Endocrine, Metabolic, Inflammatory Biomarkers to Identify Highgrade Dysplasia/invasive Carcinoma in Patients with IPMN of the Pancreas (EMI-IPMN)

Definition of Radiological and Endocrine/metabolic/inflammatory Biomarker(s) to Identify Highgrade Dysplasia/invasive Carcinoma in Patients with Intraductal Papillary Mucinous Neoplasms of the Pancreas

Under the hypotheses that a more accurate patients selection could limit the problem of overtreatment and that benign intraductal papillary mucinous neoplasms (IPMN) have a distinguishable Endocrine/Metabolic/Inflammatory (EMI) profile from those with high-grade disease/invasive carcinoma, this study has three specific aims. The first aim is to evaluate and confirm the accuracy of the updated versions of International and European guidelines for the management of IPMN and it will be addressed by retrospectively applying the criteria included in the two guidelines on 350 patients with resected IPMN in order to determine the most accurate criteria to identify High Grade Dysplasia(HGD)/Invasive Carcinoma (IC).

The second aim is to identify pre-operative biological and/or radiological/endosonographic biomarker(s) able to distinguish low- versus high-risk IPMN for cancer progression in a prospective study by enrolling a cohort of 186 (of which 145 surgically-resected) patients.

The third aim is to prospectively validate biological and/or radiological/endosonographic biomarker(s) (previously identified and optimized) on a new cohort of 50 patients with IPMN undergoing surgical resection.

Study Overview

• Status: Recruiting
• Conditions: Pancreatic Cyst; Intraductal Papillary Mucinous Neoplasm of Pancreas

Detailed Description

Up to 40% of patients (pts) undergoing abdominal imaging harbor unsuspected pancreatic cysts, the majority of which intraductal papillary mucinous neoplasms (IPMN). IPMNs are well-known precursors of pancreatic ductal adenocarcinoma (PDAC) without an established temporal window of progression. Current guidelines identify high-risk stigmata (HRS)/absolute criteria(AC) and worrisome features(WF)/relative criteria(RC) as indications for surgical resection of IPMN. Previous guideline criteria were found to be associated with high sensitivity but low specificity for malignancy, resulting in an overtreatment of benign IPMNs, a clinical relevant issue considering the high morbidity/mortality of pancreatectomy. Currently, there are no available hematic biomarkers in peripheral blood, be they DNA, RNA or protein-based, which can identify High Grade Dysplasia(HGD)/Invasive Carcinoma (IC). DNA-based molecular testing of pancreatic cyst fluid obtained during endoscopic ultrasound (EUS)/surgery have been developed and are used to identify advanced neoplasia, with good sensitivity/specificity, and therefore hypothetically, an IPMN HGD/IC-based biomarker could be more readily detected in cyst fluid or in portal blood. This strategy, however has a number of limitations: i) it is highly invasive and costly ii) poor quantity and quality of cyst fluid may lead to incorrect detection (false negatives in molecular testing) ; and iii) a lack of predictive potential of progression over time. New diagnostic tools based on samples of portal blood obtained during EUS or potentially peripheral samples (of new biomarkers) may overcome these limitations.

PDAC has been associated with altered inflammatory and endocrine/metabolic profiles but limited data are available on IPMN and other precursors. Inflammation and malignant progression have become cardinal in cancer research. Tumor-associated neutrophils and cytokines, including TNFalpha and IL-1ß, have been associated with malignant progression also in IPMN. About 40-70% of patients with PDAC experience diabetes or alterations of glucose homeostasis. Diabetes-induced hyperglycemia, hyperinsulinemia, altered insulin-like growth factors production, chronic inflammation and metabolic syndrome have been associated with cancer . In a large cohort of resected IPMNs, preoperative diabetes was significantly associated with HGD/IC, and the risk of IC was highest in patients with recent-onset diabetes.

Obesity is also a well-known risk factor for PDAC; proinflammatory cytokines, known as adipokines are released mainly from visceral adipose tissue stimulating aberrant angiogenesis. An association between visceral obesity and pancreatic fatty infiltration with poor survival was found in PDAC patients. In the setting of IPMN, in a very small cohort of resected patients, significantly higher BMI was associated to an increased rate of malignant IPMN.

