Microenvironment and tumor inflammatory features improve prognostic prediction in gastro-entero-pancreatic neuroendocrine neoplasms.

Published on Oct 1, 2019
路 DOI :10.1002/CJP2.135
Giovanna Tagliabue3
Estimated H-index: 3
: 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-2Tumor(T) > 4, PD-1Stromal(S) > 0, CD8S 4, PD-1S > 4, HLA-IS < 1, HLA-IT < 2, HLA-DRS < 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.
馃摉 Papers frequently viewed together
5 Authors (Rong Liu, ..., Hong-Hao Zhou)
#1Mauro CivesH-Index: 19
#2Jonathan StrosbergH-Index: 12
Last. Domenico CoppolaH-Index: 60
view all 4 authors...
: Immune checkpoint inhibitors have shown promising results in different cancers, and correlation between immune infiltration, expression of programmed death-ligand 1 (PD-L1) by tumor cells and response to immunotherapy has been reported. There is limited knowledge regarding the immune microenvironment of small bowel (SB) neuroendocrine tumors (NETs). This work was aimed at characterizing the immune landscape of SB NETs. Expression of PD-L1 and programmed death-1 (PD-1) was evaluated by immunohi...
Background: Well-differentiated neuroendocrine neoplasms (NENs) are usually controlled by antiproliferative, local ablative and/or radionuclide therapies, whereas poorly differentiated NENs generally require cytotoxic chemotherapy. However, treatment options for patients with advanced/metastatic high-grade NENs remain limited. Method: Review of the literature and international congress abstracts on the efficacy and safety of immunotherapy by checkpoint inhibition in advanced/metastatic NENs. Res...
#1Massimo MilioneH-Index: 33
#2Patrick Maisonneuve (IEO: European Institute of Oncology)H-Index: 136
Last. Filippo de BraudH-Index: 70
view all 15 authors...
Purpose Abnormal expression of succinate dehydrogenase, (SDH), in particular of the B subunit (SDHB), is implicated in the pathogenesis of neuroendocrine tumors. This study evaluates the distribution of SDHB in WHO grading G1 and G2 intestinal, well-differentiated neuroendocrine tumors and corresponding lymph node or liver metastases.
#1Massimo MilioneH-Index: 33
#2Patrick MaisonneuveH-Index: 136
Last. Stefano La Rosa (UNIPV: University of Pavia)H-Index: 41
view all 17 authors...
Background/Aims: Gastroenteropancreatic (GEP) neuroendocrine carcinomas (NECs) are defined as neuroendocrine neoplasms (NENs) with a Ki-67 index >20% according to
#1Nicola Fazio (IEO: European Institute of Oncology)H-Index: 45
#2Massimo MilioneH-Index: 33
Abstract Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are currently classified as grade (G) 1, G2 and G3, in accordance with the 2010 WHO classification. G1 and G2 are named neuroendocrine tumors (NETs) whereas G3 neuroendocrine carcinomas (NECs). While advanced G1 and G2 are usually treated with several different therapies, including somatostatin analogs, chemotherapy, interferon, molecular targeted agents, peptide receptor radionuclide therapy (PRRT) and liver-directed treatmen...
#2Halfdan Sorbye (University of Bergen)H-Index: 42
Last. Aurel Perren (University of Bern)H-Index: 75
view all 13 authors...
#1Santiago Zelenay (Francis Crick Institute)H-Index: 23
#2Annemarthe G. van der Veen (Francis Crick Institute)H-Index: 10
Last. Caetano Reis e Sousa (Francis Crick Institute)H-Index: 85
view all 12 authors...
The mechanisms by which melanoma and other cancer cells evade anti-tumor immunity remain incompletely understood. Here, we show that the growth of tumors formed by mutant BrafV600E mouse melanoma cells in an immunocompetent host requires their production of prostaglandin E2, which suppresses immunity and fuels tumor-promoting inflammation. Genetic ablation of cyclooxygenases (COX) or prostaglandin E synthases in BrafV600E mouse melanoma cells, as well as in NrasG12D melanoma or in breast or colo...
#1Evan J. Lipson (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 38
#2Patrick M. Forde (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 35
Last. Suzanne L. Topalian (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 99
view all 6 authors...
The PD-1 pathway, comprising the immune cell co-receptor Programmed Death 1 (PD-1) and its ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC), mediates local immunosuppression in the tumor microenvironment. Drugs designed to block PD-1 or PD-L1 鈥渞elease the brakes鈥 on anti-tumor immunity and have demonstrated clinical activity in several types of advanced cancers, validating this pathway as a target for cancer therapy. Two such drugs have recently been approved to treat melanoma and lung cancers, and regu...
#1Shoki Sato (Hokkaido University)H-Index: 5
#2Takahiro Tsuchikawa (Hokkaido University)H-Index: 20
Last. Satoshi Hirano (Hokkaido University)H-Index: 60
view all 8 authors...
