In this study, we have shown that laser marking is a safe and efficacious method for guiding endoscopic biopsy based on OFDI image data. This guided biopsy method has the potential to increase the diagnostic accuracy of current surveillance protocols, to guide alternative interventional treatments, such as the delineation of margins for mucosal resection, and to allow direct registration of the endoscopic microscopy images with histopathology.
In this study, we identified targets on the fly and marked them in real time. We have also conceived of another mode of operation, which may be more useful clinically, when the image targets are human disease as opposed to artificially generated targets. For this mode of operation, the three-dimensional dataset can be acquired in its entirety, all target regions of interest selected on the computer screen, and then marked en masse. The technology described here is fully capable of operating in this mode.
Although previous studies have demonstrated that OCT is capable of diagnosing esophageal pathology with good accuracy,1-4
in the clinical setting, images of regions that are likely to contain the most severe disease will need to be identified in the GI suite. The development and implementation of automated and semi-automated detection and diagnosis algorithms may additionally help the treating physician to mine the large volumetric OFDI data-sets, thereby reducing the time required for intraprocedural evaluation of the images.10
One criterion that we used to determine the success rate of the guided biopsy platform was the visibility of the laser markings at endoscopy. In this study, the targets were made with laser exposure durations of 8 seconds, producing markings that were more prominent at endoscopy than the 2-second marks used for guiding biopsy. As such, the endoscopy reader may have been biased in determining the visibility of the laser markings by first perceiving the target. Future clinical studies aimed at diagnosing and marking esophageal pathology will be less affected by this interpretation bias.
This study was conducted in normal squamous epithelium. Due to the increased vascularity of columnar epithelium that is typical of specialized intestinal metaplasia, we anticipate that laser marking will be effective for target delineation in Barrett's esophagus. To provide evidence in support of this assumption, we have created 2-second marks on swine duodenum ex vivo (). As can be seen in this figure, 2-second laser marks are clearly apparent in the swine duodenal tissue; however, we have yet to test this marking procedure in Barrett's mucosa. Optimizing the laser parameters for human disease and testing OFDI-guided biopsy in patients is a subject of future research. If we find that this laser does not produce visible marks in human Barrett's esophagus, we can investigate the use of other marking wavelengths that may generate greater video endoscopic contrast. Alternatively, we can register endoscopy to OFDI images by using anatomical and/or artificial landmarks placed on the esophagus (ie, India Ink tattoos) prior to imaging.
Photograph of swine duodenum depicting a 2-second laser mark performed approximately 1-hour post sacrifice. Large tick marks represent 0.5 mm.
We have previously reported on the use of a 2.5-cm diameter balloon catheter in our clinical studies, however, due to the smaller esophageal diameter of swine, a 1.8-cm diameter balloon was used here. This balloon diameter caused considerable dilation of the esophagus, reducing motion artifacts due to peristalsis and eliminating regions without contact (ie, artifacts that have been observed in our previous clinical studies). Based on an assessment of the datasets acquired in our ongoing clinical studies in which we have imaged approximately 100 patients with our balloon catheter, we do not anticipate that physiological motion, including that caused by peristalsis or respiration, will significantly affect our marking accuracy. To date we have not observed motion artifacts from respiration, however, if this motion becomes problematic we may consider the use of larger or variable diameter balloon catheters to further stabilize the esophageal wall with respect to the balloon catheter. The compression of the balloon, however, may affect diagnostic criteria,11
and may impact the generation of laser marks. These questions will be addressed in future clinical studies designed to test the efficacy of the guided biopsy procedure in patients.
The anatomic depth of the thermal injuries caused by the 2-second laser exposures was measured to extend to 27.03% of the full thickness of the mucosa, with partial healing observed at day 2. Given that the histologic depth of biopsies obtained by using standard forceps has been reported to extend to the muscularis mucosa,12
we anticipate that the risk to the patient undergoing this procedure will be low and not significantly greater than that of standard endoscopic practice.
The overarching goal of this research is to provide endoscopists with a method for guiding biopsies to decrease the sampling errors associated with surveillance. To this end, in addition to being able to accurately mark targets, the technique must be cost-effective and must be capable of being performed within an acceptable procedural time. In our studies, the time required to identify a target and place two marks surrounding the target did not exceed 2 minutes/target. Under the assumption that this technique will decrease the amount of biopsies required, we therefore believe that this entire procedure can be conducted without unduly extending the procedure time. The time required to identify disease targets has not yet been established; however, this is a topic for future studies. A cost-effectiveness analysis is also beyond the scope of this article, but we note that the use of guided biopsies should decrease the expense of surveillance by minimizing the number of biopsies obtained and by providing a more accurate diagnosis, which will result in more appropriate and timely patient management.
Although future clinical studies are required to ultimately determine the clinical viability of this technology, we have demonstrated that OFDI-guided biopsy with laser marking is feasible in the swine esophagus. OFDI-guided biopsy may prove to be a powerful diagnostic tool and, when used as an alternative to conventional random biopsy in the surveillance of Barrett's esophagus, may work to increase the biopsy yield and reduce the total number of biopsies acquired.