scholarly journals Elevated Flt3L Predicts Long-Term Survival in Patients with High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4463
Author(s):  
Katharina M. Detjen ◽  
Raik Otto ◽  
Yvonne Giesecke ◽  
Lukas Geisler ◽  
Pamela Riemer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Tumor Tissue ◽  
Treatment Decisions ◽  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Patient Stratification ◽  
Term Survival ◽  
Gastroenteropancreatic Neuroendocrine Neoplasms ◽  
Related Survival

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 evaluated Flt3L gene expression in tumor tissue as well as circulating Flt3L levels as potential biomarkers in a cohort of 54 patients with GEP-NEN. Results: We detected a prominent induction of Flt3L gene expression in individual G2 and G3 NEN, but not in G1 neuroendocrine tumors (NET). Flt3L mRNA expression levels in tumor tissue predicted the disease-related survival of patients with highly proliferative G2 and G3 NEN more accurately than the conventional criteria of grading or NEC/NET differentiation. High level Flt3L mRNA expression was associated with the increased expression of genes related to immunogenic cell death, lymphocyte effector function and dendritic cell maturation, suggesting a less tolerogenic (more proinflammatory) phenotype of tumors with Flt3L induction. Importantly, circulating levels of Flt3L were also elevated in high grade NEN and correlated with patients’ progression-free and disease-related survival, thereby reflecting the results observed in tumor tissue. Conclusions: We propose Flt3L as a prognostic biomarker for high grade GEP-NEN, harnessing its potential as a marker of an inflammatory tumor microenvironment. Flt3L measurements in serum, which can be easily be incorporated into clinical routine, should be further evaluated to guide patient stratification and treatment decisions.

scholarly journals 29 Elevated Flt3L predicts long-term survival in patients with high-grade gastroenteropancreatic neuroendocrine neoplasms

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A34-A34
Author(s):  
Katharina Detjen ◽  
Raik Otto ◽  
Yvonne Giesecke ◽  
Lukas Geisler ◽  
Pamela Riemer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Tissue ◽  
Surrogate Marker ◽  
Ethics Committee ◽  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Patient Stratification ◽  
Gastroenteropancreatic Neuroendocrine Neoplasms ◽  
Ethical Approval ◽  
Related Survival

BackgroundGastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) are a rare and heterogeneous family of tumors arising from the disseminated neuroendocrine system of the gastrointestinal tract and pancreas. Clinical management of high-grade 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 stratification of patients with otherwise comparable tumor features.MethodsWe used RNAseq data from human foregut-derived pancreatic and gastric GEP-NEN to evaluate Flt3L gene expression in tumor tissue. The data set (n=54) represented the full range of NEN grades and differentiation, and expression levels were compared to healthy control tissue as well. We also analyzed circulating Flt3L levels in serum samples of a separate cohort of G2/G3 GEP-NEN (n=59) an healthy controls (n=4). The study was approved by the local ethics committee at Charité Universitätsmedizin Berlin, Germany (ethical approval number EA1/229/17) and patient informed consent was obtained.ResultsWe detected a prominent induction of Flt3L gene expression in individual G2 and G3 NEN, but not in G1 neuroendocrine tumors (NET). Flt3L mRNA expression levels in tumor tissue predicted disease related survival of patients with highly proliferative G2 and G3 NEN more accurately than the conventional criteria of grading or NEC/NET differentiation. High level Flt3L mRNA expression was associated with increased expression of genes related to immunogenic cell death, lymphocyte effector function and dendritic cell maturation, suggesting a less tolerogenic (more proinflammatory) phenotype of tumors with Flt3L induction. Importantly, circulating levels of Flt3L were also elevated in high grade NEN and correlated with patients´ progression-free and disease-related survival, thereby reflecting the results observed in tumor tissue.ConclusionsOur results suggest Flt3L as a surrogate marker of an inflammatory tumor microenvironment. Therefore, we propose Flt3L as a prognostic biomarker for high grade GEP-NEN. Flt3L measurements in serum, which can be easily be incorporated into clinical routine, may hold the promise to guide patient stratification and tailor treatment decisions and should be further evaluated, especially in the context of immunotherapies.Ethics ApprovalThe study was approved by the local ethics committee at Charité Universitätsmedizin Berlin, Germany (ethical approval number EA1/229/17) and patient informed consent was obtained.

