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Common Bile Duct Neoplasms

Pathological Conditions, Anatomical

Bile Duct Diseases

Biliary Tract Diseases

Gastrointestinal Diseases

Common Bile Duct Diseases

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Biliary Tract Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Patients with need for cholangioscopy due to gallstones or histological evaluation of strictures

cholangioscopy with Frimberger duodenoscope system by the company of Karl Storz GmbH

cholangioscopy (Frimberger)

Thomas Rösch, Prof. Dr.

Karl Storz GmbH (Gesellschaft mit beschränkter Haftung) company developed a cholangioscopic device, which is designed to give a better flexibility to the cholangioscopy tip in order to enable optimal diagnostic and therapeutic precondition. Other than the conventional mother-baby technique, the insertion of the cholangioscope (baby part) is done by a port at the side of a specially developed duodenoscope (mother part) which is prepositioned distally to the control unit, near to the patient's mouth. Better manoeuverability of the device tip will lead to both a better accuracy in taking biopsies as well as a better flexibility in lithotripsy manoeuvres. This study is designed to test the efficiency of the device in relation to this assumption.

Cholangioscopy is a subsidiary treatment in endoscopic retrograde cholangiopancreaticography (ERCP), used for special issues. In the context of ERCP, a long,thin shaped device is introduced through the working channel of a duodenoscope and then through the papilla into the biliary duct.

Inspection of the biliary duct can be used for tumor biopsies as well as for gall stone lithotripsy by laser or electrohydraulic technique.

Manoeuverability of cholangioscopes is limited by the length of the scope, even more, since most of the device body is stuck in the working channel.

The newly designed cholangioscope by the company of Karl Storz GmbH is introduced through a shortened working channel. Introduction of the cholangioscope is done by an innovative side port for the cholangioscope at 70 cm from the insertion tube's distal end. This leads to a better flexibility of the device tip. Better manoeuverability of the device tip will lead to both a better accuracy in taking biopsies as well as a better flexibility in lithotripsy manoeuvres.

This study is designed to test the efficiency of the device in relation to this assumption.

Prospective Multicenter Evaluation of a New Short-access-cholangioscope for Biliary Duct Strictures and Gall Stones

1. complete lithotripsy in a single session
2. rate of right positive malignoma diagnostics (sensitivity)

Number of complications during examination and during monitoring over 24 hours post procedure

Time of procedure and success of stone extraction in %

Number of biopsies taken. Evaluation of quality of biopsies by pathologists (pathological department of University Hospital Hamburg Eppendorf).

Minimum number of bioptic manoeuvres: 3 Comparison with brush cytology (3 brush manoeuvres with 12 smear preparations) by reference cytologist (Dr. Topalidis, Hannover)

KARL STORZ GmbH & Co. KG, Tuttlingen, Germany

Universitätsklinikum Hamburg-Eppendorf

Rare Diseases

Cholangiocarcinoma

Adenocarcinoma

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Bile Duct Cancer

Control arm- If a patient is randomized to the Control arm, then the procedure will consist of the following: ERC with recording of ERC-based impression of malignancy .ERC-guided biopsies will be collected, consisting of 6 macroscopically visible biopsies. The biopsy forceps / brush will be selected per investigator preference. ERC-guided brushing will be performed, consisting of 10 through-and-fro passes through the target lesion. After this a biliary stent will be placed under ERC-guidance if needed. A biliary sphincterotomy will be performed as needed

If patient is randomized to the Study arm, then the procedure will consist of the following in order: Cannulation and sphincterotomy per standard of practice. POCS with recording of POCS-based impression of malignancy (yes/no/indeterminate). POCS will be performed using the Spy DS system. POCS-guided biopsies will be collected, consisting of 6 macroscopically visible biopsies. The POCS-guided biopsy forceps will be the SpyBite forceps.

single operator cholangioscopy

• If patients are randomized to the Control arm, then they will undergo an ERCP. ERCP-based impression of malignancy (yes/no/indeterminate) will be recorded. ERCP-guided brushing and ERCP-guided biopsy will be performed.

ERCP guided brushing and biopsy

Mohan Ramchandani, MD DM

Primary Objective: To assess the diagnostic accuracy of cholangioscopy-based assessment using SpyDS technology compared to cholangiography-based assessment using ERCP-guided biopsy and brushing in patients with indeterminate biliary strictures in the setting of cholangiocarcinoma.

