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Pancrelipase

Pancreatin

For inoperable patients with indeterminate cystic lesions of the pancreas,a EUS FNA will be performed and molecular biology analysis of pancreatic intra-cyst fluid collected by EUS FNA will be performed.

For operable patients, after the pancreatic surgery, molecular biology analysis of extemporaneous pancreatic tissue specimen biopsy will be conducted.

The EUS FNA will be performed according to the Francophone Club of Echo Endoscopy recommendations.

For molecular biology technique, the samples will be processed within the UMR_S910 unit. Nucleic acids will be extracted from the intra-cystic fluid or, for post-operative patients, from a resected specimen that will be collected into a tube containing a nucleic acid stabilization solution (Allprotect Tissue reagent, Qiagen).

The nucleic acids will be extracted and then sequenced. The sequencing technology chosen (HaloPlexHS, Agilent) allows a detection close to 1% in allelic frequency. This new technical approach that links high sensitivity and specificity is also suitable with degraded and/or low-volume ( \<50ng) DNA.

Molecular biology analysis of pancreatic intra-cyst fluid

Arthur Laquière, MD

The main objective of the study is to compare the diagnostic accuracy of intra-cystic fluid DNA molecular analysis to standard diagnostics.

The secondary objective of the study is to evaluate the feasibility of intra-cystic fluid DNA molecular analysis.

Multicenter study to determinate the feasibility of intra-cystic fluid DNA molecular analysis in patients with suspected cystic tumours of pancreas in whom EUS FNA is clinically indicated.

Morphological criteria obtained by MRI and computerised tomography (tumor characterization (size, metastases presence, dilatation of bile ducts), etiologic diagnosis, serious symptoms), biological exams (biomarkers), cytological analysis will lead to a diagnosis and a treatment.

The goal of this study is to compare this standard diagnostic modalities to diagnosis obtained by intra-cystic fluid DNA molecular analysis.

Is the DNA molecular analysis improve the diagnosis accuracy.

First 20 patients for pilot study to test the feasibility of the molecular analysis then 120 patients to continue the trial.

Feasibility of Molecular Biology in Pancreatic Cyst Tumors

Study of Feasibility and Diagnostic Profitability of Intra-cyst Fluid Molecular Biology Analysis in Pancreatic Cyst Tumors.

The nucleic acids of the samples will be extracted and then sequenced on a panel of about 70 genes implicated in the pancreatic tumorigenesis and targeting RAS, MAPK, AKT, JAK-STAT, WNT, TGFB, TP53 and Repair BRCA, ATM. The selected sequencing technology (HaloPlexHS ®, Agilent) will be used. A comparison of the molecular profiles between the cystic fluid and the surgical specimen will be carried out and then confronted with the pathology, biological, radiological and clinical characterization

The nucleic acids of the samples will be extracted from the different cyst fluids and then sequenced. A comparison of the molecular profiles between the different cystic fluids will be carried out and then confronted with the pathology, biological, radiological and clinical characterization

Ramsay Générale de Santé

Hospital St. Joseph, Marseille, France

Principal Investigator Dr Arthur LAQUIERE

Gland and Hormone Related Diseases

Rare Diseases

Pancreatic Neoplasms

Cystadenocarcinoma

Adenocarcinoma

Carcinoma

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Endocrine System Diseases

Pancreatic Cancer

Adenocarcinoma of the Appendix

Serous cystadenoma patients. Endoscopic ultrasound guided needle based confocal endomicroscopy will be applied in all patients.

Mucinous cystic neoplasms patients. Endoscopic ultrasound guided needle based confocal endomicroscopy will be applied in all patients.

IPMN patients. Endoscopic ultrasound guided needle based confocal endomicroscopy will be applied in all patients.

Mucinous cystadenocarcinoma patients. Endoscopic ultrasound guided needle based confocal endomicroscopy will be applied in all patients.

Other cystic lesions patients (cystic neuroendocrine tumors, solid pseudopapillary neoplasms, cystic lymphangioma, etc.) Endoscopic ultrasound guided needle based confocal endomicroscopy will be applied in all patients..

Needle based confocal laser endomicroscopy is a technique that enables in vivo microscopic analysis during ongoing endoscopy. It has good accuracy for predicting the final histopathological diagnosis based on immediate evaluation of tissue and vascular patterns. nCLE microprobe is a flexible probe thin enough that it can be passed through a 19-gauge needle. Thus under EUS guidance solid organs (i.e. the pancreas) can be accessed for real-time microscopic information.