scholarly journals 1170P The prognostic role of DLL3 expression in high-grade gastroenteropancreatic neuroendocrine neoplasms

2020 ◽  
Vol 31 ◽  
pp. S776
Author(s):  
C. Liverani ◽  
A. Bongiovanni ◽  
L. Mercatali ◽  
F. Pieri ◽  
C. Spadazzi ◽  
...  
Keyword(s):  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Prognostic Role ◽  
Gastroenteropancreatic Neuroendocrine Neoplasms

scholarly journals Characterization of kallikrein-related peptidase 4 (KLK4) mRNA expression in tumor tissue of advanced high-grade serous ovarian cancer patients

PLoS ONE ◽  
2019 ◽  
Vol 14 (2) ◽  
pp. e0212968 ◽  
Author(s):  
Weiwei Gong ◽  
Yueyang Liu ◽  
Christof Seidl ◽  
Tobias Dreyer ◽  
Enken Drecoll ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Mrna Expression ◽  
Cancer Patients ◽  
Tumor Tissue ◽  
High Grade ◽  
Serous Ovarian Cancer

scholarly journals Myeloid and T-Cell Microenvironment Immune Features Identify Two Prognostic Sub-Groups in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms

2021 ◽  
Vol 10 (8) ◽  
pp. 1741
Author(s):  
Giovanni Centonze ◽  
Vincenzo Lagano ◽  
Giovanna Sabella ◽  
Alessandro Mangogna ◽  
Giovanna Garzone ◽  
...  
Keyword(s):  
T Cell ◽  
Multivariable Analysis ◽  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
Immune Markers ◽  
Cancer Specific Survival ◽  
Ki 67 ◽  
Clinical Databases ◽  
Gastroenteropancreatic Neuroendocrine Neoplasms ◽  
Net G3

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 non-immune markers, from surgical pathology and clinical databases of 2 Italian institutions were immunostained for Arginase, CD33, CD163 and CD66 myeloid markers. The association between features was assessed by Spearman’s correlation coefficient. A unsupervised K-means algorithm was used to identify clusters of patients according to inputs of microenvironment features and the relationship between clusters and clinicopathological features, including cancer-specific survival (CSS), was analyzed. The H-NEN population was composed of 6 (13.3%) NET G3 and 39 (86.7%) NEC. Overall, significant positive associations were found between myeloid (CD33, CD163 and Arginase) and T/immune markers (CD3, CD4, CD8, PD-1 and HLA-I). Myeloid and T-cell markers CD3 and CD8 identified two clusters of patients from unsupervised K-means analysis. Cases grouped in cluster 1 with more myeloid infiltrates, T cell, HLA and expression of inhibitory receptors and ligands in the stroma (PD-1, PD-L1) had significantly better CSS than patients in cluster 2. Multivariable analysis showed that Ki-67 (>55 vs. <55, HR 8.60, CI 95% 2.61–28.33, p < 0.0001) and cluster (1 vs. 2, HR 0.43, CI 95% 0.20–0.93, p = 0.03) were significantly associated with survival. High grade gastroenteropancreatic neuroendocrine neoplasms can be further classified into two prognostic sub-populations of tumors driven by different tumor microenvironments and immune features able to generate the framework for evaluating new therapeutic strategies.

