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DNA-mutation Analysis in Cyst Fluid of Suspected Intraductal Papillary Mucinous Neoplasia of the Pancreas

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ClinicalTrials.gov Identifier: NCT03820531
Recruitment Status : Recruiting
First Posted : January 29, 2019
Last Update Posted : March 19, 2020
Sponsor:
Collaborator:
University Hospital Heidelberg
Information provided by (Responsible Party):
Theresienkrankenhaus und St. Hedwig-Klinik GmbH

Study Description
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Brief Summary:
Diagnostic tools are needed to identify mucinous cysts for further evaluation or follow-up respectively to identify cysts with HGD or invasive cancer at an early stage for surgical resection. Molecular genetic analysis of pancreatic cyst fluid is a new but rapidly evolving method to identify KRAS/GNAS oncogenic driver mutations in mucinous cysts and to identify tumour suppressor gene mutations which are involved in advanced cysts with HGD or carcinoma. The ongoing ZYSTEUS-study tries to implement DNA mutation analysis by Next Generation Sequencing in the diagnostic algorithm of pancreas cyst evaluation. The first aim is to distinguish mucinous from non-mucinous cysts. The second aim is to define relevant tumour suppressor gene mutations which are relevant to distinguish between LGD and HGD/carcinoma in mucinous cysts.

Condition or disease Intervention/treatment Phase
Pancreas Cyst Diagnostic Test: Next Generation Sequencing Diagnostic Test: CEA and lipase Diagnostic Test: Cytology Diagnostic Test: Histology of resected pancreas cyst Not Applicable

Detailed Description:
Intraductal papillary mucinous neoplasm (IPMN) with low grade dysplasia (LGD) can progress to high grade dysplasia (HGD) or invasive cancer. Main duct IPMN, mixed type IPMN or branch duct IPMN with high risk stigmata are highly predictive for malignancy. Therefore, patients in good general state should be considered for surgical resection. Guidelines like the International Fukuoka Consensus Guidelines from 2017 or the European evidence-based Guidelines on Pancreatic cyst neoplasms from 2018 provide detailed recommendations on the management of IPMNs by focusing on clinical characteristics, image morphology, cytology and laboratory parameters. However, these applied guidelines still lead to surgical overtreatment of pancreas cysts based on the pathologic outcomes as neither HGD nor carcinoma is found in up to 82.1 % of the resected cysts. Cyst fluid sent for cytology usually provides adequate cellular material for analysis in only 31% of the cases and Endoscopic Ultrasound-guided forceps biopsy has not yet shown to be better than fine needle aspiration. Hence, further diagnostic tools are needed to identify mucinous cysts for further evaluation or follow-up respectively to identify cysts with HGD or invasive cancer at an early stage for surgical resection. Molecular genetic analysis of pancreatic cyst fluid is possibly able to identify KRAS/GNAS oncogenic driver mutations in mucinous cysts and to identify tumour suppressor gene mutations which are involved in advanced cysts with HGD or carcinoma. This workgroup described a high sensitive method of targeted Next Generation Sequencing in pancreas cyst fluid with a limit of detection of allele frequency down to 0.01 %. Further investigations of the ongoing ZYSTEUS-study are focused on the implementation of DNA mutation analysis by NGS in the diagnostic algorithm of pancreas cyst evaluation. The first aim is to reliably distinguish mucinous from non-mucinous cysts respectively main duct IPMN from chronic pancreatitis with main duct dilatation as the absence of KRAS/GNAS-mutations is highly predictive for non-mucinous diseases. The second aim is to define relevant tumour suppressor gene mutations which are relevant to differentiate LGD from HGD/carcinoma in mucinous cysts. DNA mutation analysis will be compared with already established peroperative diagnostic tests of pancreas cyst fluid: Measurement of CEA and lipase as well as cytology.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

DNA-mutation analysis by Next Generation Sequencing is performed to identify IPMN pancreas cysts with LGD versus HGD/Carcinoma.

