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Original Investigation |

Effect of Vocal Fold Injection of Cidofovir and Bevacizumab in a Porcine Model

Matthew P. Connor, MD1; Ammon Brown, DVM2; Mitzi Palazzolo, MD3; Julie Kunkel, MD3; Robert Eller, MD4; Christopher Hartnick, MD5; Stephen Maturo, MD1,6
[+] Author Affiliations
1Department of Otolaryngology, San Antonio Military Medical Center, Ft Sam Houston, Texas
2Department of Pathobiology, 59th Clinical Research Division, Lackland Air Force Base, Texas
3Department of Pathology, San Antonio Military Medical Center, Ft Sam Houston, Texas
4Department of Otolaryngology, Lakenheath Air Force Base, England
5Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts
6Uniformed Services University of the Health Sciences, Bethesda, Maryland
JAMA Otolaryngol Head Neck Surg. 2014;140(2):155-159. doi:10.1001/jamaoto.2013.5853.
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Importance  Recurrent respiratory papillomatosis (RRP) is a common and often chronic disorder. Intralaryngeal bevacizumab has gained recent interest as an adjuvant therapy for RRP. However, no histologic model has been published describing the effects of bevacizumab on the vocal fold.

Objective  To investigate the histologic effects of bevacizumab injections into the vocal fold and compare these findings with those for cidofovir and saline control injections.

Design and Setting  In vivo animal study involving eighteen 1-year-old Yorkshire crossbreed pigs, with a blinded review of pathologic findings conducted in a veterinary research laboratory.

Interventions  The pigs were randomly divided into six study groups receiving 2.5 or 5.0 mg of cidofovir or bevacizumab alone or in combination. Each pig received an injection of 0.5 mL of the test drug in the right vocal fold and 0.5 mL of saline in the left vocal fold. These injections were performed 4 times during the course of 8 weeks. One pig from each group was killed humanely and the larynges harvested 2 weeks after the last injection. The remaining pigs were killed 4 months after the last injection on the remaining pigs. The vocal folds were fixed and stained with hematoxylin-eosin and trichrome and reviewed for histologic changes by 3 blinded pathologists.

Main Outcomes and Measures  Histologic changes to the vocal folds.

Results  Minimal inflammation, edema, and atypia were found in all treatment groups. No appreciable histologic differences were found among the 3 treatment groups and their controls. No difference was seen in the vocal folds that were harvested late (4 months) vs early (2 weeks) after last injection. No fibrosis was found in any of the specimens.

Conclusions and Relevance  No histologic evidence suggests that intralaryngeal cidofovir or bevacizumab alone or in combination resulted in significant changes to the porcine vocal fold. Future studies may build on this model to test higher dosages and/or may combine injections with potassium titanyl phosphate laser therapy.

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Figure 1.
Endoscopic Image of Injection of the Right Porcine Vocal Cord

Exposure was provided with an extended Miller laryngoscope blade, and injection was delivered via a Bruening syringe.

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Figure 2.
Total Laryngectomy Porcine Specimen

The pig larynx has a larger thyroid cartilage and cricothyroid muscle and a longer vocal fold than that of humans. However, the porcine vocal folds most closely resemble those of humans with regard to the density of collagen and elastic fibers, elastic properties, thickness, and acoustic properties.

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Figure 3.
Hematoxylin-Eosin Stain of Right Vocal Fold

This vocal fold was injected with bevacizumab and had a mean pathologic grade of 1.83 for epithelial inflammation, 2.25 for superficial lamina propria inflammation, 0.33 for edema, and 0.00 for atypia and fibrosis. The inflammation primarily consisted of lymphocytes with fewer neutrophils, eosinophils, and macrophages present in a multifocal manner (original magnification ×10).

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Effect of vocal fold injection of cidofovir and bevacizumab in a porcine model. JAMA Otolaryngol Head Neck Surg 2014;140(2):155-9.