Evaluation of the WavSTAT Optical Biopsy System for the detection of early neoplasia in the Barrett oesophagus

In patients with Barrett oesophagus (BO) malignant degeneration may occur
through a series of phenotypic cellular changes detected and graded on
microscopy; beginning with non-dysplastic intestinal metaplasia (IM), then low-
(LGIN) and high-grade intraepithelial neoplasia (HGIN), and eventually early
cancer (EC) may arise1,2. Endoscopic surveillance of patients with BO is,
therefore, recommended to detect early neoplasia at a curable stage3. When
using standard endoscopy, however, it may be difficult to distinguish areas
with early neoplasia (i.e. HGIN a/o EC) within the normal Barrett mucosa4.
Thus, in the absence of visible abnormalities random four-quadrant biopsies are
obtained every 1-2 cm of the BO, to allow for histological evaluation for the
presence of neoplasia (Seattle protocol)4,5. But, random biopsies are
associated with a high rate of sampling error and may miss malignant lesions in
the BO6. Moreover, the extensive biopsy protocol poses significant burden on
the patient, the endoscopist and the health care system, due to prolonged
endoscopy time and high costs.
To increase the detection rate of early neoplasia during endoscopic
surveillance of BO patients, different imaging techniques have been developed.
In this respect, roughly two imaging goals have to be distinguished: first and
foremost, suspicious lesions will have to be identified in the BO, which
requires a *red flag* imaging modality with the ability to draw attention to a
certain area of interest. Second, a differentiating tool will have to be able
to distinguish between truly suspicious areas (i.e. HGIN/EC) or false positive
areas.
The interaction between tissue and light has been studies extensively. When
light of certain wavelength is emitted on tissue, four events characterize the
physical course of the light: reflection, absorption, scattering and
fluorescence. When an incoming photon hits a fluorescent molecule
(fluorophore), an electron gets excited, after which it relaxes back into a
lower energy status. A part of the energy is thus absorbed, and the molecule
emits a photon of lower energy and longer wavelength7. Influenced by
physiological and pathophysiological fluctuations in biochemistry and
structure, each tissue has a distinct fluorescent spectral signature. Normal
oesophageal tissue, Barrett metaplasia and dysplasia have a measurable
different spectral signature, suitable for integration in a diagnostic system
using spectroscopy8. In this way, spectroscopy might be used as a
differentiating tool to distinguish between dysplastic and non-dysplastic
tissue.
Probe based spectroscopy is a technique utilizing excitation light of a single,
short wavelength, delivered to the tissue through an optical fiber, after
which the emitted light is collected by the same fiber and passed to a
spectrometer. The signal is then transferred to a computer and analyzed. The
optical fiber can be passed through an endoscope, allowing for in-vivo
spectroscopy in patients with BO.
The WavSTAT optical biopsy system comprises an optical fiber, integrated in a
modified standard biopsy forceps, which is connected to a processing system
with a spectrometer, computer and user-interface console. The WavSTAT system
allows for real-time, in-vivo spectroscopic measurements (optical biopsy) and
provides spot-on correlation with the histology of the corresponding physical
biopsy.
We therefore hypothesize that the WavSTAT optical biopsy system may improve the
endoscopists ability to detect and distinguish suspicious lesions in the BO,
while reducing the need for extensive biopsy protocols during surveillance
endoscopies.

1. to investigate the WavSTAT optical biopsy system by collecting fluorescence
spectra of non-dysplastic and dysplastic Barrett mucosa and correlate these to
the histology. The integrated optical/physical biopsy forceps will ensure
spot-on correlation. The results of this study will be used to develop a
differentiating, tissue recognition algorithm.
2. In a second validation study, the algorithm is integrated in the system and
patients with a Barrett oesophagus will be investigated by standard white light
endoscopy and with the WavSTAT optical biopsy system to assess the additional
value of this differentiation tool for the detection of early neoplasia in BO.

The study will be conducted in two distinct phases:

phase 1) 20 patients with a Barrett oesophagus (15 patients with HGIN/EC and 5
with non dysplastic Barrett oesophagus (NDBO)) will be included. During the
endoscopy, the oesophagus will be inspected in detail with standard white light
endoscopy. Suspicious areas will be recorded and imaged, after which
spectroscopic measurements will be performed using the WavSTAT optical biopsy
forceps, followed by correlating biopsies with the same WavSTAT biopsy forceps.
This ensures spot-on correlation between the measured spectra and the
corresponding histology. After this, random biopsies will be obtained with the
WavSTAT system. The collected data will be used to develop a distinguishing
algorithm, which will be integrated into the WavSTAT system.

phase 2) 150 patients with a Barrett oesophagus referred for work-up and
treatment of HGIN and EC will be included. The endoscopic procedures are equal
to phase 1. In phase 2, the algorithm will be validated and the additional and
predictive value of WavSTAT over standard endoscopy alone assessed.

The WavSTAT Optical Biopsy System is non-invasive in nature. The type of light
delivered by the optical fiber is equivalent in intensity to the standard light
source used and delivered by a standard endoscope; the excitation of tissue by
the light energy delivered by the optical biopsy system is non-damaging and
does not result in any thermal effects on tissue. The collection of physical
tissue biopsies in these subjects is standard part of the procedure for
surveillance or work-up endoscopies for Barrett oesophagus, with minimal
potential risk to the health, safety or welfare of the subject. All tissue
biopsies taken as part of this study will be part of the standard of care.
Enrollment in the study will not affect in any way the subject*s diagnosis,
treatment or mitigation of any identified disease.
Due to the spectroscopies prior to the collection of physical biopsies, the
endoscopy will take 10 minutes longer than usual.