Controls: non-neoplastic pancreas cysts and chronic pancreatitis with main duct dilation
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: DNA-mutation Analysis by Next Generation Sequencing in Cyst Fluid of Suspected Intraductal Papillary Mucinous Neoplasia of the Pancreas Obtained by Endoscopic Ultrasound-guided Fine Needle Aspiration (ZYSTEUS-Study)
Actual Study Start Date : January 1, 2018
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Suspected mucinous pancreas cyst
In all pancreas cysts > 15mm and/or pancreas duct dilatation > 5mm in patients who are fit for surgery EUS-guided pancreas cyst fluid aspiration is conducted. In cyst fluid CEA and lipase examination, cytology and Next Generation Sequencing is performed. After that, the pancreas cyst will be resected and histopathologically analysed.
 Diagnostic Test: Next Generation Sequencing
DNA Mutational Analysis in pancreas cyst fluid concerning KRAS/GNAS-mutations and mutations in tumor supressor genes

Diagnostic Test: CEA and lipase

Measuring CEA and lipase level in pancreas cyst fluid:

CEA > 192 ng/ml and lipase > 200 U/l = mucinous cyst


Diagnostic Test: Cytology

Cytology in pancreas cyst fluid:

mucinous versus non-mucinous cyst; LGD versus HGD/Carcinoma


Diagnostic Test: Histology of resected pancreas cyst
Histology of resected pancreas cyst concerning mucinous versus non-mucinous cyst, IPMN versus non-IPMN and LGD versus HGD/Carcinoma


Outcome Measures
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Primary Outcome Measures :
  1. Patients with a mucinous pancreas cyst [ Time Frame: From EUS-guided fine needle aspiration of pancreas cyst fluid up to seven days ]
    Number of patients with the preoperative diagnosis of a mucinous pancreas cyst (numerator) in correlation with the number of patients with a mucinous pancreas cyst confirmed by surgery (denominator)

  2. Pancreas cyst with HGD or carcinoma [ Time Frame: From EUS-guided fine needle aspiration of pancreas cyst fluid up to seven days ]
    Number of patients with the preoperative diagnosis of a HGD/carcinoma pancreas cyst (numerator) in correlation with the number of patients with a HGD/carcinoma pancreas cyst confirmed by surgery (denominator)


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • pancreas cysts with cyst size > 15mm
  • pancreas with main duct dilation > 5mm

Exclusion Criteria:

  • patients who are not fit for surgery
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03820531


Contacts
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Contact: Daniel Schmitz, Dr.med. 00496214245575 d.schmitz@theresienkrankenhaus.de
Contact: Jochen Rudi, Prof.Dr.med. 00496214244631 j.rudi@theresienkrankenhaus.de

Locations
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Germany
Tertiary referral hospital: Theresienkrankenhaus und St. Hedwig Hospital, Academic Recruiting
Mannheim, Germany, 68165
Contact: Daniel Schmitz, MD    00496214245575    d.schmitz@theresienkrankenhaus.de   
Contact: Jochen Rudi, MD PD    00496214245937    j.rudi@theresienkrankenhaus.de   
Principal Investigator: Daniel Schmitz, MD         
Sponsors and Collaborators
Theresienkrankenhaus und St. Hedwig-Klinik GmbH
University Hospital Heidelberg
Investigators
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Study Chair: Christel Weiß, Prof.Dr. University of Heidelberg, Department of Medical Statistis
More Information
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Publications:

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Responsible Party: Theresienkrankenhaus und St. Hedwig-Klinik GmbH
ClinicalTrials.gov Identifier: NCT03820531    
Other Study ID Numbers: ZYSTEUS-Study
First Posted: January 29, 2019    Key Record Dates
Last Update Posted: March 19, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Theresienkrankenhaus und St. Hedwig-Klinik GmbH:
DNA Mutational Analysis
Cyst Fluid
Pancreas
Additional relevant MeSH terms:
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Cysts
Pancreatic Cyst
Pancreatic Neoplasms
Neoplasms
Pathological Conditions, Anatomical
Pancreatic Diseases
Digestive System Diseases
 Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Endocrine System Diseases
Pancrelipase
Gastrointestinal Agents