scholarly journals Aberrant Expression of Long Non Coding RNA HOTAIR and De-Regulation of the Paralogous 13 HOX Genes Are Strongly Associated with Aggressive Behavior of Gastro-Entero-Pancreatic Neuroendocrine Tumors

2021 ◽  
Vol 22 (13) ◽  
pp. 7049
Author(s):  
Annabella Di Mauro ◽  
Giosuè Scognamiglio ◽  
Gabriella Aquino ◽  
Margherita Cerrone ◽  
Giuseppina Liguori ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Hox Genes ◽  
Predictive Biomarkers ◽  
Neuroendocrine Neoplasms ◽  
Low Grade ◽  
Pancreatic Neuroendocrine Tumors ◽  
Aberrant Expression ◽  
Molecular Stratification ◽  
Tubular Gland ◽  
Net G3

Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are rare diseases occurring in the gastrointestinal tract and pancreas. They are characterized by the loss of epithelial tubular gland elements, and by the increased expression of neuroendocrine markers. GEP-NENs are subdivided into two histo-pathological types, gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) and gastro-entero-pancreatic neuroendocrine carcinomas (GEP-NECs). According to WHO 2017 and 2019 classification criteria are graded and staged in four categories, NET-G1, NET-G2, NET-G3, and NEC-G3. The molecular characterization of these tumors can be fundamental for the identification of new diagnostic, prognostic and predictive biomarkers. The main purpose of this study was to analyze the expression of the paralogous 13 HOX genes, normally involved in embryogenic development and frequently deregulated in human cancers, and of the HOX regulating lncRNA HOTAIR in GEP-NENs. The expression of HOX genes is gradually lost in the transition from GEP NET G1 to NET/NEC G3 tumors, while HOTAIR expression, inversely correlated with HOX genes expression and weakly expressed in low-grade GEP NENs, becomes aberrant in NET G3 and NEC G3 categories. Our data highlights their potential role in the molecular stratification of GEP-NENs by suggesting new prognostic markers and potential therapeutic targets.

scholarly journals Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors

2016 ◽  
Vol 23 (9) ◽  
pp. 759-767 ◽  
Author(s):  
M Cives ◽  
M Ghayouri ◽  
B Morse ◽  
M Brelsford ◽  
M Black ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Proliferative Activity ◽  
Dna Methyltransferase ◽  
Predictive Biomarkers ◽  
Pancreatic Neuroendocrine Tumors ◽  
Mgmt Expression ◽  
Methylguanine Dna Methyltransferase ◽  
Response Predictors ◽  
Alternative Lengthening ◽  
Pathway Activation

The capecitabine and temozolomide (CAPTEM) regimen is active in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs), with response rates ranging from 30 to 70%. Small retrospective studies suggest that O6-methylguanine DNA methyltransferase (MGMT) deficiency predicts response to temozolomide. High tumor proliferative activity is also commonly perceived as a significant predictor of response to cytotoxic chemotherapy. It is unclear whether chromosomal instability (CIN), which correlates with alternative lengthening of telomeres (ALT), is a predictive factor. In this study, we evaluated 143 patients with advanced pNET who underwent treatment with CAPTEM for radiographic and biochemical response. MGMT expression (n=52), grade (n=128) and ALT activation (n=46) were investigated as potential predictive biomarkers. Treatment with CAPTEM was associated with an overall response rate (ORR) of 54% by RECIST 1.1. Response to CAPTEM was not influenced by MGMT expression, proliferative activity or ALT pathway activation. Based on these results, no biomarker-driven selection criteria for use of the CAPTEM regimen can be recommended at this time.

scholarly journals An analysis of 130 neuroendocrine tumors G3 regarding prevalence, origin, metastasis, and diagnostic features

2021 ◽  
Author(s):  
Atsuko Kasajima ◽  
Björn Konukiewitz ◽  
Anna Melissa Schlitter ◽  
Wilko Weichert ◽  
Günter Klöppel
Keyword(s):  
Liver Metastases ◽  
Neuroendocrine Tumors ◽  
Digestive System ◽  
Neuroendocrine Neoplasms ◽  
Limited Data ◽  
Diagnostic Features ◽  
Site Specific ◽  
Net G3 ◽  
Metastatic Sites