Evaluation of Immune-Biomarker Expression in High Grade Soft Tissue Sarcoma : Emphasis of importance of HLA-DQA1 expression as a prognostic marker

2020 ◽  
Author(s):  
Jung Yun Bae ◽  
Kyung Un Choi ◽  
Ahrong Kim ◽  
So Jung Lee ◽  
Kyungbin Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Malignant Neoplasm ◽  
High Grade ◽  
Term Survival ◽  
The Poor ◽  
Prognostic Group ◽  
Immune Related Genes ◽  
Hla Dqa1

Abstract Background: High-grade soft tissue sarcoma (STS) is a highly malignant neoplasm having an overall poor prognosis. Numerous prognostic factors determine tumor progression and patient outcome. Many immune-related cells identified in the tumor microenvironment play important roles in various tumor types. This study was undertaken to evaluate the expression of immune-related genes and to elucidate the correlation between these genes and prognosis in high grade STS.Methods: Twelve cases of formalin-fixed paraffin embedded tissue samples of high grade STS were included for gene expression analysis using the NanoString nCounter® System and 35 cases were used for immunohistochemistry. For comparison analysis, the patients were divided into two groups, depending on the overall survival (OS). Expressions of 770 Genes were analyzed using the nCounter® PanCancer Immune Profiling Panel of the NanoString nCounter® Analysis System. Immunohistochemistry for the most significantly altered genes was additionally performed. The correlation between gene expression and prognosis of high grade STS was then evaluated.Results: Of the 770 immune-related genes analyzed by NanoString nCounter® Analysis, several genes were identified as differentially expressed between the two groups. Based on the gene expression level and fold change, representative 13 genes were identified: 7 of the 13 candidate genes (C3, CD36, DOCK9, FCER2, FOS, HLA-DRB4, and NCAM1) were found to be significantly overexpressed in the poor prognostic group. In contrast, expressions of the other 6 immune-related genes (BIRC5, DUSP4, FOXP3, HLA-DQA1, HLA-DQB1, and LAG3) were increased in the good prognostic group. Positive expressions of HLA-DQA1, HLA-DQB1, and HLA-DRB4 were obtained in 74.3%, 34.3% and 48.6% tumors, respectively. The positive expression of HLA-DQA1 was associated with a significantly longer OS (p=0.028). .Conclusions: Analysis of gene expression determined that expressions of 13 immune-related genes were significantly different between two groups. HLA-DQA1 and HLA-DQB1 were significantly decreased, whereas HLA-DRB4 was significantly increased in the poor prognostic group. HLA-DQA1 expression was significantly correlated with long-term survival, and may therefore be an immune-biomarker for good prognosis of high grade STS.

TRP GENES FAMILY EXPRESSION IN COLORECTAL CANCER

2015 ◽  
Vol 37 (3) ◽  
pp. 208-212 ◽  
Author(s):  
Y Sozucan ◽  
M E Kalender ◽  
I Sari ◽  
A Suner ◽  
S Oztuzcu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Mrna Expression ◽  
Transient Receptor Potential ◽  
Tumor Tissue ◽  
Receptor Potential ◽  
Tissue Samples ◽  
Expression Levels ◽  
Normal Tissues ◽  
Trp Genes

Colorectal cancer (CRC) is the most common cancer of the gastrointestinal tract. Different factors are responsible for the development of CRC. Transient Receptor Potential (TRP) which is an important component of calcium channel is associated with several pathological conditions like cancer, neurodegenerative and cardiovascular diseases. Thirty members of the family of TRP ion channel in mammals have been determined till now. The aim of this study is to investigate TRPM, TRPV and TRPC gene expression levels in tumor tissues of CRC patients and to analyze the relationship of expression in tumor tissue of CRC with other known prognostic factors. Material and Methods: In this study, 93 CRC patients were included. The level of TRP gene expression in paraffin blocks of normal and cancerous colorectal tissue samples were studied at the level of mRNA with Real-time PCR. Results: The mRNA expression level of TRPV3, TRPV4, TRPV5, TRPM4 and TRPC6 genes in 37 female and 56 male patients diagnosed with CRC was revealed lower in tumor tissue as compared to normal tissue (p < 0.05). No statistically significant differences of mRNA expression levels of other TRP genes were found. Conclusions: TRP gene family like TRPV3, TRPV4, TRPV5, TRPM4 and TRPC6 may be thought as potential genes contributing to tumorigenesis as their expression decreases in CRC as compared to normal tissues.

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