Study Design : Prospective,multi-center, randomized controlled, Post market Study (PMS)

Two groups:

* Control arm - ERCP arm: ERCP impression and ERCP-guided brushing and biopsy
* Study arm - Cholangioscopy arm: SpyDS impression and SpyDS-guided SpyBite biopsy Randomization 1:1 ratio. Primary Endpoint: Diagnostic accuracy of cholangioscopy or cholangiography assessed at 6 months after initial ERCP procedure
* Malignancy will be determined by cytology or histology on tissue sampling during the index procedure, or from other tissue acquisition or surgical specimen histopathology up to 6 months after the index procedure.
* Overall diagnostic accuracy.
* The assessed strictures will be considered benign if there was no confirmation of malignancy by 6 months after the index procedure.
* Overall diagnostic accuracy will be assessed for
* ERCP impression of malignancy
* ERCP-guided brushing and biopsies separately and combined\*
* SpyDS impression of malignancy
* SpyBite biopsies
* In case of discordant results, the following will be followed for the combined pathology/cytology measure:
* If at least one is malignancy, then combine metric is malignant
* If both are benign or one is benign and one is non-diagnostic, then combined metric is benign
* If both are non-diagnostic, then combined metric is non-diagnostic

Secondary Endpoints:

1. Occurrence and severity of procedure related serious adverse events from index procedure through 30 days after procedure. Hospitalization and ICU admissions
2. Technical success of procedure defined as ability to collect tissue deemed adequate for cytology or histology. Indeterminate or equivocal or atypical or non-conclusive cytology or histology will be considered failures to this endpoint.
3. Correlation between impression of malignancy and cytopathology in the ERCP arm compared to the Cholangioscopy arm.
4. Additional diagnostic accuracy metrics: Sensitivity, specificity, positive predictive value, negative predictive value. The assessed strictures will be considered benign if there was no confirmation of malignancy by 6 months after the index procedure.
5. Impact of ERCP or cholangioscopy on patient management.
6. Need for additional diagnostic procedures beyond the index procedure.
7. Procedural measures: Type and number of devices used,
8. Duration of procedure from duodenoscope in to duodenoscope out

prospective, multi-center, randomized controlled, post market study

Diagnostic Accuracy of ERCP-guided Versus Cholangioscopy-guided Tissue Acquisition in Patients With Indeterminate Biliary Strictures Suspected to be Intrinsic .

Diagnostic Accuracy of ERCP-guided Versus Cholangioscopy-guided Tissue Acquisition in Patients With Indeterminate Biliary Strictures Suspected to be Intrinsic - a Randomized Controlled Study

Malignancy will be determined by cytology or histology on tissue sampling during the index procedure, or from other tissue acquisition or surgical specimen histopathology up to 6 months after the index procedure.The assessed strictures will be considered benign if there was no confirmation of malignancy by 6 months after the index procedure. • Overall diagnostic accuracy will be assessed for ERCP impression of malignancy, ERCP-guided brushing and biopsies separately and combined, SpyDS impression of malignancy and SpyBite biopsies

Occurrence and severity of procedure related serious adverse events from index procedure through 30 days after procedure.

Technical success of procedure defined as ability to collect tissue deemed adequate for cytology or histology. Indeterminate or equivocal or atypical or non-conclusive cytology or histology will be considered failures to this endpoint

Additional diagnostic accuracy metrics: Sensitivity, specificity, positive predictive value, negative predictive value. The assessed strictures will be considered benign if there was no confirmation of malignancy by 6 months after the index procedure

Number of patients in whom management plan is altered based on ERCP or cholangioscopy will be determined

Need for additional diagnostic procedures beyond the index procedure will be noted

The total number of accessories used during the procedure in both arms will be determined.

Duration of procedure is defined as time from duodenoscope in to duodenoscope out

Number of participants will be compared for outcome of visual impression ( benign/ malignant disease) on ERCP or cholangioscopy with final out come of cytopathology in both arms.