Endoscopic ultrasound guided needle based confocal endomicroscopy

Peter Vilmann

Stephen Pereira

Bill Brugge

Manoop Bhutani

Virendra Joshi

Ali Siddiqui

Reem Sharaiha

The study is based on a multi-center approach of needle based confocal laser endomicroscopy (nCLE) combined with endoscopic ultrasound (EUS) and EUS-guided fine needle aspiration (FNA) to evaluate pancreatic cystic lesions (PCL), in order to obtain a correct histopathological diagnosis.After detection of PCL, certain morphological EUS features allow the discrimination of specific cyst types. Additionally, EUS-FNA is recommended as the first-line procedure whenever pathological diagnosis is required; however the procedure has its drawbacks, mainly represented by the relatively low negative predictive value in diagnosing pancreatic cancer. In this case a more precisely diagnostic tool is required; the potential role of CLE has been explored in gastrointestinal (GI) pathology showing good accuracy for predicting the final histopathological diagnosis based on immediate evaluation of tissue and vascular patterns. Although the clinical impact of nCLE for the decision making algorithms in cystic pancreatic neoplasm has not yet been described, the hypothesis is that EUS-nCLE could allow targeted tissue sampling of cystic pancreatic neoplasms resulting in more accurate diagnosis. The aim of the study is to describe the clinical impact of nCLE for the clinical decision management algorithm based on EUS, EUS-FNA and/or EUS-CLE imaging criteria for cystic pancreatic neoplasms, while evaluating also the feasibility and safety of nCLE examination.

Clinical Impact of Needle-based Confocal Laser Endomicroscopy of Cystic Pancreatic Lesions (CINE-Cyst)

Background The diagnostic evaluation of cystic pancreatic lesions represents a difficult problem for clinical decision making, due to the increased incidental discovery of such lesions during cross-sectional imaging (computed tomography or magnetic resonance). Prevalence of cystic pancreatic lesions is estimated between 2 to 20% in the adult population (1-3), while autopsy studies show that the prevalence increases with age (4). The WHO classification (revised in 2010) reported several categories, with serous cystadenoma (SCA), mucinous cystic neoplasms (MCN), intraductal papillary mucinous neoplasms (IPMN) and pseudopapillary neoplasms representing more than 90% (5). Several of these lesions progress to cystadenocarcinoma (with the notable exception of SCA), hence the differential diagnosis is extremely important for the clinical decisions that currently involve either imaging follow-up (usually based on EUS and magnetic resonance imaging \[MRI\]) or referral to surgery with a final pathological diagnosis established after resection.

Nevertheless, there is considerable overlap in the imaging characteristics of benign, premalignant or malignant pancreatic cysts which leads to unclear clinical management algorithms. Several international guidelines addressed the diagnosis and management of cystic pancreatic lesions (6-8). The most comprehensive guideline reported a clinical decision algorithm which included clinical and imaging criteria, like pancreatitis / jaundice or cyst size \> 3 cm, thickening / enhancing cyst walls, main pancreatic duct (MPD) size 5-9 mm, non-enhancing mural nodules and abrupt changes in the caliber of pancreatic duct with distal pancreatic atrophy \[8\]. If any of these clinical / imaging characteristics are present then EUS is considered mandatory to assess a definite mural nodule, main duct features suspicious for involvement, as well as to perform EUS-guided fine needle aspiration (FNA) with cytopathology exam in order to exclude malignancy.

Endoscopic ultrasound (EUS) represents a highly valuable tool in the management of patients with focal pancreatic masses, either solid or cystic. As a minimally invasive technique that enables high-resolution imaging of the pancreatic parenchyma and surrounding structures it is considered the method of choice for the detection of clinically suspected pancreatic lesions, with a negative predictive value close to 100% \[9\]. Its diagnostic sensitivity was shown by previous studies to be superior compared to other imaging techniques, especially in the case of smaller tumors \[10, 11\]. After detection of cystic pancreatic lesions, certain morphological features allow the discrimination of specific types \[12\]:

