{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["5(4)"],"submitter":["Milione M"],"funding":["Novartis"],"pubmed_abstract":["Microenvironment-related immune and inflammatory markers, when combined with established Ki-67 and morphology parameters, can improve prognostic prediction in gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs). Therefore, we evaluated the prognostic value of microenvironment and tumor inflammatory features (MoTIFs) in GEP-NENs. For this purpose, formalin-fixed paraffin-embedded tissue sections from 350 patients were profiled by immunohistochemistry for immune, inflammatory, angiogenesis, proliferation, NEN-, and fibroblast-related markers. A total of 314 patients were used to generate overall survival (OS) and disease-free survival (DFS) MoTIFs prognostic indices (PIs). PIs and additional variables were assessed using Cox models to generate nomograms for predicting 5-year OS and DFS. A total of 36 patients were used for external validation of PIs and nomograms' prognostic segregations. From our analysis, G1/G2 versus G3 GEP-NENs showed phenotypic divergence with immune-inflammatory markers. HLA, CD3, CD8, and PD-1/PD-L1 IHC expression separated G3 into two sub-categories with high versus low adaptive immunity-related features. MoTIFs PI for OS based on COX-2<sup>Tumor(T)</sup> > 4, PD-1<sup>Stromal(S)</sup> > 0, CD8<sup>S</sup> < 1, and HLA-I<sup>S</sup> < 1 was associated with worst survival (hazard ratio [HR] 2.50; 95% confidence interval [CI], 2.12-2.96; p < 0.0001). MoTIFs PI for DFS was based on COX-2<sup>T</sup> > 4, PD-1<sup>S</sup> > 4, HLA-I<sup>S</sup> < 1, HLA-I<sup>T</sup> < 2, HLA-DR<sup>S</sup> < 6 (HR 1.77; 95% CI, 1.58-1.99; p < 0.0001). Two nomograms were developed including morphology (HR 4.83; 95% CI, 2.30-10.15; p < 0.001) and Ki-67 (HR 11.32; 95% CI, 5.28-24.24; p < 0.001) for OS, and morphology (PI = 0: HR 10.23; 95% CI, 5.67-18.47; PI = 5: HR 2.87; 95% CI, 1.21-6.81; p < 0.001) and MoTIFs PI for DFS in well-differentiated GEP-NENs (HR 6.21; 95% CI, 2.52-13.31; p < 0.001). We conclude that G1/G2 to G3 transition is associated with immune-inflammatory profile changes; in fact, MoTIFs combined with morphology and Ki-67 improve 5-year DFS prediction in GEP-NENs. The immune context of a subset of G3 poorly differentiated tumors is consistent with activation of adaptive immunity, suggesting a potential for responsiveness to immunotherapy targeting immune checkpoints."],"journal":["The journal of pathology. Clinical research"],"pagination":["217-226"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6817832"],"repository":["biostudies-literature"],"pubmed_title":["Microenvironment and tumor inflammatory features improve prognostic prediction in gastro-entero-pancreatic neuroendocrine neoplasms."],"pmcid":["PMC6817832"],"pubmed_authors":["Anichini A","de Braud F","Centonze G","Mangogna A","Spaggiari P","Pusceddu S","Cotsoglou C","Sozzi G","Mazzaferro V","Paolino C","Pruneri G","Milione M","Pellegrinelli A","Kankava K","Corti A","Giacomelli L","Miceli R","Tagliabue G","Barretta F"],"additional_accession":[]},"is_claimable":false,"name":"Microenvironment and tumor inflammatory features improve prognostic prediction in gastro-entero-pancreatic neuroendocrine neoplasms.","description":"Microenvironment-related immune and inflammatory markers, when combined with established Ki-67 and morphology parameters, can improve prognostic prediction in gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs). Therefore, we evaluated the prognostic value of microenvironment and tumor inflammatory features (MoTIFs) in GEP-NENs. For this purpose, formalin-fixed paraffin-embedded tissue sections from 350 patients were profiled by immunohistochemistry for immune, inflammatory, angiogenesis, proliferation, NEN-, and fibroblast-related markers. A total of 314 patients were used to generate overall survival (OS) and disease-free survival (DFS) MoTIFs prognostic indices (PIs). PIs and additional variables were assessed using Cox models to generate nomograms for predicting 5-year OS and DFS. A total of 36 patients were used for external validation of PIs and nomograms' prognostic segregations. From our analysis, G1/G2 versus G3 GEP-NENs showed phenotypic divergence with immune-inflammatory markers. HLA, CD3, CD8, and PD-1/PD-L1 IHC expression separated G3 into two sub-categories with high versus low adaptive immunity-related features. MoTIFs PI for OS based on COX-2<sup>Tumor(T)</sup> > 4, PD-1<sup>Stromal(S)</sup> > 0, CD8<sup>S</sup> < 1, and HLA-I<sup>S</sup> < 1 was associated with worst survival (hazard ratio [HR] 2.50; 95% confidence interval [CI], 2.12-2.96; p < 0.0001). MoTIFs PI for DFS was based on COX-2<sup>T</sup> > 4, PD-1<sup>S</sup> > 4, HLA-I<sup>S</sup> < 1, HLA-I<sup>T</sup> < 2, HLA-DR<sup>S</sup> < 6 (HR 1.77; 95% CI, 1.58-1.99; p < 0.0001). Two nomograms were developed including morphology (HR 4.83; 95% CI, 2.30-10.15; p < 0.001) and Ki-67 (HR 11.32; 95% CI, 5.28-24.24; p < 0.001) for OS, and morphology (PI = 0: HR 10.23; 95% CI, 5.67-18.47; PI = 5: HR 2.87; 95% CI, 1.21-6.81; p < 0.001) and MoTIFs PI for DFS in well-differentiated GEP-NENs (HR 6.21; 95% CI, 2.52-13.31; p < 0.001). We conclude that G1/G2 to G3 transition is associated with immune-inflammatory profile changes; in fact, MoTIFs combined with morphology and Ki-67 improve 5-year DFS prediction in GEP-NENs. The immune context of a subset of G3 poorly differentiated tumors is consistent with activation of adaptive immunity, suggesting a potential for responsiveness to immunotherapy targeting immune checkpoints.","dates":{"release":"2019-01-01T00:00:00Z","publication":"2019 Oct","modification":"2025-04-04T08:26:14.316Z","creation":"2019-11-12T08:05:13Z"},"accession":"S-EPMC6817832","cross_references":{"pubmed":["31136102"],"doi":["10.1002/cjp2.135"]}}