Assessment of copy number in protooncogenes are predictive of poor survival in advanced gastric cancer.

The copy number (CN) gain of protooncogenes is a frequent finding in gastric carcinoma (GC), but its prognostic implication remains elusive. The study aimed to characterize the clinicopathological features, including prognosis, of GCs with copy number gains in multiple protooncogenes. Three hundred thirty-three patients with advanced GC were analyzed for their gene ratios in EGFR, GATA6, IGF2, and SETDB1 using droplet dPCR (ddPCR) for an accurate assessment of CN changes in target genes. The number of GC patients with 3 or more genes with CN gain was 16 (4.8%). Compared with the GCs with 2 or less genes with CN gain, the GCs with 3 or more CN gains displayed more frequent venous invasion, a lower density of tumor-infiltrating lymphocytes, and lower methylation levels of L1 or SAT-alpha. Microsatellite instability-high tumors or Epstein-Barr virus-positive tumors were not found in the GCs with 3 or more genes with CN gain. Patients of this groups also showed the worst clinical outcomes for both overall survival and recurrence-free survival, which was persistent in the multivariate survival analyses. Our findings suggest that the ddPCR-based detection of multiple CN gain of protooncogenes might help to identify a subset of patients with poor prognosis.

Image analyzer-based assessment of tumor-infiltrating T cell subsets and their prognostic values in colorectal carcinomas.

To find useful tools to evaluate the prognosis in colorectal carcinoma (CRC) patients, we investigated the prognostic values of tumor-infiltrating T lymphocyte subsets according to intratumoral subsites as well as clinical or molecular characteristics. Immunohistochemistry for CD8, CD45RO, and FOXP3 was performed, and densities of the T cell subsets in each tissue microarray core (cells/mm2) were measured by image analysis. In the training set (n = 218) of CRC, T cell subset densities in the invasion front were more strongly associated with patient outcome than those in the tumor center. In the validation set (n = 549), T cell subset densities in the invasion front were evaluated. Univariate analysis showed that all three T cell subset densities were significantly associated with longer progression free survival and overall survival time (p < 0.001). In multivariate analysis, a high CD45RO density correlated independently with longer progression free survival (p = 0.011) and overall survival time (p = 0.007) in CRC patients, regardless of tumor location or adjuvant chemotherapy status. Our results showed that CD45RO density in the invasion front was the only independent prognostic factor regarding CRC. However, CD8 and FOXP3 densities were also independent prognostic factors in certain clinical settings. Thus, image analysis of tissue microarray cores in the invasion front of CRC could be used as a valid method for evaluating the prognostic significance of T cell subset densities.

Comparative validation of assessment criteria for Crohn-like lymphoid reaction in colorectal carcinoma.

AIMS: Crohn-like lymphoid reaction (CLR) in colorectal carcinoma (CRC) is associated with a favourable prognosis and microsatellite instability-high (MSI-H) status. However, there is a lack of consensus on optimal criteria for CLR assessment. The aim of this study was to comparatively validate traditional and novel assessment criteria for CLR. METHODS: CLR status in 212 MSI-H CRCs was assessed independently by two pathologists using three different criteria: (1) traditional semiquantitative criteria (Graham-Appelman criteria), (2) the largest lymphoid aggregate (LA) size-based criteria (Ueno criteria) and (3) LA density-based criteria (Väyrynen-Mäkinen criteria). RESULTS: Among the three criteria, the Väyrynen-Mäkinen criteria-based CLR assessment showed the best interobserver agreement (κ value, 0.71; intraclass correlation coefficient, 0.76). Pathologically, intense CLR (grade 2) by Graham-Appelman criteria, active CLR (largest LA size ≥1 mm) by Ueno criteria and high-density CLR (≥0.38 LAs/mm) by Väyrynen-Mäkinen criteria significantly correlated with an early cancer stage (stage I/II). In Kaplan-Meier analysis, both CLR statuses determined by Ueno criteria and Väyrynen-Mäkinen criteria were associated with significant differences in disease-free survival in MSI-H CRC patients (p=0.005 and p=0.001, respectively). In multivariable analysis, both active CLR and high-density CLR proved to be independent favourable prognostic factors in MSI-H CRC (HR, 0.47; 95% CI 0.24 to 0.9 for active CLR and HR, 0.5; 95% CI 0.28 to 0.89 for high-density CLR). CONCLUSIONS: Our study confirms that the two recently suggested criteria (Ueno criteria and Väyrynen-Mäkinen criteria) for CLR assessment are fairly reproducible methods and can serve as superior prognosticators in CRC.