Accepted Manuscript Confocal laser endomicroscopy guided endoscopic myotomy Helmut Neumann, Michael Vieth, Bernard Dallemagne, Jacques Marescaux, Haru Inoue, Silvana Perretta

PII: DOI: Reference:

S0016-5085(14)00600-3 10.1053/j.gastro.2014.04.044 YGAST 59118

To appear in: Gastroenterology Accepted Date: 15 April 2014 Please cite this article as: Neumann H, Vieth M, Dallemagne B, Marescaux J, Inoue H, Perretta S, Confocal laser endomicroscopy guided endoscopic myotomy, Gastroenterology (2014), doi: 10.1053/ j.gastro.2014.04.044. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. All studies published in Gastroenterology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.

ACCEPTED MANUSCRIPT Confocal laser endomicroscopy guided endoscopic myotomy

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Helmut Neumann1, Michael Vieth2, Bernard Dallemagne4, Jacques Marescaux4, Haru Inoue3, Silvana Perretta4

Department of Medicine I, University Hospital Erlangen, Erlangen, Germany

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Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany

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Digestive Disease Center, Showa University Toyosu Hospital, Japan

Strasbourg Institute of Image-Guided Surgery (IHU Strasbourg), University of

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Short title: Confocal guided myotomy.

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Strasbourg, France

Disclosures: None of the authors has any conflicts of interest related to this work to declare.

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Concept and design: SP, HN

Acquisition of data: SP, HN, MV

Analysis and interpretation of data: HN, SP, HI, MV

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Drafting of the manuscript and critical revision of the manuscript: HN, SP, MV, HI Study supervision: SP, HN, BD, JM

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Address for Correspondence:

Helmut Neumann, M.D., Ph.D. Department of Medicine I, University of Erlangen-Nuremberg, Ulmenweg 18 91054 Erlangen, Germany Tel: +49 9131 85-35000 Fax: +49 9131 85-35209 e-mail: [email protected]

ACCEPTED MANUSCRIPT Introduction Achalasia is a primary esophageal motor disorder characterized by degenerative changes of the myenteric plexus [1]. Until recently laparoscopic Heller myotomy, represented the most successful treatment option [2]. Most recently,

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peroral endoscopic myotomy (POEM) was introduced as a novel, minimally invasive treatment option for patients with achalasia [3-5]. Nevertheless, adequate length of the myotomy, either performed surgically or endoscopically, remains still unknown

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and is guided by an approximation extrapolated by clinical, manometric and

radiological findings. Adequate clearance of the esophagus, the main objective of the

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operation, is sometimes difficult to achieve as about 25% of patients complain of residual dysphagia or gastroesophageal reflux symptoms when myotomy alone is employed [6]. In addition, ultrastructural examinations of the myenteric plexus were only performed on esophagectomy specimens and biopsies taken at Heller myotomy.

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Recent data has shown that myenteric neurons could selectively be visualized by using confocal laser endomicroscopy (CLE), an endoscopic imaging technique allowing obtainment of optical biopsies at 1000-fold magnification during ongoing

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endoscopy after application of appropriate fluorescence agents [7]. Fluorescence agents yet used to visualize myenteric neurons include acriflavine hydrochloride and

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a specific fluorescent neuronal molecular probe. Although the potential of CLE to visualize the myenteric neuronal network has been shown in these initial studies, none of the fluorescent stains used are approved for their use in humans [8, 9]. In contrast, intravenously injected fluoresceine sodium is widely used as the contrast stain for CLE in humans. Here, we present the potential of fluoresceine-guided CLE to visualize the myenteric neuronal network during POEM procedures.

ACCEPTED MANUSCRIPT Description of technology For the purpose of this study, the probe-based confocal laser endomicroscopy system (pCLE; Cellvizio, Mauna Kea Technologies, Paris, France) was used. CLE is based on tissue illumination with a lower power laser. The handheld pCLE probe is

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advanced through the working channel of a standard endoscope and gently applied to the esophageal tissue. In order to obtain real time videos, confocal images are streamed at a frame rate of 12 frames per second. In our study, the GastroFlex UHD

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probe was used. Technical features of the probe include a lateral resolution of 1 µm,

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a field of view of 240 µm and an imaging plane depth of 55-65 µm.

