Society: ASGE

Background: Biological treatment in inflammatory bowel disease (IBD) patients is currently hampered by high non-response rates. To enhance personalized medicine and predict response to biological therapeutics such as vedolizumab, the working mechanism should be elucidated. We aimed to visualize macroscopic and microscopic vedolizumab distribution and detect drug target cells during quantified fluorescence molecular endoscopy (QFME) to improve understanding of the mechanism of action.

Methods: Vedolizumab-800CW was developed and GMP produced. Forty-three QFME procedures were performed in thirty-seven IBD patients +/- three days after intravenous administration of vedolizumab-800CW. Each QFME procedure consisted out of endoscopic assessment of the inflammation status per colonic segment by high-definition white light endoscopy, followed by real-time in vivo assessment of the macro-distribution of fluorescent vedolizumab-800CW and quantification by spectroscopy of selected segments. Dose escalation was performed using 0.0 mg, 4.5 mg and 15 mg. Subsequently, two patient cohorts were added that received 75 mg or a therapeutic (300 mg) dose of unlabelled vedolizumab prior to vedolizumab-800CW to assess target saturation. Tissue biopsies were obtained for histopathological assessment, for further ex vivo analysis of the fluorescent signal and for visualization of the microscopic distribution and identification of vedolizumab-800CW target cells by fluorescence microscopy (fig 1).

Results: Macroscopically and microscopically a significant difference between inflamed and non-inflamed tissue was visualized (fig 2A) and quantified (0.0227 and 0.0470 Q*μfa,x [mm-1], p<0.0001) for the 15 mg cohort. In addition, ex vivo analysis showed a clear dose-dependent increase (p<0.0001) of the fluorescent drug signal, whereas a decrease could be established after adding an unlabelled dose (p<0.0001) (fig 2B). Fluorescence microscopy revealed clear membrane binding of vedolizumab-800CW to inflammatory cells and migration into the inflamed mucosa. Additional analyses to identify specific target cells are ongoing and immune compositions of regions with high and low vedolizumab signal will be unravelled.

Conclusion: QFME using vedolizumab-800CW elucidated novel detailed macroscopic and microscopic vedolizumab distribution in the inflamed target organ. In addition, its shows the potential of QFME to better understand local drug distribution, target cell identification and target engagement, which could improve understanding of targeted drugs over standard pharmacokinetic and pharmacodynamic analysis.

Background and study aim:
Dysplasia is frequent in Inflammatory Bowel Disease (IBD) patients and can be managed endoscopically providing organ sparing, in contrast to surgery. Endoscopic submucosal dissection (ESD) allows en-bloc resection and very low recurrence rates. ESD is a validated endoscopic resection technique for sporadic colorectal superficial neoplasms. However, data is still missing to confirm its short and long term efficacy for visible dysplasia in IBD patients.

Patients and methods:
We conducted a retrospective multicentric study including all consecutive ESD in IBD patients with visible dysplasia in 20 French centers.
The primary outcome was the rate of R0 resection.

Results:
89 lesions in 83 patients including 20 Crohn’s disease (CD) were resected. Mean follow-up was 26 months (+/- 25 SD). Median IBD duration was 21.3 years (+/- 11.9 SD). PSC was associated with 9 lesions (10.8%). 50% of ulcerative colitis (UC) patients were classified E3. Among CD patients, 13 were L2 (68.4%) and 5 were L3 (26.3%).
En-bloc resection, R0 resection and curative resection were achieved in 80 (91%), 71 (80%) and 69 (77.5%) lesions, respectively. 1 (1.2%) patient required surgery for complication, 3 (3.6%) for ESD failure and 6 (7.2%) for bad prognostic histological features. Traction strategy was used in 53 cases (59.55%) providing higher en-bloc resection rates (50 [96.2%] versus 30 [83.3%], p=0.040) of larger (48.84 mm +/-20.86 SD versus 34 mm +/-15.75 SD, p=0.001) and more severe fibrotic (34 [65.4%] versus 12 [38.7%], p=0.023) lesions than without traction. High-volume centers (> 100 colorectal ESD per year) performed larger (50.56 mm +/-20.37 SD versus 35.96 +/-17.63 SD, p=0,001) and faster (23.34 mm²/min +/-19.11 SD versus 10.36 mm²/min +/- 5.45 SD, p<0.0001) resections with less recurrences (0 [0%] versus 8 [16.7%], p=0.006) than low-volume centers. Recurrence was found to be more frequent in CD patients (n = 6, 26.1%) than in UC patients (n = 2, 3.1%) (p=0.004).

Discussion:
Concerning en-bloc and R0 resection, the results are close to those obtained from ESD for sporadic neoplasms. Perforation rate was higher than those from studies in sporadic lesions (14%) confirming the more complexity of these lesions that should be reserved for high volume experts centers.

Conclusion:
This study is the world’s largest reported so far concerning ESD for associated IBD visible dysplasia, and with the largest CD cohort. This study confirms the efficacy of ESD regarding en-bloc, R0 and curative resections, even in the CD population. ESD in IBD patients should be performed in high-volume centers with traction strategy to improve oncological outcomes and decrease complications. However, a long term follow-up is necessary to assess the impact of ESD on long-term surgery rate in the era of “treat to target”.

Philippe Seksik

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