Early detection of cancer onset based on sensing field cancerization at the organ level in the alimentary tract using an integrated Raman/scattering modality for endoscopic real-time in vivo measurements

Patients with Barrett*s esophagus and Lynch syndrome (LS) are known to be at
risk of developing respectively esophageal adenocarcinoma (EAC) and colorectal
carcinoma (CRC). Therefore, both these patients are subject to regular
endoscopic surveillance examinations in order to detect these tumors during
their premalignant stages and subsequently enable early endoscopic
intervention. However, these time-consuming screening programs have an
empirical basis and thus, individual patients are either examined too little or
too much. In addition, satisfying results of these programs are impeded by
relatively high miss rates of neoplasias in these patients as they exhibit
solely subtle morphological changes. Interestingly, nanoarchitectural changes
in cells and tissue throughout the whole organ occur as elements of field
cancerization before neoplastic lesions become manifest in the gastrointestinal
tract. Thus, detection of field cancerization in the tissue could prompt
further endoscopic examination of the whole organ and allow real-time in vivo
tissue diagnosis. Through the integration of biophotonics in optical imaging,
an approach is created that allows a label-free visualization of the smallest
alterations in the tissue of interest in a non-destructive manner. Through
integration of Raman spectroscopy and scattering spectroscopy into one
modality, detailed information upon the biochemical composition and tissue
structure on a nanoscale can be respectively obtained. Therefore, this
Raman/scattering integrated modality would be able to measure the intracellular
processes and nanoarchitectural changes that are associated to field
cancerization. Therefore, we hypothesize that detection of field cancerization
in the GI tract could be performed during endoscopy by performing Raman and
scattering measurements. In the context of the SENSITIVE project, an
investigational medical device was developed that integrates probe-based Raman
and scattering measurements for endoscopic purposes: the SENSITIVE system. In
addition, a spontaneous Raman spectroscopy device (SRM1 device) was developed
specifically for this study to validate the SRS measurements. During
preclinical ex vivo studies, we have established that scattering and Raman
measurements were able to discriminate between non-field cancerized tissue and
field cancerized tissue. Considering these results, we aim to assess the safety
of in vivo Raman/scattering during endoscopy. Secondly, we to assess the
feasibility of this approach measurements to determine field cancerization in
the alimentary tract during endoscopy through the SENSITIVE system. Therefore,
we assess the precision of the stimulated Raman spectroscopy measurements of
the SENSITIVE system by performing spontaneous Raman measurements with the SRM1
device.

The primary objective involves the safety of in vivo Raman/scattering during
endoscopy. Therefore, we will assess safety parameters (AEs, SAEs, SUSARs).
Secondary objective involves the feasibility of the probe-based
scattering/(stimulated) Raman spectroscopy integrated system (The SENSITIVE
system and SRM1 device respectively) to enable real-time in vivo detection of
field cancerization in the GI tract in patients with BE and in patients that
are at risk of developing CRC. Therefore, we will correlate the scattering and
Raman measurements to both histopathology and additional ex vivo analysis of
the targeted biopsies. Furthermore, we will correlate the measurements to the
endoscopic diagnosis of the organ (esophagus or colon), and the
histopathological diagnosis of other clinical biopsies that are obtained during
the endoscopic procedure.

Study design: The study concerns a non-randomized, non-blinded, prospective,
phase I medical device study.

An interim analysis will be conducted by the investigators involved in this
study after the first 15 patients. The interim analysis will include the
assessment key safety parameters: AEs, SAEs and SUSARS.

Secondary, we will assess the feasibility of Raman/scattering measurements for
distinguishing Raman spectra and scattering properties between morphologically
aberrant and morphologically non-aberrant tissue.

If these criteria are met, we will continue the inclusion up to 60 patients.

Patients that are scheduled for a diagnostic or therapeutic endoscopic
procedure and have provided informed consent will undergo Raman and scattering
measurements during endoscopy. Preparations for endoscopy and the endoscopy
procedure itself will be performed according to the dedicated clinical routine.
After evaluation of the mucosa under white light illumination and narrow band
imaging, the mucosa will be rinsed and Raman and scattering measurements will
be performed of the spot of interest using a fiber that is passed through the
working channel of a normal endoscope (this approach is comparable to the
approaches that we employ during our studies of fluorescence molecular
endoscopy (of which we have performed >200 procedures). First we will perform
Raman measurements with the SENSITIVE system, and subsequently with the SRM1
device. After measurements, targeted biopsies will be taken for histopathology
analysis, immunohistochemistry and FGmRNA-profiling.

Patients are not required to pay an extra visit to the UMCG for study
procedures. Clinical indication for endoscopic procedure is necessitated and
measurements will be performed during endoscopic examination. In order to
verify the in vivo measurements, extra biopsies will be obtained of tissue that
has been measured. Overall, the study procedures will take around 20 minutes
per patient. We consider the risk for patients to participate in the study to
be negligible. There is no direct diagnostic or treatment benefit for the
patients as the procedures are conducted according to standard clinical
guidance. No decisions in the context of clinical care will be based upon study
findings.