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

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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Are Cystic Pancreatic Neuroendocrine Tumors an Indolent Entity Results from a Single-Center Surgical Series

Neuroendocrinology ◽

10.1159/000477849 ◽

2017 ◽

Vol 106 (3) ◽

pp. 234-241 ◽

Cited By ~ 10

Author(s):

Salvatore Paiella ◽

Giovanni Marchegiani ◽

Marco Miotto ◽

Anna Malpaga ◽

Harmony Impellizzeri ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Survival Rates ◽

Disease Free Survival ◽

Postoperative Outcome ◽

Tumor Diameter ◽

Pancreatic Neuroendocrine Tumors ◽

Ki 67 ◽

Excellent Outcome ◽

Comparison Results ◽

Well Differentiated

Introduction: Cystic pancreatic neuroendocrine tumors (CPanNETs) represent an uncommon variant of pancreatic neuroendocrine tumors (PanNETs). Due to their rarity, there is a lack of knowledge with regard to clinical features and postoperative outcome. Methods: The prospectively maintained surgical database of a high-volume institution was queried, and 46 resected CPanNETs were detected from 1988 to 2015. Clinical, demographic, and pathological features and survival outcomes of CPanNETs were described and matched with a population of 92 solid PanNETs (SPanNETs) for comparison. Results: CPanNETs accounted for 7.8% of the overall number of resected PanNETs (46/587). CPanNETs were mostly sporadic (n = 42, 91%) and nonfunctioning (39%). Two functioning CPanNETs were detected (4.3%), and they were 2 gastrinomas. The median tumor diameter was 30 mm (range 10-120). All tumors were well differentiated, with 38 (82.6%) G1 and 8 (17.4%) G2 tumors. Overall, no CPanNET showed a Ki-67 >5%. A correct preoperative diagnosis of a CPanNET was made in half of the cases. After a median follow-up of >70 months, the 5- and 10-year overall survival of resected CPanNETs was 93.8 and 62.5%, respectively, compared to 92.7 and 84.6% for SPanNETs (p > 0.05). The 5- and 10-year disease-free survival rates were 94.5 and 88.2% for CPanNETs and 81.8 and 78.9% for SPanNETs, respectively (p > 0.05). Conclusion: In the setting of a surgical cohort, CPanNETs are rare, nonfunctional, and well-differentiated neoplasms. After surgical resection, they share the excellent outcome of their well-differentiated solid counterparts for both survival and recurrence.

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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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Genetic Analysis of Small Well-differentiated Pancreatic Neuroendocrine Tumors Identifies Subgroups With Differing Risks of Liver Metastases

Annals of Surgery ◽

10.1097/sla.0000000000003022 ◽

2020 ◽

Vol 271 (3) ◽

pp. 566-573 ◽

Cited By ~ 20

Author(s):

Antonio Pea ◽

Jun Yu ◽

Luigi Marchionni ◽

Michael Noe ◽

Claudio Luchini ◽

...

Keyword(s):

Genetic Analysis ◽

Liver Metastases ◽

Neuroendocrine Tumors ◽

Pancreatic Neuroendocrine Tumors ◽

Well Differentiated

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Histologic and molecular features of small well-differentiated pancreatic neuroendocrine tumors associated with the development of liver metastases

HepatoBiliary Surgery and Nutrition ◽

10.21037/hbsn.2019.04.10 ◽

2019 ◽

Vol 8 (4) ◽

pp. 433-435 ◽

Cited By ~ 1

Author(s):

Paula Jiménez-Fonseca ◽

Patricia Morales del Burgo ◽

Felipe Alvarez-Manceñido

Keyword(s):

Liver Metastases ◽

Neuroendocrine Tumors ◽

Pancreatic Neuroendocrine Tumors ◽

Molecular Features ◽

Well Differentiated

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A new immunohistochemistry prognostic score (IPS) for recurrence and survival in pancreatic neuroendocrine tumors (PanNET).

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.241 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 241-241

Author(s):

Antonio Viudez ◽

Filipe LF Carvalho ◽

Zahra Maleki ◽

Marianna Zahurak ◽

Daniel A. Laheru ◽

...

