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Glycerol

Protective Agents

Submucosal injection using glycerol during an ESD procedure in a specific population with superficial gastric and rectal (pre)neoplastic lesions.

Submucosal injection using ORISETM gel during an ESD procedure in a specific population with superficial gastric and rectal (pre)neoplastic lesions.

Dissecting superficial gastric or rectal lesion/polyp after injection of the submucosa for lifting, using a electrosurgical knife through the endoscope

Endoscopic submucosal dissection

Injection of some colloidal solution (ORISE gel) in the submucosal layer in order to obtain long lifting effect and thus allowing the endoscopist to dissect under the lesion.

use of Orise Gel as lifting agent for endoscopic submucosal dissection

Injection of some colloidal solution (glycerol) in the submucosal layer in order to obtain long lifting effect and thus allowing the endoscopist to dissect under the lesion.

use of glycerol as lifting agent for endoscopic submucosal dissection

Arnaud Lemmers, MD,PhD

The EPSILON study aims to comparatively evaluate the submucosal injection using ORISETM gel and glycerol during an ESD procedure in a specific population with superficial gastric and rectal (pre)neoplastic lesions.

Traditionally, ESD requires the injection of some colloidal solution (glycerol, geloplasma, hydroxyethylstrach, etc.) in the submucosal layer in order to obtain long lifting effect and thus allowing the endoscopist to dissect under the lesion. Alternatives to colloid-solution assisted ESD have also been developped: pocket creation method and saline-immersion ESD.

Recently, other colloidal solutions have arrived on the market, such as gel (ORISETM gel) in order to improve the lifting during ESD.Our preliminary experience using ORISETM gel as a lifting solution for ESD was unexpectedly favourable with few per-procedural bleeding, quick time and facility.

As the spread of ESD is closely associated to its easiness, procedure duration (itself associated to number of procedural bleedings and instruments change through the operating channel) and safety, we sought to study comparatively two submucosal solutions when conducting ESD in a specific population presenting gastric or rectal superficial lesions.

A multicentric, randomized, open label prospective study:

* All subjects with indications of gastric and rectal ESD undergo screening and baseline visit
* Informed consent is obtained when scheduling the ESD procedure
* Randomization is made at the time of the ESD procedure after confirmation of the indication
* ESD is performed using a 25 G needle, a dual-knife-J with glycerol (standard solution) or ORISETM gel in order to remove the lesion en-bloc. Additional saline injection through the electrosurgical knife will be left at the discretion of the endoscopist
* A follow-up visit is scheduled at 2-4 weeks

A computer-based block randomization scheme will be created using block randomization and stratifying by center and by organ type (stomach/rectum). Data will be collected through a printed CRFs and then anonymized and entered into a central web based secured platform.

EndoscoPic Submucosal dIssection Using geL Versus glycerOl for Submucosal iNjection

EndoscoPic Submucosal dIssection Using geL Versus glycerOl for Submucosal iNjection: a Randomized Controlled Multicentric Trial (EPSILON)

Number of per-procedural bleeding (+ severity scale: oozing / severe non pulsating/ severe pulsating)

Total hemostatic time (addition of each hemostasis time for each per-procedural bleeding)

Difficulty of the dissection (scale) (very easy / easy / moderately difficult / difficult / very difficult)

Amount of submucosal solution (glycerol or gel) used for ESD in ml

Combined use of saline through the knife during ESD (number and ml)

Number of needle injection dots during ESD (initially / during ESD)

Need to adjust electrosurgical settings during ESD

Clear visualisation of the plane of dissection during ESD (scale). The scale will be defined according the endoscopists evaluation of the delineation between the submucosa ad the underlying muscular layer:

* Very-good visualization: clear delineation between the two layers with clear visualization of the blood vessels.
* Good visualization: mostly clear delineation between the two layers, but with blurred regions
* Bad visualization: delineation between the two layers is unclear (i.e.:

fibrosis)

Rate of en-bloc dissection (defined as endoscopic resection of the targeted area in one bloc)

Rate of complete endoscopic resection (defined as endoscopic evaluation of complete removal of the targeted area in the treated organ)

Quality assessment of the pathological specimen (absolute measure of the depth of resected submucosa on the specimen, rate of clear (horizontal and vertical) margins)

Adverse events:

* Per-procedural (incidence of all adverse technical events during the procedure)
* Early (clinical and laboratory at 24 h post procedure according to CTCAE v 5.0)
* Late (clinical at 2-3 weeks follow-up)

Increase the dissection speed of the ESD procedure (defined as the dissected surface (mm2)/ESD duration (min). The dissected surface is defined as maximal diameter of specimen (mm) x perpendicular minimal diameter of specimen (mm) measured on ex-vivo pinned stretched specimen onto a cork. ESD duration is defined as the time from first submucosal injection to final cut time.