Prince of Wales Hospital, Shatin, Hong Kong

Evangelisches Krankenhaus Düsseldorf

Asian Institute of Gastroenterology, India

Consultant Gastroenterologist

Hematinics

All Drugs and Chemicals

Gastrointestinal Agents

Pharmaceutical Solutions

Liver Extracts

Pancrelipase

Pancreatin

Sclerosing Solutions

This group is confirmed by DSOC videos from patients with DSOC-confirmed neoplastic bile duct lesions, coming from each participating group. Each DSOC video corresponds to a complete DSOC procedure in a single patient. The neoplastic bile duct criteria are in accordance with the two following tools: the Robles-Medranda et al and the Mendoza classification. A further follow will be necessary to confirm neoplastic bile duct lesion and the type: pCCA or dCCA, local extension of iCCA, hepatocarcinoma mixed CCA/hepatocarcinoma, gallbladder cancer, pancreas cancer, or any other neoplastic bile duct lesion. Based on follow-up, videos from patients with confirmed non-neoplastic bile duct lesions will be re-assessed and re-classified or finally excluded by an expert blinded to clinical records and who do not participate in videos classification.

This group is confirmed by DSOC videos from patients with DSOC-confirmed non-neoplastic bile duct lesions, coming from each participating group. Each DSOC video corresponds to a complete DSOC procedure in a single patient. The non-neoplastic bile duct criteria are in accordance with the two following tools: the Robles-Medranda et al and the Mendoza classification. A further follow will be necessary to confirm non-neoplastic bile duct lesion and the type, when available: acute or chronic cholangitis secondary to stones or parasite's location, autoimmune cholestatic liver diseases as autoimmune sclerosant cholangitis, and primary biliary cholangitis. Based on follow-up, videos from patients with confirmed neoplastic bile duct lesions will be re-assessed and re-classified or finally excluded by an expert blinded to clinical records and who do not participate in videos classification.

AIWorks is an artificial intelligence model for real-time cholangioscopic detection of neoplastic and non-neoplastic bile duct lesions. It allows you to choose using a video file or a USB camera input as the detection source. Once the input source has been selected, the software performs real-time detection by surrounding the area of interest (i.e., the area with malignancy features) inside a bounding box. All detections made are displayed on the right side of the screen and can also be reviewed afterwards.

AI model classification

Six endoscopists with high DSOC expertise will observe and classify a set of videos among neoplastic or non-neoplastic bile duct lesions following a Bernoulli distribution; blinded to clinical records and should have never attended said patients.

Gastroenterologists from each center, with non-DSOC responsibility, will select DSOC videos and corresponding baseline data. DSOC videos and data will be gathered in one set. Each video represents a full DSOC for a single patient. The patient will be the unit of this study.

The neoplastic bile duct criteria are in accordance with the Robles-Medranda et al and the Mendoza classifications (ie. Irregular mucosa surface, Tortuous and dilated vascularity, Irregular nodulations, Polyps, Ulceration, Honeycomb pattern, etc.). The experts will assess neoplastic bile duct by presence or absence of disaggregated criteria. Likewise, by Boolean logical operators, the statistical software will compute disaggregated answers.

DSOC endoscopist experts' classification

Carlos Robles-Medranda

Digital single-operator cholangioscopy (DSOC) findings achieve high diagnostic accuracy for neoplastic bile duct lesions. To date, there is not a universally accepted DSOC classification. Endoscopists' Intra and interobserver agreements vary widely. Cholangiocarcinoma (CCA) assessment through artificial intelligence (AI) tools is almost exclusively for intrahepatic CCA (iCCA). Therefore, more AI tools are necessary for assessing extrahepatic neoplastic bile duct lesions.

In Ecuador, the investigators have recently proposed an AI model to classify bile duct lesions during real-time DSOC, which accurately detected malignancy patterns. This research pursues a clinical validation of our AI model for distinguishing between neoplastic and non-neoplastic bile duct lesions, compared with high DSOC experienced endoscopists.

Distinguishing neoplastic from non-neoplastic bile duct lesions is a challenge for clinicians. Magnetic resonance (MR) and biopsy guided by endoscopic retrograde cholangiopancreatography (ERCP) reached a negative predictive value (NPV) around 50%. On the other hand, Digital single-operator cholangioscopy (DSOC) findings achieve high diagnostic accuracy for neoplastic bile duct lesions. DSOC could be even better than DSOC-guided biopsy, which is inconclusive in some cases. However, to date, there is no universally accepted DSOC classification for that purpose. Also, endoscopists' Intra and interobserver agreements vary widely. Therefore, a more reproducible system is still needed.