AbstractLimited data exist on high-grade neuroendocrine tumors (NETs G3) which represent a new category among neuroendocrine neoplasms (NEN). We analyzed NETs G3 in a consultation series regarding prevalence, origin, metastasis, and diagnostic problems. Based on the WHO classification of digestive system tumors, 130 NETs G3 (9%) were identified in 1513 NENs. NET G3 samples were more often obtained from metastatic sites (69%) than NET G1/G2 samples (24%). NET G3 metastases presented most frequently in the liver (74%) and originated from the pancreas (38/90, 42%), followed by the lung (9%), ileum (7%), stomach (3%), rectum (1%), and rare sites (2%) such as the prostate and breast. The primaries remained unknown in 15%. NETs G3 had a median Ki67 of 30% that distinguished them from NECs (60%), though with great overlap. The expression of site-specific markers, p53, Rb1, and SST2 was similar in NETs G3 and NETs G1/G2, except for p53 and Rb1 which were abnormally expressed in 8% and 7% of liver metastases from NET G3 but not from NET G1/G2. NETs G3 were frequently referred as NECs (39%) but could be well distinguished from NECs by normal p53 (92% versus 21%) and Rb1 expression (93% versus 41%) expression. In conclusion, NETs G3 are frequently discovered as liver metastases from pancreatic or pulmonary primaries and are often misinterpreted as NEC. p53 and Rb1 are powerful markers in the distinction of NET G3 from NEC. Rarely, carcinomas from non-digestive, non-pulmonary organs with neuroendocrine features may present as NET G3.

scholarly journals EPB41L5 is Associated With the Metastatic Potential of Low-grade Pancreatic Neuroendocrine Tumors

2019 ◽  
Vol 16 (5) ◽  
pp. 309-318 ◽  
Author(s):  
JAMES SALLER ◽  
SHABNAM SEYDAFKAN ◽  
MOHAMMAD SHAHID ◽  
MANOJ GADARA ◽  
MAURO CIVES ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Metastatic Potential ◽  
Low Grade ◽  
Pancreatic Neuroendocrine Tumors

Mo1478 KI-67 Cytological Index Can Distinguish Low Grade From High Grade Pancreatic Neuroendocrine Tumors: a Comparative Cyto-Histological Study of 53 Cases

2014 ◽  
Vol 79 (5) ◽  
pp. AB452
Author(s):  
Gabriele Carlinfante ◽  
Paola Baccarini ◽  
Paolo Cecinato ◽  
Debora Berretti ◽  
Tiziana Cassetti ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Histological Study ◽  
Low Grade ◽  
High Grade ◽  
Pancreatic Neuroendocrine Tumors ◽  
Ki 67

Redefining the Ki-67 Index Stratification for Low-Grade Pancreatic Neuroendocrine Tumors: Improving Its Prognostic Value for Recurrence of Disease

2017 ◽  
Vol 25 (1) ◽  
pp. 290-298 ◽  
Author(s):  
Alexandra G. Lopez-Aguiar ◽  
Cecilia G. Ethun ◽  
Lauren M. Postlewait ◽  
Kristen Zhelnin ◽  
Alyssa Krasinskas ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Prognostic Value ◽  
Low Grade ◽  
Pancreatic Neuroendocrine Tumors ◽  
Ki 67

scholarly journals Unmet Needs in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms (WHO G3)

2018 ◽  
Vol 108 (1) ◽  
pp. 54-62 ◽  
Author(s):  
Halfdan Sorbye ◽  
Eric Baudin ◽  
Ivan Borbath ◽  
Martyn Caplin ◽  
Jie Chen ◽  
...  
Keyword(s):  
Patient Group ◽  
Unmet Needs ◽  
Proliferation Rate ◽  
Pancreatic Tumors ◽  
Neuroendocrine Neoplasms ◽  
Low Grade ◽  
High Grade ◽  
Primary Tumor Site ◽  
Net G3 ◽  
Well Differentiated

Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are classified based on morphology and graded based on their proliferation rate as either well-differentiated low-grade (G1 to G2) neuroendocrine tumors (NET) or poorly differentiated high-grade (G3) neuroendocrine carcinomas (NEC). Recently, a new subgroup of well-differentiated high-grade pancreatic tumors (NET G3) has been defined. The GEP NEN G3 group consisting of both NEC and NET G3 has recently been shown to be a quite heterogeneous patient group concerning prognosis and treatment benefit, depending on factors such as the primary tumor site, differentiation, proliferation rate, and molecular alterations. In this review we discuss the existing data on diagnostics, treatment, and biomarkers in this patient group, the unmet needs, and the future perspectives.