The disease frequency of pancreatic neuroendo- crine tumors (PNETs) has been growing, and postoperative hepatic recurrence (PHR) is one of the factors affecting patient prognosis. The present study aimed to investigate biomarkers of PNETs in the primary disease site to predict PHR using immunohistochemical analysis for tumor-infiltrating lympho - cytes (TILs: CD3, CD8 and CD45RO), human leukocyte antigen (HLA) class I, 伪-thalassemia/mental retardation X-linked (ATRX), death domain-associated pro...
#1Roy S. Herbst (Yale University)H-Index: 113
#2Jean-Charles Soria (University of Paris)H-Index: 53
Last. F. Stephen Hodi (Brigham and Women's Hospital)H-Index: 130
view all 22 authors...
Clinical and correlative biomarker results from a phase 1 clinical trial in patients with different solid tumours are presented; the findings indicate that PD-L1 expression on tumour-infiltrating immune cells is associated with clinical response to MPDL3280A (anti-PD-L1).
Cited By12
Pancreatic neuroendocrine tumors (PanNETs) are heterogeneous; thus, individual prognostic prediction is important. Clinicopathological features, like TNM stage, grade, and differentiation, are independent clinical predictors. However, single predictors are insufficient, as patients sharing similar clinicopathological features usually show distinct prognoses. Accordingly, novel nomograms and risk stratifications have been developed for more accurate PanNET prognostic prediction. Moreover, the exp...
#1Katharina Detjen (Charit茅)H-Index: 21
#2Raik Otto (Humboldt University of Berlin)H-Index: 5
Last. T L眉dde (HHU: University of D眉sseldorf)
view all 16 authors...
BACKGROUND The clinical management of high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is challenging due to disease heterogeneity, illustrating the need for reliable biomarkers facilitating patient stratification and guiding treatment decisions. FMS-like tyrosine kinase 3 ligand (Flt3L) is emerging as a prognostic or predictive surrogate marker of host tumoral immune response and might enable the stratification of patients with otherwise comparable tumor features. METHODS We...
#1Junjie KongH-Index: 1
#2Guangsheng YuH-Index: 1
Last. Jun LiuH-Index: 17
view all 0 authors...
#1Martina TorchioH-Index: 10
#2Laura CattaneoH-Index: 12
Last. Giulia Bertino (UNIPV: University of Pavia)H-Index: 18
view all 15 authors...
This case report shows, for the first time, a patient experiencing a complete response after one dose of avelumab following extensive disease progression with prior electrochemotherapy (ECT) treatment. We suggest that ECT may help to establish a tumor microenvironment favorable to immunotherapy. Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with seldom durable chemotherapy responses. ECT has recently emerged as a potential treatment option for several malignancies, including MCC...
#1V茅ronique DebienH-Index: 1
#3Philippe Baltzinger (French Institute of Health and Medical Research)
Well-differentiated pancreatic neuroendocrine tumors (pNET) have an unpredictable natural history. The identification of both blood and tumor immune features associated with patients鈥 outcomes remains limited. Herein, we evaluated the best prognostic value of the neutrophils-to-lymphocyte ratio (NLR) in a cohort of 144 pNETs. The NLR 鈮 4 was associated with worse overall survival in both univariate analysis (HR = 3.53, CI95% = 1.50鈥8.31, p = 0.004) and multivariate analysis (HR = 2.57, CI95% = 1...
#1Giovanni CentonzeH-Index: 12
#2Vincenzo LaganoH-Index: 2
Last. Massimo MilioneH-Index: 33
view all 19 authors...
High-grade Gastroenteropancreatic Neuroendocrine neoplasms (H-NENs) comprehend well-differentiated tumors (NET G3) and poorly differentiated carcinomas (NEC) with proliferative activity indexes as mitotic count (MC) >20 mitoses/10 HPF and Ki-67 >20%. At present, no specific therapy for H-NENs exists and the several evidences of microenvironment involvement in their pathogenesis pave the way for tailored therapies. Forty-five consecutive cases, with available information about T-cell, immune, and...
#1Si XieH-Index: 1
#2Lei LiH-Index: 1
Last. Le-Qun Li (Guangxi Medical University)H-Index: 32
view all 4 authors...
ABSTRACT Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are increasing in incidence. Clinicians urgently need a method that can effectively predict the prognosis of GEP-NENs.A total of 14770 GEP-NENs patients with pathologically confirmed between 1975 and 2016 were obtained from the surveillance, epidemiology, and end results database. All the patients were divided into primary (n鈥=鈥10377) and validation (n鈥=鈥4393) cohorts based on the principle of random grouping. Multivariate Cox p...
#1Chiara LiveraniH-Index: 15
#2Alberto BongiovanniH-Index: 19
Last. Toni IbrahimH-Index: 30
view all 14 authors...
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a rare and heterogeneous subgroup of tumors with a challenging management because of their extremely variable biological and clinical behaviors. Due to their different prognosis, there is an urgent need to identify molecular markers which would enable to discriminate between grade 3 neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs), despite both being diagnosed mainly on the basis of proliferation index and cell diffe...
This website uses cookies.
We use cookies to improve your online experience. By continuing to use our website we assume you agree to the placement of these cookies.
To learn more, you can find in our Privacy Policy.