With interesting results, Cholangiocarcinoma (CCA) assessment through artificial intelligence (AI) tools has been developed based on imaging radiomics. Nevertheless, CCA AI resources are almost exclusively for intrahepatic CCA (iCCA), with an endoscopic technique. Therefore, more AI tools are necessary for assessing extrahepatic neoplastic bile duct lesions. Perihilar (pCCA) and distal (dCCA) cholangiocarcinoma as the most typical neoplastic bile duct lesions. Both represent 50-60% and 20-30% of all CCA, including secondary malignancies by local extension (hepatocarcinoma, gallbladder, and pancreas cancer).

A recent Portuguese proof-of-concept study developed an AI tool based on convolutional neuronal networks (CNNs). It let to differentiate between malignant from benign bile duct lesions or normal tissue with very high accuracy. Still, it needs more external validation, including endoscopists' Intra and interobserver agreement comparison. In Ecuador, the investigators recently proposed an AI model to classify bile duct lesions during real-time DSOC, which has been able to detect malignancy pattern in all cases.

This research pursues a clinical validation of our AI model for distinguishing between neoplastic and non-neoplastic bile duct lesions, compared with six endoscopists with high DSOC experience.

Artificial Intelligence for Digital Cholangioscopy Neoplasia Diagnosis

Clinical Validation of an Artificial Intelligence Software for Digital Cholangioscopy Diagnosis: an Observational Trial

Cases will be first followed up during one year to confirm or discard neoplastic bile duct lesions. A definite diagnosis of neoplastic bile duct lesion will be based on DSOC-guided biopsy specimen or findings from further indicated procedures, including brush cytology fluoroscopy-guided, endoscopic ultrasound-guided tissue sampling, surgical samples, and even imaging test in the context of a more impaired patient. Finally, the agreement between one-year follow-up (gold standard) vs. AI model and DSOC endoscopist experts' classification will be verified through a 2 x 2 contingency table.

The Methodist Hospital Research Institute

University of Sao Paulo

Vrije Universiteit Brussel

Advanced Endoscopy Research, Robert Wood Johnson Medical School Rutgers University

Baylor St. Luke's Medical Center

Universitair Ziekenhuis Brussel

Instituto Ecuatoriano de Enfermedades Digestivas

Complement System Proteins

This group is comprised by patients with suggestive malignant biliary lesions assessed by DSOC for biopsy. In this group, the investigators aim to use as a complement tool an AI model for the detection of features suggestive of malignancy to perform the biopsy on the detecting bounding box signal.

A further follow-up of 6 months is necessary for a confirming diagnosis of neoplastic lesions.

This group is comprised by patients with suggestive malignant biliary lesions assessed by DSOC for biopsy without AI guidance. A further follow-up of 6 months is necessary for a confirming diagnosis of neoplastic lesions.

Patients with a presumptive diagnosis of biliary malignancy will undergo DSOC + Artificial intelligence model (AIWorks) guidance for detection of neoplastic lesion during real-time procedure, tissue sampling acquisition, and histopathological analysis.

DSOC with AI biopsy guidance

Patients with lesions suggestive of malignancy will undergo DSOC without AI guidance for sampling.

Based on the observer´s criteria regarding areas suggestive of malignancy, the collected tissue sample will be sent for histopathological studies.

DSOC biopsy without AI guidance

Carlos Robles-Medranda, MD FASGE

Digital single-operator cholangioscopy (DSOC) has emerged as a medical advance with an important role in the evaluation of indeterminate biliary lesions. This technique has demonstrated higher sensitivity in the guidance for tissue acquisition when compared with standard endoscopic retrograde cholangiopancreatography (ERCP). DSOC-guided biopsy is considered technically safe and successful for tissue collection.

Hand in hand with the development of more precise diagnostic techniques, comes the implementation of artificial intelligence (AI) for diagnostic assessment. For the past decade, the role of artificial intelligence (AI) has been increasing at a rapid pace. In the biliary tract, different models have been proposed for the characterization of malignant features. Nevertheless, to date, the discrepancy between the visual impression of the operator and the histological results obtained by cholangioscopy still present, affecting the accuracy the diagnosis.

