Stroma AReactive Invasion Front Areas (SARIFA) predict poor survival in adenocarcinomas of the stomach and gastrooesophageal junction: a validation study.

Recently, the presence of "Stroma AReactive Invasion Front Areas" (SARIFA) has been described as a promising adverse prognostic factor in gastric cancer. However, the validity of this approach still needs to be tested. The aim of this study was to independently assess the utility of the proposed method in a well-characterised cohort of primary resected adenocarcinomas of stomach and gastrooesophageal junction (n = 392). SARIFA status was analysed on routine slides of resection specimens. Cases were divided into SARIFA-positive and negative groups and analysed in relation to clinicopathological and survival data. SARIFA positivity was found in 15.1% (n = 59) cases and was significantly associated with Lauren phenotype (p < 0.001), pT (p = 0.001), pN (p = 0.018), UICC stage (p = 0.031), tumour budding (p = 0.002), overall survival (p < 0.001) and cancer-specific survival (p < 0.001). SARIFA-positive tumours had a worse prognosis in the multivariate setting (HR = 1.847, 95% CI: 1.300-2.624, p = 0.001). SARIFA status is an independent prognostic factor in gastric cancer, in particular in locally advanced tumours.

LAG3 in gastric cancer: it's complicated.

PURPOSE: Lymphocyte activation gene 3 (LAG3) is thought to contribute to T cell exhaustion within the tumor microenvironment of solid tumors. This study aimed to analyze the spatial distribution of LAG3 + cells in relation to clinicopathological and survival data in a large set of 580 primary resected and neoadjuvantly treated gastric cancers (GC). METHODS: LAG3 expression was evaluated in tumor center and invasive margin using immunohistochemistry and whole-slide digital image analysis. Cases were divided into LAG3-low and LAG3-high expression groups based on (1) median LAG3 + cell density, (2) cut-off values adapted to cancer-specific survival using Cutoff Finder application. RESULTS: Significant differences in spatial distribution of LAG3 + cells were observed in primarily resected GC, but not in neoadjuvantly treated GC. LAG3 + cell density showed evident prognostic value at following cut-offs: in primarily resected GC, 21.45 cells/mm2 in tumor center (17.9 vs. 10.1 months, p = 0.008) and 208.50 cells/mm2 in invasive margin (33.8 vs. 14.7 months, p = 0.006); and in neoadjuvantly treated GC, 12.62 cells/mm2 (27.3 vs. 13.2 months, p = 0.003) and 123.00 cells/mm2 (28.0 vs. 22.4 months, p = 0.136), respectively. Significant associations were found between LAG3 + cell distribution patterns and various clinicopathological factors in both cohorts. In neoadjuvantly treated GC, LAG3 + immune cell density was found to be an independent prognostic factor of survival (HR = 0.312, 95% CI 0.162-0.599, p < 0.001). CONCLUSION: In this study, a higher density of LAG3 + cells was associated with favorable prognosis. Current results support the need for extended analysis of LAG3. Differences in the distribution of LAG3 + cells should be considered, as they could influence clinical outcomes and treatment responses.

Gastric Carcinomas with Stromal B7-H3 Expression Have Lower Intratumoural CD8+ T Cell Density.

CD8+ T cells are the main effector cells of anti-cancer immune response that can be regulated by various costimulatory and coinhibitory molecules, including members of the B7 family. B7 homolog 3 (B7-H3) appears as a promising marker for immunotherapy; however, its significance in gastric cancer (GC) is unclear yet. We evaluated the spatial distribution of CD8+ T cells in relation to the expression of B7-H3 by double immunohistochemical staining. The level of B7-H3 intensity was scored manually (0-3) and dichotomized into B7-H3-low and B7-H3-high groups. The distribution and density of CD8+ T cells was analysed using whole slide digital imaging. B7-H3 was expressed mainly in the stromal compartment of GC (n = 73, 76% of all cases). Tumours with high expression of B7-H3 showed larger spatial differences of CD8+ T cells (86.4/mm2 in tumour centre vs. 414.9/mm2 in invasive front) when compared to B7-H3-low group (157.7/mm2 vs. 218.7/mm2, respectively) (p < 0.001). This study provides insight into the expression pattern of B7-H3 in GC of Western origin. In GCs with higher level of B7-H3 expression, CD8+ T cells were spatially suppressed in the tumour centre suggesting that B7-H3 might be involved in tumour escape mechanisms from the immune response.

Prognostic significance of tumour budding assessed in gastric carcinoma according to the criteria of the International Tumour Budding Consensus Conference.