Total procedure duration (from scope insertion to scope retrieval) (min)

Erasme University Hospital

MD, PhD, Professor, Head of Clinic, Endoscopy Unit

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Intestinal Diseases

Rectal Diseases

Central Nervous System Depressants

Anesthetics

400 patients with a known rectal tumour that has not demonstrated evidence of cancer to date - may be benign or indeterminate on biopsy or without biopsy performed to date.

Patients in this cohort will undergo examination under anaesthesia as is standard of care. During this examination the pattern of fluorescence seen in NIR camera within the tumour will be observed following administration of ICG (dose 0.25mg/kg) and recorded. Following this, patients will continue with standard of care at the discretion of their surgeon.

The operative video will be uploaded to a secure cloud based system and annotated by the surgeon where further mathematical analysis will be carried out for the purposes of tissue classification.

200 patients with a rectal tumour that has proven previously to contain cancer. Both patients who have and have not undergone neoadjuvant therapy are suitable for inclusion in this group.

Patients in this group will undergo the same processes as the patients in cohort 1.

Alice Moynihan

Ronan Cahill

Cancer of the lowermost part of the intestine (the rectum) is a common disease and both this disease and its treatment can have major impact on patients. Unless treated early, the disease can progress, spread to other parts of the body and ultimately cause death. Treatment often involves radical surgery, but this too has consequences and risks major complications. Best outcomes regarding cure with least impact depend on the disease being detected at an early stage as rectal cancer tends to start first as a non-cancerous polyp.

The smallest of these precursor polyps can be easily removed during a routine colonoscopy but once the polyp grows over 2cm in size it is much harder to categorise correctly as the risk of it containing cancer somewhere in it increases markedly. If there is definitely cancer present in such a polyp it is best treated from the outset as a cancer with major surgery, but if there is definitely not a cancer in it then it can be removed from inside the bowel with minimally invasive techniques. Unfortunately, despite our current very best methods, up to 20% of tumours initially thought to be benign are found to be malignant only after they are excised

We have previously shown that cancerous and non-cancerous tissues can be visually differentiated by analysis of their perfusion during the examination. For this we use a specific approved fluorescent dye, indocyanine green (ICG). ICG is commonly used in bowel surgery anyway to assess the blood supply to the bowel and has a very good safety profile. ICG is injected into the bloodstream during surgery and the rate at which it is taken up by various tissue types is detected by specific and approved cameras which can reveal fluorescence in tissue. We have previously found that the rate of uptake of this dye is different in cancer tissue compared to non-cancer tissue and have used artificial intelligence algorithms to measure this difference. However, we now need to ensure that this method can work also in other patients, in other centres and indeed in other countries to ensure it is indeed a valid and useful way of assessing rectal polyps.

The goal of this observational study is to validate the use of fluorescence pattern analysis in the classification of rectal tumours. Patients enrolled in the study will attend for a visual examination of the rectal tumour in theatre as is standard practice. During this examination a video recording of the fluorescence perfusion will be taken following ICG administration. Patients will then have the tumour excised or treated as is standard of care by their surgeon. The video will later be analysed to determine the pattern of fluorescence perfusion within the tumour, and a classification will be assigned based on the pattern seen. All tumours that are excised are examined under the microscope by a pathologist to determine the final diagnosis. The fluorescence based classification will be compared to this pathological diagnosis to determine the accuracy of the method. So, patients will still have the exact same standard of care as currently happens, the hope is that in future this method can be developed to the point where it could be useful by means of a useable, accurate automated software process. If so, that will form the basis of another study in the future to look to see if it can guide or even replace biopsies and help with ensuring complete removal ('clear margins') after excision.

Rectal polyps \>2cm in size (affecting c. 10,000 patients a year in Europe alone) represent a considerable clinical challenge. While smaller polyps can be addressed by routine endoscopic polypectomy and frank clinical cancer will advance through a traditional cancer surgery paradigm, polyps of this size have the option of being locally excised, intact by transanal endoscopic resection (also referred to as Transanal Minimally Invasive Surgery, TAMIS). This is the treatment of choice in this site due to its ability to provide a single complete unfragmented specimen versus other modalities (e.g. endoscopic submucosal resection). While the technology and training to enable transanal resection has become much more available over the past decade (especially TAMIS) meaning more patients can have large benign lesions and even some early rectal cancers excised in their local specialist centres, the major brake now on such care is patient selection: i.e. how to tell if a given patient has a benign polyp or a cancer in advance of its resection.