Based on the above, the investigators aim to assess the diagnostic accuracy of AI for the guidance of tissue acquisition with DSOC compared to DSOC without AI for suspected cholangiocarcinoma. As a secondary aim, the investigators pursue to compare quality of AI-guided biopsies samples vs. DSOC biopsies without AI.

The diagnosis and management of biliary malignancy currently represents a medical challenge. To date, DSOC has demonstrated high sensitivity in the detection of malignant biliary lesions, nevertheless there is not a universal expert consensus for the characterization of this lesions. Also, DSOC has shown to be safe and successful for specimen collection with higher sensitivity when compared with standard ERCP.

Moreover, most of the AI models proposed for characterization of neoplastic features in biliary lesions have demonstrated high reliability during DSOC performance. A model was the proposed by investigators in Ecuador, focused on the identification of features of malignancy. The detection is performed by surrounding the suspected lesion in a bounding box. The detected area is displayed in the right side of the screen. Also, the box/image of the presumptive lesion can also be recorded and reviewed afterwards. After the AI model detects the "malignant area", a tissue sample is collected and taken for histopathological studies.

In addition, due to a variation of the endoscopists´ intra and interobserver agreement and the discrepancy between the visual impression and histopathological findings, the investigators intend to take advantage of our AI model as a diagnostic tool for a more precise acquisition of tissue in lesions suggestive of malignancy during real-time DSOC.

AI Guidance for Biopsy in Suspected Cholangiocarcinoma

Efficacy of Artificial Intelligence Aid-digital Single-operator Cholangioscopy (DSOC) Guided-biopsy Sampling in Suspected Cholangiocarcinoma: A Prospective, Randomized Trial

To confirm the diagnosis based on pathology results from specimens obtained through DSOC (with or without AI-guided biopsy) or findings from further indicated procedures, including brush cytology fluoroscopy-guided biopsy, endoscopic ultrasound-guided tissue sampling, and surgical samples.

Finally, the gold standard is a six-month follow-up compared against the AI model (group 1) or the DSOC endoscopist experts' classification. The data will be verified through a 2 x 2 contingency table.

Four biopsies will be performed per each case. Rate of insufficient samples by each study group will be recorded and compared.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Prospective Multicenter Evaluation of a New Short-access-cholangioscope for Biliary Duct Strictures and Gall Stones	NCT01683240	Choledocholithi... Common Bile Duc... Cholestasis	cholangioscopy ...	18 Years -	Universitätsklinikum Hamburg-Eppendorf
Diagnostic Accuracy of ERCP-guided Versus Cholangioscopy-guided Tissue Acquisition in Patients With Indeterminate Biliary Strictures Suspected to be Intrinsic .	NCT03140007	Cholangiocarcin... Biliary Strictu...	single operator... ERCP guided bru...	18 Years - 75 Years	Asian Institute of Gastroenterology, India
Artificial Intelligence for Digital Cholangioscopy Neoplasia Diagnosis	NCT05147389	Common Bile Duc... Non-Neoplastic ...	AI model classi... DSOC endoscopis...	18 Years - 79 Years	Instituto Ecuatoriano de Enfermedades Digestivas
AI Guidance for Biopsy in Suspected Cholangiocarcinoma	NCT05374122	Neoplasms Non-Neoplastic Bile Duct Neopl... Bile Duct Lesio...	DSOC with AI bi... DSOC biopsy wit...	18 Years - 99 Years	Instituto Ecuatoriano de Enfermedades Digestivas
Prospective Multicenter Evaluation of a New Short-access-cholangioscope for Biliary Duct Strictures and Gall Stones	NCT01683240	Choledocholithi... Common Bile Duc... Cholestasis	cholangioscopy ...	18 Years -	Universitätsklinikum Hamburg-Eppendorf
Artificial Intelligence for Digital Cholangioscopy Neoplasia Diagnosis	NCT05147389	Common Bile Duc... Non-Neoplastic ...	AI model classi... DSOC endoscopis...	18 Years - 79 Years	Instituto Ecuatoriano de Enfermedades Digestivas
AI Guidance for Biopsy in Suspected Cholangiocarcinoma	NCT05374122	Neoplasms Non-Neoplastic Bile Duct Neopl... Bile Duct Lesio...	DSOC with AI bi... DSOC biopsy wit...	18 Years - 99 Years	Instituto Ecuatoriano de Enfermedades Digestivas

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