The Impact of Phosphohistone-H3-Assisted Mitotic Count and Ki67 Score in the Determination of Tumor Grade and Prediction of Distant Metastasis in Well-Differentiated Pancreatic Neuroendocrine Tumors

We evaluated outcomes of treatment with 5-fluorouracil (5-FU), doxorubicin, and streptozocin (FAS) in well-differentiated pancreatic neuroendocrine tumors (PanNETs) and its impact on subsequent therapy (everolimus or temozolomide). Advanced PanNET patients treated at our center from 1992 to 2013 were retrospectively reviewed. Patients received bolus 5-FU (400 mg/m2), streptozocin (400 mg/m2) (both IV, days 1-5) and doxorubicin (40 mg/m2 IV, day 1) every 28 days. Overall response rate (ORR) was assessed using RECIST version 1.1. Of 243 eligible patients, 220 were evaluable for ORR, progression-free survival (PFS), and toxicity. Most (90%) had metastatic, nonfunctional PanNETs; 14% had prior therapy. ORR to FAS was 41% (95% confidence interval [CI]: 36-48%). Median follow-up was 61 months. Median PFS was 20 (95% CI: 15-23) months; median overall survival (OS) was 63 (95% CI: 60-71) months. Cox regression analyses suggested improvement with first-line vs subsequent lines of FAS therapy. Main adverse events ≥ grade 3 were neutropenia (10%) and nausea/vomiting (5.5%). Dose reductions were required in 32% of patients. Post-FAS everolimus (n=108; 68% second line) had a median PFS of 10 (95% CI: 8-14) months. Post-FAS temozolomide (n=60; 53% > fourth line) had an ORR of 13% and median PFS of 5.2 (95% CI: 4-12) months. In this largest reported cohort of PanNETs treated with chemotherapy, FAS demonstrated activity without significant safety concerns. FAS did not appear to affect subsequent PFS with everolimus; this sequence is being evaluated prospectively. Responses were noted with subsequent temozolomide-based regimens although PFS was possibly limited by line of therapy.

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Prognostic transcriptome classes of duodenopancreatic neuroendocrine tumors

Endocrine Related Cancer ◽

10.1530/erc-21-0051 ◽

2021 ◽

Author(s):

Marc Diedisheim ◽

Solène Dermine ◽

Anne Jouinot ◽

Amandine Septier ◽

Sébastien Gaujoux ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Pancreatic Beta Cell ◽

Tumor Biology ◽

Disease Free Survival ◽

Tumor Grade ◽

Pancreatic Alpha Cell ◽

Liver Gene ◽

Well Differentiated ◽

Grade 3 ◽

Definition Of

Duodenopancreatic neuroendocrine tumors (DPNETs) aggressiveness is heterogeneous. Tumor grade and extension are commonly used for prognostic determination. Yet, grade classes are empirically defined, with regular up-dates changing the definition of classes. Genomic screening may provide more objective classes, and reflect tumor biology. The aim of this study was to provide a transcriptome classification of DPNETs. We included 66 DPNETs, covering the entire clinical spectrum of the disease in terms of secretion, grade, and stage. Three distinct molecular groups were identified, associated with distinct outcome (log-rank p<0.01): (i) better-outcome DPNETs with pancreatic beta-cell signature. This group was mainly composed of well-differentiated, grade 1 insulinomas; (ii) poor-outcome DPNETs with pancreatic alpha-cell and hepatic signature. This group included all neuroendocrine carcinomas and grade 3 DPNETs, but also some grade 1 and grade 2 DPNETs; and (iii) intermediate-outcome DPNETs with pancreatic exocrine and progenitor signature. This group included grade 1 and grade 2 DPNETs, with some insulinomas. Fibrinogen gene FGA expression was one of the top most expressed liver gene. FGA expression was associated with disease-free survival (HR=1.13, p=0.005), and could be validated on two independent cohorts. This original pathophysiologic insight provides new prognostic classification perspectives.

