI: 23.5-28.9) was significantly shorter than that of MC dominant pattern (25.6, 95%CI: 28.5-35.6) (P =0.002). By receiver operating characteristic curve (ROC) analysis, the predictive value of TAMs distribution pattern was superior to histological grade and pM stage, but inferior to pN and TNM stage. CONCLUSIONS: TAMs distribution pattern could be an independent prognostic factor for the OS of GC patients, and patients with MF/MS dominant pattern had worse outcomes.

Long noncoding RNA HULC promotes colorectal carcinoma progression through epigenetically repressing NKD2 expression.

Recently, long noncoding RNAs (lncRNAs) have been emerged as crucial regulators of human diseases and prognostic markers in numerous of cancers, including colorectal carcinoma (CRC). Here, we identified an oncogenetic lncRNA HULC, which may promote colorectal tumorigenesis. HULC has been found to be up-regulated and acts as oncogene in gastric cancer and hepatocellular carcinoma, but its expression pattern, biological function and underlying mechanism in CRC is still undetermined. Here, we reported that HULC expression is also over-expressed in CRC, and its increased level is associated with poor prognosis and shorter survival. Knockdown of HULC impaired CRC cells proliferation, migration and invasion, and facilitated cell apoptosis in vitro, and inhibited tumorigenicity of CRC cells in vivo. Mechanistically, RNA immunoprecipitation (RIP) and RNA pull-down experiment demonstrated that HULC could simultaneously interact with EZH2 to repress underlying targets NKD2 transcription. In addition, rescue experiments determined that HULC oncogenic function is partly dependent on repressing NKD2. Taken together, our findings expound how HULC over-expression endows an oncogenic function in CRC.

Morphological study and comprehensive cellular constituents of milky spots in the human omentum.

OBJECTIVE: To analyze morphological features of omental milky spots (MS). METHOD: Hematoxylin-eosin staining and immunohistochemistry technique were used to study the omental MS of gastric cancer (GC) patients and rectal cancer (RC) patients. We focused on morphological features of MS and conducted quantitative analysis on the cells number and cellular constituents. Differences in MS parameters between GC and RC were also analyzed. RESULTS: Various shapes of MS were mainly round, oval, irregular form in the adipose and perivascular annular. The median MS perimeter was 2752 (range 817~7753) computer-based pixels. The median value of immune cells in one MS was 141 (43~650), comprising T lymphocytes (46.1%), B lymphocytes (28.4%), macrophages (12.4%) and other immune cells (13.1%). Relatively high density of vessels in MS could be calculated by micro-vessel density (MVD) as 4 (0~13). The median value of mesothelial cells loosely arranged in the surface layer was 5 (0~51). There were no significant differences in MS perimeter, MVD, the number of mesothelial cells, total immune cells, T lymphocytes and macrophages between GC and RC (P>0.05), while the number of MS B lymphocytes in RC was significantly higher than that in GC (P<0.001). CONCLUSION: MS are primary immune tissues in the omentum and structural bases for development and progression of peritoneal dissemination of GC and RC. Analyzing the morphology and cellular constituents could help understanding the mechanism of peritoneal metastasis.