AIMS: In this study, we aimed to independently evaluate the utility and prognostic value of tumour budding (TB) according to the International Tumour Budding Consensus Conference (ITBCC) criteria in a large and a well-characterised European gastric cancer (GC) cohort. METHODS AND RESULTS: In 456 consecutive, surgically treated GCs, TB was assessed according to the ITBCC criteria and scored as Bd0 (no buds), Bd1 (one to four buds), Bd2 (five to nine buds) or Bd3 (≥10 buds). Cases with TB present were divided into low- (Bd1/Bd2) and high-budding (Bd3) groups. The TB score was analysed in relation to the clinicopathological parameters, overall survival (OS) and tumour-specific survival (TSS); 115 (25.2%) cases had no, 104 (22.8%) had low and 237 (52.0%) had high TB. The TB score correlated significantly with sex, Laurén phenotype, pT-, pN- and M categories, histological grade, R status; and lymph node ratio, lymphatic invasion, perineural invasion and HER2-, MET- and MSI status. In both total and intestinal-type early invasive GC (n = 57 and n = 41, respectively), significant associations between the presence and extent of TB and presence of lymph node metastasis were detected. Significant differences in OS and TSS between the TB groups were found; however, TB did not retain significance in multivariate models. CONCLUSIONS: Our data show that the ITBCC criteria can be applied to GC. The data correlated significantly with the diverse clinicopathological characteristics, including patient outcome, and can help to standardise diagnostics and research into special histological features of malignant tumours in general and GC in particular.

The expression of the insulin receptor in gastric cancer correlates with the HER2 status and may have putative therapeutic implications.

BACKGROUND: Metabolic reprogramming in gastric cancer (GC) involves not only an alteration of glucose metabolism, but also of insulin receptor (IR) expression. We investigated if (1) GCs express the IR in cancer cells (CC-IR) and vasculature (VIR), (2) IR expression is clinically relevant and may be a novel target of GC treatment. METHODS: 467 primary GCs were studied by immunohistochemistry using an IR-specific antibody. CD31-immunostaining ensured the presence of representative intratumoral microvasculature. VIR, and membranous and cytoplasmic CC-IR (mCC-IR, cCC-IR) were evaluated using a modified HistoScore (HScore) and subsequently dichotomized into low or high IR expressions. The IR status was correlated with clinico-pathological patient characteristics, including survival and HER2 status. RESULTS: VIR, mCC-IR, and cCC-IR (HScore > 0) were found in 97.0%, 87.6%, and 95.7% of all GCs. After dichotomization of the HScores, 50.7, 48.8, and 50.3% were classified as VIR-high, mCC-IR-high, and cCC-IR-high, respectively. IR was associated with the Laurén phenotype, tumor localization, local tumor growth, vascular invasion, perineural invasion, tumor budding, mucin phenotype, UICC stage, worse survival, and the HER2 status. On multivariate analysis, VIR status was an independent prognosticator of overall (p = 0.010) and tumor-specific (p = 0.006) patient survival. CONCLUSIONS: VIR and CC-IR expressions are frequent in GC, biologically significant and even correlate with the HER2 status, opening avenues for novel putative therapeutic interventions in GC.

Upregulation of insulin-like growth factor II mRNA-binding protein 3 (IMP3) has negative prognostic impact on early invasive (pT1) adenocarcinoma of the esophagus.

PURPOSE: Therapeutic decisions in esophageal adenocarcinomas (EAC) restricted to mucosa (pT1a) or submucosa (pT1b) depend mainly on classic histomorphology-based criteria like tumor grading or lymphovascular invasion with limited success. There is a strong need for reliable pre-therapeutical biomarker-based evaluation also applicable on endoscopically obtained biopsies. METHODS: Patients who underwent esophagectomy due to EAC in a high volume center between 1999 and 2016 were included. Tissue microarrays (TMA) were retrospectively established from the formalin-fixed and paraffin-embedded material of the resected specimens and immunohistochemically stained using a monoclonal primary antibody specific for IMP3. IMP3 staining intensity was scored manually according to a 3-tier-scoring system (negative, weak and strong). RESULTS: 371 EACs were interpretable for analysis. 109 patients (29%) had early invasive (pT1a/pT1b) and 262 patients (71%) locally advanced EAC (> pT2). 259 EACs (70%) revealed positive immunostaining for IMP3 including 167 strongly and 92 weakly positive. Early EAC had significantly lower IMP3 expression compared to advanced tumor stages (p < 0.0001). IMP3 positive pT1 EAC revealed higher levels of lymph node metastases (LNM) (p = 0.0001) and pT1b tumors showed higher rates of IMP3 positivity compared to pT1a (p = 0.007). Subdividing the submucosa in thirds, there was a significant trend for higher IMP3 expression with deeper tumor infiltration from pT1a to pT1b (sm3) (p = 0.0001). There was an association between IMP3 expression and shortened survival in pT1 EAC (p = 0.038). CONCLUSIONS: IMP3 expression correlates with depth of tumor infiltration, rate of LNM and is associated with worse outcome. Thus, IMP3 might be useful for therapeutic decisions in early-invasive EAC.