* pseudocysts - parenchymal changes , without septation or nodules
* serous cystadenomas - multiple microcysts and honeycomb appearance
* mucinous cystadenoma - thickened septations and wall, with calcifications
* intrapapillary mucinous neoplasia (IPMN) - communication with the MPD There aren't universally accepted morphological parameters to predict either the type or the risk of malignancy by EUS \[8\]. "Worrisome features" on imaging include cyst size (above 3 cm), thickened cyst walls, MPD size of 5-9 mm, non-enhanced mural nodules, abrupt changes in MPD caliber with distal pancreatic atrophy, and lymphadenopathy. "High risk stigmata" include obstructive jaundice in a cystic pancreatic head mass, enhanced solid component or MPD size of over 10 mm, thus warranting an indication for surgery, if clinically feasible. Generally, all cysts with "worrisome features" and cysts over 3 cm, without worrisome features, should undergo EUS, while all cysts with "high-risk stigmata" should undergo surgical resection \[8\].

Additionally, EUS enables guided fine needle aspiration (EUS-FNA) which is currently recommended as the first-line procedure whenever pathological diagnosis is required \[13\]. However, EUS-FNA as a sampling technique has its drawbacks, mainly represented by the relatively low negative predictive value in diagnosing pancreatic cancer. It thus cannot reliably rule out a diagnosis of malignancy and patients with high clinical suspicion usually need repeated FNA \[14\]. The role of EUS-FNA for the differential diagnosis of focal cystic lesions is still controversial, as CEA and amylase levels as well as cytology are often useful to differentiate various lesions, but not all of them \[8\]. Thus, SCA have low levels of both CEA and amylase. For CEA, values over 192-200 ng/ml have 80% diagnostic accuracy for mucinous cysts \[15\]. Likewise, amylase levels might be increased in both IPMN and MCN, making the differential diagnosis difficult \[16\]. Cytology has a limited sensitivity, as the aspirates yield a low number of cells, being most useful if it detects atypical epithelial cells which can highly predict malignancy, again with an 80% accuracy \[17\].

Confocal laser endomicroscopy (CLE) has emerged in recent years as a novel technique that actually enables in vivo microscopic analysis during ongoing endoscopy. Endomicroscopy can be performed either with dedicated (eCLE) or with miniprobe-based systems (pCLE) \[18\]. It is a contrast based technique, the most widely used agent being the intravenously administered fluorescein \[19\]. The probe-based endomicroscopy system consists of a flexible catheter probe representing a bundle of optical fibers linked to a micro-objective, a laser scanning unit and the control and acquisition software (Cellvizio; Mauna Kea Technology, Paris, France). The flexible confocal miniprobes were specifically designed to be passed through the working channels of standard endoscopes, biliary catheters or cholangioscopes and thus the pCLE system can be easily integrated in any endoscopy unit. The principle of the technique is based on a laser beam of defined wavelength being focused towards the targeted tissue and the recaptured signal is displayed as 'optical biopsies' in a single horizontal plane.

The potential role of CLE has been explored in pathology of both upper and lower gastrointestinal tract, showing good accuracy for predicting the final histopathological diagnosis based on immediate evaluation of tissue and vascular patterns \[20\]. Recently CLE has gone beyond the superficial luminal indications with the development of a new microprobe, i.e. a flexible probe thin enough that it can be passed through a 19-gauge needle. Thus under EUS guidance solid organs can be accessed for real-time microscopic information. nCLE imaging of abdominal organs has been so far achieved in animal models \[21, 22\]. The feasibility of the technique was also proved in a clinical study \[23\] and descriptive criteria for the diagnosis of pancreatic cystic neoplasms were developed from a multicentre trial \[24\]. However, the clinical impact of nCLE for the decision making algorithms in cystic pancreatic neoplasm has not yet been described. The hypothesis is that EUS-nCLE could allow targeted tissue sampling of cystic pancreatic neoplasms resulting in more accurate diagnosis. With further validation of the technique real-time pathological diagnosis could be obtained with immediate initiation of an adequate therapy after a single investigation.

Aim The aim of the proposed study is to describe the clinical impact of nCLE for the clinical decision management algorithm based on EUS, EUS-FNA and/or EUS-CLE imaging criteria for cystic pancreatic neoplasms, while evaluating also the feasibility and safety of nCLE examination.

Imaging tests All patients with a suspicion (clinical, US, CT/MRI) of cystic pancreatic lesions will be evaluated by EUS, EUS-FNA and EUS-nCLE and compared with the final pathological diagnosis.

