ATRX/DAXX in EUS-FNB Specimens of Pan-NETs

NCT06406387 | Active Not Recruiting

• 1 other identifier: FORESEE
• Study Type: observational
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

P-NENs are classified as functional (F-) or non-functional (NF-) depending on the presence or absence of a clinical hormonal hypersecretion syndrome. Moreover, the WHO 2017 classification of pNENs distinguishes between well-differentiated pancreatic neuroendocrine tumors (pNETs) and poorly differentiated pancreatic neuroendocrine carcinomas (pNECs). pNETs are then divided according to a grading scheme based on Ki67 index in pNETs-G1 (Ki67 index ≤3%) and pNETs-G2 (Ki67 index between 4% and 20%). pNECs are all G3, with a Ki67 index \>20%. Endoscopic ultrasound with fine-needle biopsy (EUS-FNB) demonstrated safe and effective preoperative grading based on the Ki-67 proliferative index. However, downstaging rate is not neglectable, reaching 15% in a recent metanalysis. Moreover, recent whole-exome and whole genome sequencing studies revealed that the mutually exclusive inactivating mutations in death domain-associated protein (DAXX) and/or in α-thalassemia/mental retardation X-linked (ATRX) chromatin remodeling genes are associated with more aggressive disease. In a retrospective study, the investigators recently evaluated the correspondence of DAXX/ATRX expression on 41 EUS-FNB samples with corresponding surgical specimens demonstrating a 95.1% (almost perfect agreement, κ = 0.828; p \< 0.001) and 92.7% (substantial agreement, κ = 0.626; p \< 0.001) concordance for DAXX and ATRX expression, respectively. This study aims to evaluate the potential clinical/prognostic role of DAXX/ATRX expression as implementation of the currently used Ki67-based grading, evaluated on EUS-FNB samples in a prospective cohort of patients with NF-pNETs

Conditions

Pancreatic Neuroendocrine Tumor

Outcome Measures

Primary Outcomes (1)

• ATRX/DAXX loss-tumor aggressiveness association

  To assess the association between ATRX/DAXX loss of expression assessed on endoscopic ultrasound biopsy specimens and pathological features indicative of tumor aggressiveness evaluated on surgical pathology

  18 months

Secondary Outcomes (4)

• Ki-67 concordance

  18 months

• DAXX/ATRX concordance

  18 months

• Ki-67-tumor aggressiveness association

  18 months

• Preoperative prognosis assessment

  60 months

Study Arms (2)

ATRX/DAXX loss

The "positive" group including patients with loss of DAXX or ATRX expression evaluated on immunohistochemistry on endoscopic ultrasound biopsy specimens

Diagnostic Test: ATRX/DAXX immunohistochemistry

ATRX/DAXX preserved

The "negative" group including those with preserved DAXX and ATRX expression evaluated on immunohistochemistry on endoscopic ultrasound biopsy specimens

Diagnostic Test: ATRX/DAXX immunohistochemistry

Interventions

ATRX/DAXX immunohistochemistry DIAGNOSTIC_TEST

Immunohistochemistry will be performed using an Autostainer Leica (Leica Biosystems) according to the manufacturer's instructions. Four μm formalin-fixed paraffin-embedded sections will be immunostained with antibodies for Cytokeratin AE1/AE3 (AE1-AE3, 1:100 dilution, Novocastra/United Kingdom) Chromogranin A (DAK-A3, 1:2500, Dako/Denmark), and Synaptophysin (27G12, 1:100, Novocastra), Ki67 (MIB1, 1:100, Dako/Denmark), ATRX (1:400, Sigma-Aldrich), DAXX (1:200, Sigma-Aldrich). After antigen retrieval, immunostaining will be performed in an automated Bond instrument (Vision-Biosystem, Leica, Milan, Italy) using a sensitive peroxidase-based 'Bond polymer Refine' detection system.

ATRX/DAXX loss; ATRX/DAXX preserved

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with a diagnosis of pancreatic neuroendocrine tumors

You may qualify if:

• Age ≥18 years
• Cyto/histologic diagnosis of pNETs
• Signed informed consent

You may not qualify if:

• Functional pNETs
• Multiple pancreatic nodules
• Diagnosis of MEN-1 or Von-Hippel Lindau
• Mixed types (e.g., mixed neuroendocrine-acinar/adenocarcinoma) or neuroendocrine carcinomas
• Predominantly cystic lesions (more than 50% of the volume).
• Metastatic tumors at the time of diagnosis
• Known bleeding disorder that cannot be sufficiently corrected with co-fact or fresh frozen plasma
• Use of anticoagulants that cannot be discontinued
• INR \>1.5 or platelet count \<50.000
• Pregnancy or breastfeeding
• Failure to sign the patient's or closest relative's informed consent

Sponsors & Collaborators

• Azienda Ospedaliera Universitaria Integrata Verona: lead

Study Sites (1)

University Hospital of Verona

Verona, Italy

Location

MeSH Terms

Conditions

Adenoma, Islet Cell

Condition Hierarchy (Ancestors)

Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Pancreatic Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 6, 2024
• First Posted: May 9, 2024
• Study Start: June 1, 2024
• Primary Completion: March 30, 2025
• Study Completion (Estimated): November 30, 2029
• Last Updated: January 13, 2026

Record last verified: 2025-01

Locations

IT (1)