Keyword(s):

Prognostic Factors ◽

Neuroendocrine Tumors ◽

Dna Methyltransferase ◽

Prognostic Score ◽

Prognostic Significance ◽

Disease Free Survival ◽

Nuclear Staining ◽

Pancreatic Neuroendocrine Tumors ◽

Ki 67 ◽

Significant Difference

241 Background: We aimed to evaluate the expression and prognostic significance of N-myc downstream-regulated gen-1 (NDRG-1), O6-methylguanine DNA methyltransferase (MGMT) and Pleckstrin homology-like domain family A member 3 (PHLDA-3) by immunohistochemistry (IHC) and methylation analysis in resected pancreatic neuroendocrine tumors (PanNET). Methods: Ninety-two patients with resected primary PanNET and follow-up > 24 months were included in this study. Nuclear staining for MGMT and PHLDA-3 were scored as 0, 1-5%, 6-50% and ≥ 51%; cytoplasmic NDRG-1 staining was scored based on intensity and pattern from 0 to 2. We then grouped IHC scores for MGMT (absent versus any expression); for NDRG-1 (0 versus 1 versus 2) and for PHLDA-3 ( < 50% versus ≥ 51%). Finally, we developed an immunohistochemistry prognostic score (IPS) based on MGMT, NDRG-1 and PHLDA-3 IHC expression to predict disease free survival (DFS) and overall survival (OS). The discriminatory ability of multivariate models combining the IPS and important clinical variables was assessed with Harrel’s c-index (HCI) and a modification of Harrell’s c-index (mHCI). Results: DFS was significantly worse in patients without any expression of MGMT compared with those with any grade of expression (HR: 2.21; 95%CI: 0.97-5.02; p = 0.013), in patients with moderate or high score for NDRG-1 (p = 0.005), and in those with high-expression for PHLDA-3 (HR: 1.94; 95%CI: 1.05,3.6; p = 0.036). A significant difference in OS was observed based on NDRG-1 score (p = 0.013). In multivariate analyses, ki-67 (HR: 2.45; 95% CI: 1.20-5.01; p = 0.01) and IPS (HR: 2.68; 95% CI: 1.60,4.49; p = 0.00018) were independent prognostic factors for DFS, while age (HR: 7.67; 95% CI: 2.14,27.45; p = 0.0017) and IPS (HR: 2.67; 95% CI: 1.11, 6.41; p = 0.03) were independent prognostic factors for OS. HCI for the multivariate DFS and OS models were 0.796 and 0.788, respectively. Conclusions: Our IPS is a useful prognostic biomarker for recurrence and survival in patients following resection for PanNET. Prospective studies are warranted to validate our findings and determine its role for patients’ selection to neo/adjuvant treatments

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Predictive value of preoperative MRI features for the Ki-67 index in well-differentiated G1/G2 pancreatic neuroendocrine tumors

Acta Radiologica ◽

10.1177/0284185119840212 ◽

2019 ◽

Vol 60 (11) ◽

pp. 1394-1404

Author(s):

Haitao Sun ◽

Shilong Zhang ◽

Kai Liu ◽

Jianjun Zhou ◽

Xingxing Wang ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Predictive Value ◽

Pancreatic Neuroendocrine Tumors ◽

Ki 67 ◽

Mri Features ◽

Well Differentiated

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Efficacy and Prognostic Factors for Y-90 Radioembolization (Y-90) in Metastatic Neuroendocrine Tumors with Liver Metastases

Canadian Journal of Gastroenterology and Hepatology ◽

10.1155/2020/5104082 ◽

2020 ◽

Vol 2020 ◽

pp. 1-5

Author(s):

Erica S. Tsang ◽

Jonathan M. Loree ◽

Janine M. Davies ◽

Sharlene Gill ◽

David Liu ◽

...

Keyword(s):