* For EUS examination linear instruments will be used to perform complete examination of the pancreas.

  * Lesion characteristics (echogenicity, echostructure, size, wall, mural nodules, septations, etc.) will be described.
  * The presence of regional lymph nodes will be reported with their maximal size, echogenicity, shape and margins.
  * Identification of liver metastasis will also be looked upon.
* EUS-nCLE will be performed after EUS identification of the cystic pancreatic lesion / lymph node / liver metastasis:

  * The confocal microprobe will be preloaded in a 19G FNA needle as previously described \[13\] and advanced into the lesion under EUS guidance.
  * nCLE examination will follow after the intravenous administration of the contrast agent (2.5 ml fluorescein 10%).
  * Image data will be stored digitally for offline analysis (at least 2 suggestive images and 2 suggestive movies of 10 seconds, each).
* EUS-FNA will be performed after image acquisition for cytology smears and cell blocks to enable a final pathological diagnosis. CEA, CA19-9 and amylase levels will be measured in the aspirate. Molecular analyses like KRAS and GNAS will be performed, if available.
* nCLE images will be analyzed during the examination by the principal investigator, with clinical and other procedural information in mind. In a second step offline analysis, the correlations between representative CLE images and classical hematoxylin and eosin sections will be identified.

Needle-based Confocal Laser Endomicroscopy on Pancreatic Cystic Lesions

Clinical Impact of Needle-based Confocal Laser Endomicroscopy of Cystic Pancreatic Lesions

Final diagnosis reached by surgical pathology and/or follow-up

Adverse events like acute pancreatitis, cyst infection, etc.

Copenhagen University Hospital at Herlev

University College London Hospitals

Massachusetts General Hospital

M.D. Anderson Cancer Center

Ochsner Health System

Jefferson Medical College of Thomas Jefferson University

New York Presbyterian Hospital

University of Medicine and Pharmacy Craiova

For patients with indeterminate cystic lesions of the pancreas, in addition to routine diagnostic investigations, patients participating in the study will undergo needle based confocal laser endomicroscopy (using the AQ-flex 19 probe - Mauna Kea Technologies, Paris France) at the time of their endoscopic ultrasound.

Needle-based Confocal Laser Endomicroscopy (nCLE)

AQ-Flex 19 probe (Mauna Kea Technologies, Paris)

Steve Pereira, PhD FRCP

A multicentre phase II study to determine the safety and efficacy of EUS-guided nCLE in patients with suspected cystic tumours of the pancreas in whom endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is clinically indicated. Patients will be recruited sequentially to undergo nCLE as part of their routine diagnostic evaluation, followed by standard surveillance. This part of the study will recruit 60 patients.

A multicentre phase II study to determine the safety and efficacy of EUS-guided nCLE in patients with suspected cystic tumours of the pancreas in whom endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is clinically indicated. Patients will be recruited sequentially to undergo nCLE as part of their routine diagnostic evaluation, followed by standard surveillance. This part of the study will recruit 60 patients. The study also includes a feasibility study to evaluate the role of intraoperative nCLE in the diagnosis and staging of pancreatic tumours. This part of the study will recruit a further 20 patients.

Primary endpoint:

Assess the diagnostic performance of the Cellvizio nCLE system in the characterization of pancreatic cysts, compared to standard diagnostic modalities.

Secondary endpoints:

* Assess the safety and efficacy of EUS-nCLE.
* Assess the impact of the Cellvizio nCLE system on the management of patients with pancreatic cysts.
* Develop and validate interpretation criteria for nCLE in the pancreas.
* Assess the diagnostic performance of nCLE in characterising and staging pancreatic tumours intraoperatively.

A Phase II MULTICENTRE Trial of Needle Based Laser Confocal Endomicroscopy of Cystic and Solid Tumours of the Pancreas

Assess the diagnostic accuracy of the Cellvizio nCLE system for diagnosing cystic lesions of the pancreas, compared to standard diagnostic modalities

Record the number of participants with an adverse event due to EUS-nCLE

Develop and validate interpretation criteria for nCLE in the pancreas

Assess the diagnostic accuracy of nCLE in defining the margins and extent of pancreatic tumours intraoperatively

Cambridge University Hospitals NHS Foundation Trust

University College, London

Mucocele

Pancreatic Intraductal Neoplasms

The registry will be populated with a retrospective cohort of patients previously identified as having pancreatic cysts.