EUS, Computed tomography(CT) and magnetic resonance imaging(MRI) are of use in current clinical practice to study and monitor pancreatic diseases. They are all imaging techniques that allow to characterize pancreatic alterations and simultaneously detect endocrino-metabolic alterations (i.e.visceral obesity, liver steatosis, pancreatic fatty infiltration) that may be associated to pancreatic diseases.

Current literature is still debating the superiority of radiological imaging (specifically MRI) or endoscopic ultrasound in identifying worrisome features/high risk stigmata and in correctly distinguishing benign/malignant IPMNs. Preliminary analysis performed in the context of this study, specifically in retrospective Cohort A, aimed at validating International and European guidelines, supports an important role for EUS in identifying risk of malignancy in IPMNs. In fact, 31/116 patients (26.7%) with WF at MRI were "upstaged" by EUS and the majority of these (77.4%) had malignancy at final pathology. Furthermore, EUS confirmed MRI findings in 87.5% of cases, including 72.4% of radiological WF.

The association among obesity, diabetes, inflammation, alterations of specific endocrine/metabolic pathways and pancreatic cancer development from its precursors (IPMN) are more complex, and needs further investigations.

The driving hypotheses of this study are that i) a more accurate patients selection could limit the problem of overtreatment, ii) that benign/indolent IPMN have a distinguishable Endocrine/Metabolic/Inflammatory (EMI) profile from those with HGD/IC, and therefore this research has the following three specific aims.

Aim 1: To retrospectively evaluate and to validate the updated versions of International and European guidelines for the management of IPMN (Cohort A) Aim 2: To identify pre-operative biological and/or imaging biomarker(s) to distinguish low- versus high-risk IPMN for cancer progression in a prospective study of surgically-resected patients (Cohort B) Aim 2.1: To compare MRI and EUS in the pre-operative evaluation of IPMNs and with respect to pathological findings. In particular, primary endpoint will be the identification of main pancreatic duct involvement. Secondary endpoints will be evaluation of the degree of main duct involvement (extension of IPMN involvement, MPD diameter at predetermined points, maximum diameter of MPD), the presence of thickened ductal walls, mural nodules and the characteristics of the surrounding parenchyma (fatty infiltration/vanishing pancreas).

Aim 3: To prospectively validate biological and/or imaging biomarker(s) previously identified (Aim 2) on patients with IPMN undergoing surgical resection (Cohort C)

• Study Type: Observational
• Enrollment (Estimated): 586

Contacts and Locations

• Study Contact: Name: Stefano Crippa, MD; Phone Number: +39 0226437811; Email: crippa.stefano@hsr.it
• Study Contact Backup: Name: Paolo Camisa, MD; Phone Number: +39 0226436046; Email: camisa.paoloriccardo@hsr.it

Study Locations

• Italy
  • Milan, Italy, 20132
    • Recruiting
    • San Raffaele Hospital
    • Contact: Stefano Crippa, MD; Phone Number: +39 0226436046; Email: crippa.stefano@hsr.it
    • Contact: Stefano Crippa, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The patients will be enrolled in the outpatient clinic, if they meet the required criteria for inclusion.

Description

cohort A: inclusion criteria:

• histologically proven IPMNs with full pathological data (type of IPMNs, grade of dysplasia; for invasive IPMNs: grading, pTNM classification, presence of perineural (microvascular infiltration)
• availability of clinical and imaging criteria for surgical resections defined by International and European guidelines (worrisome features and high-risk stigmata according to International Guidelines and absolute/relative criteria for surgery according to European guidelines
• age ≥18 years

exclusion criteria:

- lack of preoperative clinical and radiological data according the two guidelines

Cohort B and C:

inclusion criteria:

• Age >= 18 years
• Charlson comorbidity index <7
• indication for surgery for suspected IPMN