Progesterone Receptor and PTEN Expression Predict Survival in Patients With Low- and Intermediate-Grade Pancreatic Neuroendocrine Tumors

2014 ◽  
Vol 138 (8) ◽  
pp. 1027-1036 ◽  
Author(s):  
Jeannelyn S. Estrella ◽  
Russell R. Broaddus ◽  
Amber Mathews ◽  
Denái R. Milton ◽  
James C. Yao ◽  
...  
Keyword(s):  
Progesterone Receptor ◽  
Neuroendocrine Tumors ◽  
Mammalian Target Of Rapamycin ◽  
Negative Regulator ◽  
Small Subset ◽  
Low Grade ◽  
Pancreatic Neuroendocrine Tumors ◽  
Intermediate Grade ◽  
Low Profile ◽  
Phosphatase And Tensin Homologue

Context.—The PI3K-AKT-mTOR (phosphatidylinositol 3-kinase–AKT–mammalian target of rapamycin) pathway plays a crucial role in a subset of advanced pancreatic neuroendocrine tumors (PanNETs). In breast and endometrial carcinoma, activation of this pathway inhibits progesterone receptor (PR) expression. Objective.—To determine whether combined low expression of PR and phosphatase and tensin homologue (PTEN), a negative regulator of the PI3K-AKT-mTOR pathway, is a prognostic factor. Design.—A total of 160 resected PanNETs (89 low grade and 71 intermediate grade) were analyzed for PR and PTEN immunohistochemical positivity and staining was correlated with metastasis-free survival (MFS) and overall survival (OS). Progesterone receptor staining was scored as positive by using 1% or greater as cutoff. Weak/faint staining in greater than 90% of tumor cells was considered low PTEN positivity. Results.—Most PanNETs (110 cases, 69%) were both PR and PTEN positive, 45 (28%) were either PR or PTEN positive, and only 5 (3%) had a PR-negative and PTEN-low profile. Combined PR-PTEN positivity was significantly associated with MFS in patients with stage I and II disease (P <.001) and OS in all patients (P < .001) and remained a significant predictor of survival after adjusting for other factors. Patients with PR-negative–PTEN-low PanNETs had the shortest median MFS and OS, compared to those with tumors that were either PR or PTEN positive and with tumors positive for both PR and PTEN (P ≤ .001). Conclusion.—Combined immunohistochemical assessment of PR and PTEN may help identify a small subset of PanNETs with more aggressive behavior and may aid in risk stratification.

Tumor burden in serotonin secreting pancreatic neuroendocrine tumors after initiating telotristat ethyl.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 367-367
Author(s):  
Susan Giacalone ◽  
Valentina Di Gialleonardo ◽  
Kris Murali ◽  
Vijay N. Joish
Keyword(s):  
Neuroendocrine Tumors ◽  
Clinical Laboratory ◽  
Data Extraction ◽  
Tumor Burden ◽  
Low Grade ◽  
Pancreatic Neuroendocrine Tumors ◽  
Radiological Data ◽  
Before And After ◽  
Well Differentiated ◽  
Practice Methods

367 Background: Pancreatic neuroendocrine tumors (pNETs) characterized by high serotonin levels and carcinoid syndrome (CS) are rare. We evaluated tumor burden in a subgroup of patients with pNETS from the real-world TELEACE study before and after initiating telotristat ethyl (TE) in US clinical practice. Methods: Detailed methods of the TELEACE study have been reported previously. This was a retrospective, single arm, pre-post physician panel-based chart review of patients who received TE for at least 6 months. Descriptive statistics analyzed demographic, clinical, laboratory and radiological data extracted from medical charts of TELEACE patients with pNETS. Results: Fifty-two patients with pNETS initiating TE were eligible for this analysis. The average age at the time of TE initiation was 60+10.4 years; 64% were males. The majority of patients had well-differentiated (60%) tumors and low-grade (54%) tumor status. Patients received TE for an average of 11.5+7.84 months, and 21% were still receiving TE at the time of data extraction. Diarrhea and flushing were the most common CS symptoms recorded at the time of TE initiation. Urinary 5-HIAA levels were reported for 9 patients before and for 2 patients after TE initiation. Mean (median) 5-HIAA levels before and after TE initiation were 693 (211) and 22 (22) µmol/24h, respectively. Significant mean reduction in tumor size of 0.67 cm after TE initiation (P = 0.017) was observed. Conclusions: This subgroup analysis of the TELEACE study population showed that the addition of TE to somatostatin analog treatment may positively impact tumor burden for patients with functional pNETs.

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