The prospectively enrolled patients in this study are the primary population of interest.

There are no study-specific interventions, as this is a prospective registry. However, patients will be asked to complete approximately 1-2 hours worth of surveys on things such as demographics, medical and surgical history, and pancreatic cyst-specific questionnaires.

Survey

Charysa Santos, BS

Kimberly S Kirkwood, MD

M.D.

Kimberly Kirkwood, MD

Paige M Bracci, PhD, MPH, MS

Pancreatic cysts are found incidentally on 15-50% of CT and MRIs for all indications and their prevalence is increasing. Many of these cysts may be precursors to pancreatic cancer, and thus pose a substantial risk, however, the vast majority are benign. Increased detection of pancreatic cysts provides an opportunity to diagnose pancreatic malignancy at an early, curable stage yet also increases the potential to over-treat clinically insignificant lesions. This presents a clinical challenge to prevent unnecessary resection of indolent disease, with associated risks of infections, bleeding, diabetes, and costly disability. Unfortunately, there is little information on the epidemiology and natural history of pancreatic cysts to help guide management.

This study develops a large, prospectively managed, electronic, patient-directed pancreatic cyst registry based at UCSF. The UCSF Pancreatic Cystic Lesions Registry (PANC Cyst) will facilitate work to improve clinical care and understanding of pancreatic cysts by prospective follow-up of patients with cystic lesions, especially the diagnostically challenging small cysts, to identify factors related to cyst formation and progression to malignancy. Longitudinal data capture that includes clinical outcomes will also enable us to more precisely define anatomic, radiographic and biomarker information that can be used to differentiate populations of patients for whom surgery is indicated, surveillance is warranted, or no further evaluation is necessary.

Patients in this study will have the option of donating blood for biobanking, approximately 10cc of plasma and 10cc of serum. Patients will also have the opportunity to donate a saliva sample at the time of study registration, or at a later date.

Further, samples that are routinely collected for diagnostic purposes may be collected and banked at the time of their clinically routine procedure. If a patient consents to the use of extra material for research purposes, the biological samples will be banked and the blood, and/or pancreatic juice/cystic fluid, tissues, and saliva will be used for identification and characterization of potential biomarkers from de-identified samples.

UCSF PANC Cyst Registry

Population-Based Analysis of Neoplastic Changes in Cystic Lesions of the Pancreas.

While not the primary outcome measure, the development of cancer from a pancreatic cyst is a critically important study endpoint, which the investigators do not expect to be frequent occurrence.

If a patient with a pancreatic cyst experiences no or minimal change in size, and no development of worrisome or high-risk stigmata (Tanaka 2017), this will be considered to be an indolent lesion. Most patients will fall under this category.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Feasibility of Molecular Biology in Pancreatic Cyst Tumors	NCT03305146	Pancreatic Cyst Pancreas Cyst Serous Cystaden... Mucinous Cystad... IPMN	Molecular biolo...	18 Years -	Hospital St. Joseph, Marseille, France
Needle-based Confocal Laser Endomicroscopy on Pancreatic Cystic Lesions	NCT02494388	Pancreatic Cyst... Pancreatic Muci... Intraductal Pap... Solid Pseudopap... Cystadenocarcin... Serous Cystaden...	Endoscopic ultr...	18 Years -	University of Medicine and Pharmacy Craiova
A Phase II MULTICENTRE Trial of Needle Based Laser Confocal Endomicroscopy of Cystic and Solid Tumours of the Pancreas	NCT02523170	Pancreatic Cyst Serous Cystaden... Intraductal Pap... Cystadenoma, Mu...	AQ-Flex 19 prob...	18 Years -	University College, London
UCSF PANC Cyst Registry	NCT04291651	Pancreatic Cyst Pancreatic Neop... Pancreatic Canc... Pancreatic Dise... Pancreatic Intr... Intraductal Pap... Pancreatic Duct... Mucinous Cyst	Survey	18 Years -	University of California, San Francisco
A Phase II MULTICENTRE Trial of Needle Based Laser Confocal Endomicroscopy of Cystic and Solid Tumours of the Pancreas	NCT02523170	Pancreatic Cyst Serous Cystaden... Intraductal Pap... Cystadenoma, Mu...	AQ-Flex 19 prob...	18 Years -	University College, London

Spots Global Cancer Trial Database for serous cystadenoma