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Erratum to: KI-67 heterogeneity in well differentiated gastro-entero-pancreatic neuroendocrine tumors: when is biopsy reliable for grade assessment?

Endocrine ◽

10.1007/s12020-017-1389-z ◽

2017 ◽

Vol 57 (3) ◽

pp. 503-503

Author(s):

Federica Grillo ◽

Luca Valle ◽

Diego Ferone ◽

Manuela Albertelli ◽

Maria Pia Brisigotti ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Pancreatic Neuroendocrine Tumors ◽

Ki 67 ◽

Well Differentiated ◽

Grade Assessment

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Expression of the phosphorylated variant of the AKT1-kinase (p-AKT1) in well-differentiated pancreatic neuroendocrine tumors: immunohistochemical evaluation

Almanac of Clinical Medicine ◽

10.18786/2072-0505-2018-46-4-314-322 ◽

2018 ◽

Vol 46 (4) ◽

pp. 314-322

Author(s):

V. V. Delektorskaya ◽

O. N. Solov'eva ◽

G. Yu. Chemeris ◽

Yu. I. Patyutko

Keyword(s):

Liver Metastases ◽

Neuroendocrine Tumors ◽

Treatment Effectiveness ◽

Disease Free Survival ◽

Immunohistochemical Analysis ◽

Pancreatic Neuroendocrine Tumors ◽

Ki 67 ◽

New Treatment ◽

Well Differentiated ◽

High Level

Background:Well-differentiated pancreatic neuroendocrine tumors (pNETs) represent a group of rare epithelial neoplasms with a highly variable clinical course. AKT1 is one of the most frequently activated protein kinases in pNETs, which promotes the tumor growth and is of interest as a prognostic factor and a target for new treatment approaches.Aim:To study the expression of the phosphorylated variant of AKT1-kinase (p-AKT1) in primary pNETs and their liver metastases and to correlate the results with various clinical and pathological parameters and the disease prognosis.Materials and methods:P-AKT1 expression was studied by the immunohistochemical analysis of the primary lesions and liver metastases in 52 pNETs patients.Results:A high level of cytoplasmic and/or nuclear immunoreactivity was detected in 24/52 of the primary pNETs (46.2%) and in 16/27 of their liver metastases (59.3%). p-AKT1 expression was observed in 3 (21.4%) of NET grade (G) 1, in 14 (46.7%) of NET G2, and in 7 (87.5%) of NET G3. p-AKT1 expression was more frequently identified in pNET G3 category and increased during the tumor progression in metachronous liver metastases, as compared to the corresponding primary tumor. In addition, p-AKT1 positivity was significantly associated with an increase of grade from G1 to G3 (p = 0.004), the Ki-67 index (p = 0.029), the pTNM stage (p = 0.0008), perineural invasion (p = 0.031) and a decrease in disease-free survival (p = 0.05).Conclusion:The results suggest that p-АКТ1 plays an important role in the pathogenesis of pNETs and may be an additional criterion for assessment of the prognosis and treatment effectiveness in this type of tumors.

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Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors

Oncogenesis ◽

10.1038/s41389-021-00372-5 ◽

2021 ◽

Vol 10 (12) ◽

Author(s):

Angela M. Carter ◽

Nilesh Kumar ◽

Brendon Herring ◽

Chunfeng Tan ◽

Rachael Guenter ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Islet Cells ◽

