Pilot Feasibility Study: Laser Marking Using the NvisionVLE® Imaging System

When using standard endoscopy it may be difficult to distinguish areas with
early neoplasia (i.e. HGIN a/o EC) within the normal Barrett mucosa. Therefore,
in the absence of visible abnormalities, random biopsies are obtained of the
Barrett*s esophagus, to allow for histological evaluation for the presence of
neoplasia. Optical Frequency Domain Imaging (OFDI) is an imaging modality that
may have the ability to improve the current paradigm for endoscopic screening
and surveillance. OFDI can be thought of as an analogous technique to
ultrasound, but with light instead of sound waves. OFDI was incorporated in a
probe-based system for easy, through the scope access to the esophagus lumen:
Volumetric laser endomicroscopy (VLE). VLE enables imaging of large,
continuous, areas of the esophagus, up to 38 cm2 per scan, with microscopic
resolution. This technique may improve the efficiency of surveillance of
Barrett*s esophagus. Furthermore, the number of random biopsies may be
decreased, which could reduce procedure time, -costs and -burden.
This study examines an additional tool of the VLE system: the laser marking
system. Suspicious areas identified in the VLE scan need to be accurately
located on the esophageal surface to allow the physician to acquire tissue or
guide therapy to those locations. The laser marking system is capable of
applying a directed superficial cautery mark on the mucosal surface of the
esophagus.
The rationale for this study is to assess the visibility and positional
accuracy of the laser marks. Ongoing VLE studies in our center are examining
the ability of VLE to differentiate dysplasia from non-dysplastic Barrett*s
using VLE images correlated to histology. Combined with VLE imagery, the
targeting enabled by the laser marking system could have the potential to
increase the diagnostic accuracy of current surveillance protocols, to guide
interventional treatments such as the delineation of margins for mucosal
resection, and to allow direct registration of the endomicroscopy images
obtained by VLE with the resulting histopathology. In the future these advances
could positively impact the management of patients with BE by extending
surveillance intervals, enabling minimally invasive endoscopic techniques at an
earlier stage of disease and preventing unnecessary esophagectomy.

Primary objective
The primary objective of this trial is to determine the visibility and
positional accuracy of laser marks applied by the NvisionVLE Imaging System.

This is a prospective, single-site trial including two phases:
1.) *Learning Phase* - Two patients will be enrolled to optimize procedural
workflow.
2.) The second phase will include 15 patients.

The NVision VLE System is non-invasive in nature. The type of light delivered
by the optical probe 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 expandable balloon of the
guide sheath has the potential of causing lacerations or * in very rare
occasions * perforation of the esophagus when inflated above maximum allowed
pressure. A safety valve is included in the design of the balloon to avoid this
problem. In patients with an esophageal stricture, the risk of laceration
increases, and these patients are therefore excluded from participation in this
trial. The endoscopic procedure will take an estimated 30-60 minutes (estimated
average 45 minutes) longer compared to the standard endoscopy.
This study will evaluate the use of the marking laser (IPG Photonics * 3W Raman
Laser), which is coupled to the NvisionVLE Imaging System. The trial will also
evaluate the use a new Hand Controller which is attached to the endoscope (see
page 9, 10). The VLE procedure is not expected to produce any additional
discomfort or unique risks to the subject as compared to those already
associated with endoscopy and biopsy. In a previous study by our group, tissue
was marked using the tip of an endoscopic snare with coagulation current (these
cautery marks are the standard procedure for example for delineation of
lesions) (11). No marking-related adverse events were noted when using cautery
marks. The marking laser will have similar risks as the cautery marks. The
risks of bleeding or perforation from marking the site are minimal. The laser
marks on the esophageal tissue will not affect histopathological diagnosis, as
the use of cautery marking in clinical setting for delineation of lesions
didn*t affect histopathological diagnosis.

Potential adverse events/risks
Below a brief summary is given of potential risks when using the NVision VLE
system. The full text is provided in the Appendix on page 33 and onwards. In
addition the document *NvisionVLE Operators Manual (Clinical)_9sep015* is
provided with an entire overview of the system (chapter 5 contains the Risks
section). Secondly, an extensive document on marking laser engineering safety
controls of the system is available describing all safety measures incorporated
in the system to ensure safety of the patient and all co-operators working with
and in the room with the laser marking device (see table 2 in Appendix, page 25
onwards).

Optical Hazards:
The NvisionVLE Imaging System contains two laser systems, one for imaging and a
second optional for marking tissue. The imaging laser is classified as Class
1M, while the marking laser is classified as a Class 4 Laser Product. Light
energy emitted by the NinePoint Medical NvisionVLE Imaging System lies in the
invisible, near-infrared region of the electromagnetic spectrum. It cannot be
seen with the naked eye. Inadvertent exposure to laser light may cause skin or
eye damage. Precautions will be made to ensure that the optical probe portion
of the Optical Probe is inside the endoscope prior to transmitting laser energy
through the system. Laser energy can be transmitted during self-test, during
scanning (Full or Scout Scan) or marking (Manual Scan).
Viewing the laser output with certain optical instruments (for example eye
loupes, magnifiers, and microscopes) within a distance of 100 mm may pose an
eye hazard. During imaging, laser safety eyewear is not required. During laser
marking, additional safety steps must be taken (please see Appendix, page 33):
Warning: Always ensure the distal end of the Optical Probe has been inserted
into the body or an endoscope prior to activating laser. Never look directly
into the laser beam coming from the system or reflected from a surface.
Electrical and Mechanical Hazards:
When the exterior housing of the NvisionVLE Imaging System is not displaced,
there is no risk from high voltage risks from inside the system. Movement of
the system has to be done carefully and slowly. To reduce the risk of electric
shock, do not connect the system*s input power connection to equipment that is
not protectively earth grounded.

Previous laser marking studies
Several previous studies have been conducted with the laser marking system
whereby safety issues were being addressed. Please find a summary on page 3 of
this protocol and for a complete overview Preliminary laser marking studies in
the Appendix (page 17 onwards). The current study is the logical next step
following the results of the preliminary studies.

The participating expert endoscopists, research nurses and researchers will
receive training on the Nvision VLE marking system prior to use.