Video description

With the pig supine under general anesthesia a single channel endoscope

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(Storz, Tuttlingen, Germany) is advanced in the esophagus and the gastroesophageal junction (GEJ) is carefully inspected to determine adequate landmarks for the myotomy. The site for mucosotomy in the midesophagus is

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selected to be 15 cm from the GEJ. A submucosal “lift” is achieved at the 12 o’clock position, by submucosal injection of 10 ml saline with 1% methylen blue. A triangle-tip

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(TT) endoscopic cautery knife (Triangle Tip Knife; Olympus) is used to make a 1.5–2 cm longitudinal mucosal incision at the site of the submucosal bleb. The endoscope is subsequently inserted into the newly created submucosal space and a submucosal tunnel is created to the GEJ and 2 cm beyond onto the lesser curve using a combination of blunt dissection, CO2 insufflation and electrocautery. Then, the pCLEprobe is advanced through the working channel of the endoscope and gently applied onto the newly created muscular pit within the submucosal space. Afterwards, 7 ml of 10% fluoresceine sodium (Alcon Pharma, Freiburg, Germany) are administered

ACCEPTED MANUSCRIPT intravenously. In vivo CLE is performed using blue laser light (488 nm) for fluorophore excitation and returning light is detected from 205 to 585 nm. Optical sections are collected with 12 frames per second, a lateral resolution of 1.4 µm, an optical sectioning of 10 µm and a 240 µm field of view. Image interpretation is

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performed in real time. The clear distal cap (Olympus, Tokyo, Japan) attached to the endoscope facilitated the stabilization of the probe for subsequent high-magnification imaging. Confocal imaging reveals muscle fibers as reticular, light grey fibers while

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microvessels appear as white (fluorescein-filled) structures containing red blood cells appearing as small dark spots flowing through the blood vessels. In contrast, the

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myenteric plexus is identified as dark bands existing in the muscle layer of the esophagus. After the procedure, the pig is euthanized, after biopsies were taken at studied sites and fixed in 10% formalin for subsequent histopathological analysis. Biopsies are showing findings consistent with the endomicroscopic findings.

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Additionally, post hoc assessment of confocal images is completed with an expert

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gastrointestinal pathologist.

Take home message

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o Adequate length of the myotomy in patients with achalasia still remains unknown.

o Confocal laser endomicroscopy (CLE) provides optical biopsies at 1000-fold magnification. o Fluoresceine-guided CLE allows visualization of myenteric neurons in real time in peroral endoscopic myotomy (POEM) procedures. o Confocal imaging may serve as a helpful clinical tool to improve the determination of the adequate length of myotomy in patients with achalasia.

ACCEPTED MANUSCRIPT References

1. Francis DL, Katzka DA. Achalasia: update on the disease and its treatment. Gastroenterology. 2010;139:369-74.

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2. Boeckxstaens GE, Zaninotto G, Richter JE. Achalasia. Lancet. 2014;383:83-

3. Inoue H, Minami H, Kobayashi Y, et al. Peroral endoscopic myotomy (POEM)

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for esophageal achalasia. Endoscopy. 2010;42:265-71.

4. Von Renteln D, Fuchs KH, Fockens P, et al. Peroral endoscopic myotomy for

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the treatment of achalasia: an international prospective multicenter study. Gastroenterology. 2013;145:309-11.

5. Perretta S, Dallemagne B, Marescaux J. STEPS to POEM: introduction of a new technique at the IRCAD. Surg Innov. 2012;19:216-20. 6. Bombeck CT, Nyhus LM, Donahue PE. How far should the myotomy extent on

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the stomach? In: Giuli R, McCallum RW, Skinner DB, eds. Primary Motility Disorders of the Esophagus 450 questions, 450 answers. Paris, John Libbey

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Eurotext, 1991.

7. Neumann H, Kiesslich R, Wallace MB, et al. Confocal laser endomicroscopy:

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technical advances and clinical applications. Gastroenterology. 2010;139:38892.

8. Sumiyama K, Kiesslich R, Ohya TR, et al. In vivo imaging of enteric neuronal networks in humans using confocal laser endomicroscopy. Gastroenterology. 2012;143:1152-3. 9. Ohya TR, Sumiyama K, Takahashi-Fujigasaki J, et al. In vivo histologic imaging of the muscularis propria and myenteric neurons with probe-based

ACCEPTED MANUSCRIPT confocal laser endomicroscopy in porcine models (with videos). Gastrointest Endosc. 2012;75:405-10.

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Figures:

Figure 1: The pCLE-probe is advanced through the working channel of the

endoscope and gently applied onto the newly created muscular pit within the

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submucosal space.

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muscle layer of the esophagus.

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Figure 2: The myenteric plexus (arrows) is identified as dark bands existing in the

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ACCEPTED MANUSCRIPT

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ACCEPTED MANUSCRIPT

Confocal laser endomicroscopy guided endoscopic myotomy.

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