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Cohort A; A retrospective study of a cohort of 350 resected patients with a histologically-confirmed IPMN, diagnosed from the 1st January 2009 to the 31st May 2018 following these inclusion criteria: histologically proven IPMNs with full pathological data (type of IPMNs, grade of dysplasia; for invasive IPMNs: grading, pTNM classification, presence of perineural (microvascular infiltration); availability of clinical and imaging criteria for surgical resections defined by International and European guidelines (worrisome features and high-risk stigmata according to International Guidelines and absolute/relative criteria for surgery according to European guidelines; age ≥18 years and exclusion criteria:; lack of preoperative clinical and radiological data according the two guidelines
Cohort B; A prospective observational study whose aim is to identify EMI profiles and radiological/endosonographical biomarker(s) associated to surgically removed IPMNs with HGD/IC. Patients diagnosed with IPMN and candidates for resection with following inclusion criteria will be enrolled: Age >= 18 years; Charlson comorbidity index <7 [26] The patients' cohort will be selected following the best criteria for surgery identified in the retrospective study (Cohort A). At the admission, patients will be informed by PI, or his delegates about the study, and they will be asked to sign the specific informed consents (see par. 5.1) In the course of standard pre-operative evaluation, all patients will undergo MRI and EUS, within no more than 3 months between exams.
Cohort C; A prospective study with the aim to validate potential biomarker(s) identified in the Cohort B. Patients with a diagnosis of IPMN candidate for resection with the following inclusion criteria will be enrolled: Age >= 18 years; Charlson comorbidity index <7 [26] The patients' cohort will be selected following the best criteria for surgery identified in the retrospective study (Cohort A). At the admission patients will be informed by PI or his delegates about the study and they will be asked to sign specific informed consents

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
evaluation of the best guideline between the International and European guidelines	The criteria included in the two guidelines will be retrospectively applied on 350 patients with resected IPMN. Clinical pathological and imaging data will be retrieved from institutional archives systems. As we may be not able to identify a more accurate guideline, we may select specific criteria from each of the two guidelines, thus selecting p batients for surgery based on a combination of criteria from both guidelines. The identified best criteria will be applied to select the discovery cohort and the validation cohort of the prospective studies.	from the collection of the retrospective cohort to 12 months
endocrine, metabolic and inflammatory profile	The following parameters will be measured in peripheral and portal serum/plasma and in the cyst fluid with commercially available kits	from the enrollment to 8 month
imaging-based biomarker(s)	As per standard-of-care current clinical practice in our institution, all patients will undergo 1.5T contrast-enhanced MR cholangiopancreatography (MRCP) with 3D acquisition protocol of the pancreatic ducts/ biliary tree	at the time of enrollment
evaluation of the accuracy of the biomarkers in predicting the pathological diagnosis	the accuracy at identifying malignant IPMN of the identified biomarkers will be tested.	at the end of the enrollment

Secondary Outcome Measures

Outcome Measure	Time Frame
evaluation of the accuracy of the MRI versus the EUSP in identifying the involvement of the main pancreatic duct	at the end of the enrollment

Collaborators and Investigators

• Sponsor: IRCCS San Raffaele

Study record dates

Study Major Dates

• Study Start (Actual): July 13, 2020
• Primary Completion (Estimated): January 31, 2025
• Study Completion (Estimated): March 31, 2025

Study Registration Dates

• First Submitted: November 22, 2024
• First Submitted That Met QC Criteria: November 22, 2024
• First Posted (Estimated): November 26, 2024

Study Record Updates

• Last Update Posted (Estimated): November 26, 2024
• Last Update Submitted That Met QC Criteria: November 22, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: intraductal papillary mucinous neoplasm of the pancreas; ipmn; Pancreatic Cysts
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Neoplasms, Glandular and Epithelial; Cysts; Neoplasms, Ductal, Lobular, and Medullary; Pancreatic Intraductal Neoplasms; Neoplasms; Pancreatic Neoplasms; Pancreatic Cyst; Neoplasms, Cystic, Mucinous, and Serous
• Other Study ID Numbers: EMI-IPMN

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No