Tumor Development ◽

Heterogeneous Population ◽

Targeted Therapeutics ◽

Pancreatic Neuroendocrine Tumors ◽

The Past ◽

Regulated Expression ◽

Well Differentiated ◽

Conditional Mouse Model

AbstractPancreatic neuroendocrine tumors (PanNETs) are a heterogeneous population of neoplasms that arise from hormone-secreting islet cells of the pancreas and have increased markedly in incidence over the past four decades. Non-functional PanNETs, which occur more frequently than hormone-secreting tumors, are often not diagnosed until later stages of tumor development and have poorer prognoses. Development of successful therapeutics for PanNETs has been slow, partially due to a lack of diverse animal models for pre-clinical testing. Here, we report development of an inducible, conditional mouse model of PanNETs by using a bi-transgenic system for regulated expression of the aberrant activator of Cdk5, p25, specifically in β-islet cells. This model produces a heterogeneous population of PanNETs that includes a subgroup of well-differentiated, non-functional tumors. Production of these tumors demonstrates the causative potential of aberrantly active Cdk5 for generation of PanNETs. Further, we show that human PanNETs express Cdk5 pathway components, are dependent on Cdk5 for growth, and share genetic and transcriptional overlap with the INS-p25OE model. The utility of this model is enhanced by the ability to form tumor-derived allografts. This new model of PanNETs will facilitate molecular delineation of Cdk5-dependent PanNETs and the development of new targeted therapeutics.

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Epigenetic-based targeted therapies for well-differentiated pancreatic neuroendocrine tumors: recent advances and future perspectives

Expert Review of Endocrinology & Metabolism ◽

10.1080/17446651.2021.1982382 ◽

2021 ◽

Author(s):

Francesca Marini ◽

Francesca Giusti ◽

Maria Luisa Brandi

Keyword(s):

Neuroendocrine Tumors ◽

Targeted Therapies ◽

Pancreatic Neuroendocrine Tumors ◽

Future Perspectives ◽

Recent Advances ◽

Well Differentiated

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Lymphovascular Invasion Predicts Lymph Node Involvement in Small Pancreatic Neuroendocrine Tumors

Neuroendocrinology ◽

10.1159/000502581 ◽

2019 ◽

Vol 110 (5) ◽

pp. 384-392 ◽

Cited By ~ 2

Author(s):

Andrew M. Blakely ◽

Kelly J. Lafaro ◽

Daneng Li ◽

Jonathan Kessler ◽

Sue Chang ◽

...

Keyword(s):

Lymph Node ◽

Neuroendocrine Tumors ◽

Lymphovascular Invasion ◽

Pancreatic Head ◽

Tumor Grade ◽

Mitotic Rate ◽

Endoscopic Biopsy ◽

Pancreatic Neuroendocrine Tumors ◽

Regional Lymphadenectomy ◽

Node Involvement

Introduction: Pancreatic neuroendocrine tumors (p-NETS) are increasing in incidence, and prognostic factors continue to evolve. The benefit of lymphadenectomy for p-NETS ≤2 cm remains unclear. We sought to determine the significance of lymphovascular invasion (LVI) for small p-NETS. Methods: The National Cancer Database was queried for patients with p-NETS ≤2 cm and with ≥1 evaluated lymph node (LN), years 2004–2015. Demographic, clinical, and treatment characteristics were analyzed. Multivariate logistic regression was performed to identify predictors of LN positivity. Results: Among 2,499 patients identified, tumor location was delineated as the head (26%), body (18%), tail (38%), or unspecified (18%); 74% were well-differentiated versus 10% moderate, 2% poor, and 14% unknown. LVI occurred in 11%. A median of 9 LNs were evaluated; overall positivity was 18%. Mean survival was significantly longer in node-negative patients (115 vs. 95 months, log-rank p < 0.0001). LVI was the strongest predictor of node involvement (OR 10.4, p < 0.0001) when controlling for tumor size, grade, and location. Subset analysis of patients with known LVI status, grade, location, and mitoses found that LVI was more likely in the setting of moderate-to-high tumor grade, 1–2 cm size, pancreatic head location, and high mitotic rate. Among patients with ≥2 of these 4 factors, 25% were node-positive. Conclusions: Presence of LVI was the strongest predictor of node positivity. LVI on endoscopic biopsy should prompt resection and regional LN dissection to fully stage patients with small p-NETS. Patients with other high-risk factors should also be considered for resection and regional lymphadenectomy.

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