Endoscopic biopsies are notoriously inaccurate in up to 20% of such lesions (rectal cancers commence most often as adenomatous lesions and so superficial biopsies may miss a malignant focus). Mistakenly identifying a cancer as a benign lesion and treating it by local excision significantly worsens prognosis and compromises subsequent cancer surgery - including potentially converting a reconstructable site of resection (i.e. a lesion suitable for anterior resection) to an unreconstructable one (i.e. needing an abdominoperineal resection with permanent colostomy) and by seeding cancer cells into a deep margin or different plane, particularly as in the case for anteriorly positioned lesions. Additionally, transanal excision techniques continue to have relatively high rates of positive margins; this risks regrowth in benign lesions and limits effective local therapy for earliest stage cancers due to the presence of inapparent disease close to the main tumour bulk.

We have previously demonstrated, through the use of fluorescent indocyanine green (ICG), that perfusion is visibly different, between tumour and healthy tissue. This difference can be captured via infrared video and mathematical analysis can differentiate the perfusion pattern of malignant areas from any benign/normal tissue also visible in the same endoscopic view. In brief, the saturation of fluorescence in each region of interest (ie tumour or area of normal mucosa), can be measured from the recorded video using existing software developed by IBM. The change in fluorescence over time can be plotted on a curve, demonstrating the inflow, peak and outflow of ICG, which is depending on the perfusion patters within the region of interest. These curves differ depending on the tissue being examined and so can be used to classify benign from malignant tumours through calculating the slope of the uptake and area under the curve to measure outflow. Therefore, in a location (such as the rectum) where a cancer is suspected, analysis of the video can be used to differentiate between healthy and cancerous tissues. This discovery can be made exploited for clinical use by the application of AI methods including computer vision and machine learning. In essence, the fluorescence intensity of pixels displaying tissues of interest varies with blood flow (perfusion), when the blood is dyed with ICG and lit by near-infra-red (NIR) light. The intensity is captured over time, from multiple video frames, and this intensity is plotted as a curve. The intensity curves of tumour tissue are different from those of healthy tissue, and those of benign tumours are different from malignant tumours. Analysis of the curve features for each pixel in a region of interest can thus lead to a classification.

Such an AI system has been prototyped and trained in the Mater Hospital previously with videos from a population of Irish cancer patients from two regional centres, so that it can automatically identify malignant tumours and benign lesions from healthy tissue by their perfusion patterns. This prototype has previously demonstrated accuracy of \>80%.

In this study, we clinically validate the basic concept or method of classifying tissue by its fluorescence signal characteristics while also seeing if a device can be built on the basis of this that can extrapolate the data being generated from the videos by UCD staff. We also address the question of generalisability - can other surgeons use the system and get similar results from their specific patient cohorts? This will pave the way for future studies which are planned to determine the roles of biopsy (can the system enable optimal choice of biopsied tissue, and thus reduce biopsy error?); and tumour resection (can the system increase the completeness and accuracy of tumour resection?).

CLASSICA: Validating AI in Classifying Cancer in Real-Time Surgery Study 1

Given the sensitive nature of the data being collected (health data) individual participant data will not be shared, in line with GDPR and as described in the patient information leaflet. However metadata will be made publicly available at the end of the project. A decision regarding the degree of pooled participant data that will be made available to other researchers will be made towards the conclusion of the project.

The primary objective of CLASSICA Study 1 is to validate the concept of tissue characterisation by ICG signal perfusion patterns in a large series of data across multiple centres using mathematical models. Accuracy of this measurement will be determined through calculation of sensitivity and specificity rates of the classification system.

CLASSICA-Web and CLASSICA-OR platforms will be deployed across all five clinical sites. Accessability and usablity of these systems will be assessed through user surveys and analysis of video quality measures.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
EndoscoPic Submucosal dIssection Using geL Versus glycerOl for Submucosal iNjection	NCT04977401	Early Gastric C... Rectal Polyp	Endoscopic subm... use of Orise Ge... use of glycerol...	18 Years -	Erasme University Hospital
CLASSICA: Validating AI in Classifying Cancer in Real-Time Surgery Study 1	NCT05793554	Rectum Neoplasm Rectum Polyp Rectal Cancer		18 Years -	Mater Misericordiae University Hospital
EndoscoPic Submucosal dIssection Using geL Versus glycerOl for Submucosal iNjection	NCT04977401	Early Gastric C... Rectal Polyp	Endoscopic subm... use of Orise Ge... use of glycerol...	18 Years -	Erasme University Hospital

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