Liver Metastases ◽

Neuroendocrine Tumors ◽

Performance Status ◽

Population Based ◽

Somatostatin Analogue ◽

Ecog Performance Status ◽

Ki 67 ◽

Well Differentiated ◽

Grade 3 ◽

Metastatic Liver

Background. Yttrium-90 (Y-90) can be an effective liver-directed therapy for patients with metastatic neuroendocrine tumors (NETs), but population-based data are limited. We characterized the use of Y-90 in NET patients and identified factors associated with response. Methods. We identified 49 patients with metastatic liver-dominant NETs across BC Cancer’s six regional centres who received Y-90 between June 2011 and January 2017 in British Columbia, Canada. Baseline characteristics, radiographic responses, and outcomes were summarized. Results. Of the 49 patients who received Y-90, the median age was 56 years (range 21–78), 49% were male, and 94% had an ECOG performance status of 0–1. The primary location of the NET included pancreas (31%), small bowel (41%), large bowel (6%), unknown (14%), and others (12%). 69% of these patients had liver metastases alone, and tumors were graded as G1 (61%), G2 (25%), G3 (2%), and unknown (12%). Prior therapies included surgery (63%), local ablative therapy (25%), somatostatin analogue (69%), and systemic therapy (35%). The median Y-90 dose was 2.2 GBq (range 0.8–3.6), as SIR-spheres (69%) or TheraSpheres (29%). Median time to Y-90 from diagnosis of metastases measured 1.54 years. 88% received segmental Y-90, with 1 (69%), 2 (29%), and 3 (2%) treatments. Y-90 resulted in partial response (53%), stable disease (33%), and progressive disease (12%). Y-90 was well-tolerated, with infrequent grade 3-4 biochemical toxicities (2%) and grade 3 abdominal pain (6%). Longer overall survival (OS) was associated with resection of primary tumor, well-differentiated histology, and low Ki-67. Median OS was 27.2 months (95% CI 8.0–46.5).Conclusions. In our population-based cohort, Y-90 was well-tolerated in patients with metastatic liver-dominant NETs. Prior surgical resection was an important predictor of OS.

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

Endocrine ◽

10.1007/s12020-017-1364-8 ◽

2017 ◽

Vol 57 (3) ◽

pp. 494-502 ◽

Cited By ~ 6

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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Subgroup analysis by Ki-67 and baseline CgA of the randomized, placebo-controlled phase 3 study of surufatinib in advanced well-differentiated pancreatic neuroendocrine tumors (SANET-p).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4111 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4111-4111

Author(s):

Xianjun Yu ◽

Jianming Xu ◽

Lin Shen ◽

Chunmei Bai ◽

Jie Li ◽

...

Keyword(s):

Partial Response ◽

Neuroendocrine Tumors ◽

Objective Response ◽

Evaluation Criteria ◽

Progression Free Survival ◽

Pancreatic Neuroendocrine Tumors ◽

Phase 3 ◽

Ki 67 ◽

Meaningful Improvement ◽

Well Differentiated

4111 Background: In the phase 3 SANET-p trial (NCT02589821), surufatinib significantly increased progression-free survival (PFS) compared with placebo in patients with progressive, well-differentiated (grade 1 or 2), advanced pancreatic neuroendocrine tumors (NETs). Here we report the relationship of Ki-67 and baseline Chromogranin A (CgA) on efficacy outcomes. Methods: A total of 172 patients with advanced pancreatic NETs were randomized to surufatinib or placebo in a 2:1 ratio. Investigator-assessed PFS and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 were used for the analysis. The post-hoc subgroup analyses were performed on Ki-67 subcategory: < 5% (n = 40 vs 21), 5-10% (n = 57 vs 31), > 10% (n = 16 vs 7), and baseline CgA subcategory: ≤ 2 times of upper limit of normal (ULN) (n = 59 vs 31), > 2 × ULN (n = 44 vs 24). Results: In the intent-to-treat population, surufatinib was superior to placebo, median PFS (mPFS) of 10.9 vs 3.7 months (mo) ( p = 0.0011), with a stratified hazard ratio (HR) of 0.491 (95% confidence interval [CI]: 0.319, 0.755). mPFS was statistically significantly longer in the surufatinib arm versus that in the placebo arm in subgroups of Ki-67 5-10% (11.0 vs 3.7 mo, HR = 0.33, p= 0.0002), Ki-67 > 10% (11.1 vs 2.8 mo, HR = 0.04, p = 0.0003) and CgA > 2 × ULN (11.0 vs 3.7 mo, HR = 0.36, p = 0.0036). There was numerical PFS improvement with surufatinib compared to placebo in subgroup of Ki-67 < 5% (9.3 vs 5.6 mo, HR = 0.91, p = 0.8015) and CgA ≤ 2 × ULN (9.4 vs 3.7 mo, HR = 0.61, p = 0.0809). ORRs in the subgroups of Ki-67 < 5%, 5-10%, and > 10% with surufatinib were 15.8%, 24.0% and 12.5% respectively. There was only one partial response in the placebo arm (with Ki-67 < 5%). ORRs in the subgroups of CgA ≤ 2 × ULN and > 2 × ULN with surufatinib were 18.9% and 21.4%, while also only one partial response in the placebo arm with CgA ≤ 2 × ULN. Conclusions: Surufatinib showed statistically significant and clinically meaningful improvement in PFS compared to placebo in patients with advanced, progressive, well-differentiated pancreatic NETs. From this exploratory analysis, surufatinib demonstrated benefit irrespective of Ki-67 expression levels or baseline CgA. Clinical trial information: NCT02589821.

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