Octreotide may improve pharyngocutaneous fistula healing through downregulation of cystatins: A pilot study

Abstract

Background: Pharyngocutaneous fistula (PCF) and salivary leaks are well known complications of head and neck surgery. The medical management of PCF has included the use of octreotide without a well-defined understanding of its therapeutic mechanism. We hypothesized that octreotide induces alterations in the saliva proteome and that these alterations may provide insight into the mechanism of action underlying improved PCF healing. We undertook an exploratory pilot study in healthy controls that involved collecting saliva before and after a subcutaneous injection of octreotide and performing proteomic analysis to determine the effects of octreotide.Methods: Four healthy adult participants provided saliva samples before and after subcutaneous injection of octreotide. A mass-spectrometry based workflow optimized for the quantitative proteomic analysis of biofluids was then employed to analyze changes in salivary protein abundance after octreotide administration.Results: There were 3076 human, 332 Streptococcus mitis, 102 G. haemolyans, and 42 Granulicatella adiacens protein groups quantified in saliva samples. A paired statistical analysis was performed using the generalized linear model (glm) function in edgeR. There were and $300 proteins that had a p < .05 between the pre-and post-octreotide groups $50 proteins with an FDR-corrected p < .05 between pre-and post-groups. These results were visualized using a volcano plot after filtering on proteins quantified by 2 more or unique precursors. Both human and bacterial proteins were among the proteins altered by octreotide treatment. Notably, four isoforms of the human cystatins, belonging to a family of cysteine proteases, that had significantly lower abundance after treatment. Conclusion:This pilot study demonstrated octreotide-induced downregulation of cystatins. By downregulation of cystatins in the saliva, there is decreased inhibition of cysteine proteases such as Cathepsin S. This results in increased cysteine protease activity that has been linked to enhanced angiogenic response, cell proliferation and migration that have resulted in improved wound healing. These insights provide first Jonathan Cohen and William Reed are the co-first authorship.

Transnasal negative pressure therapy for accelerating healing and improving the prognosis of pharyngocutaneous fistula

“…PCF develops as a result of failure of pharyngeal repair and consists of a communication between the pharynx and the cervical skin or the tracheal stoma at the site of the surgical incision 22,23 . An increasing amount of research attention is now focused on not only early detection and prevention of PCF but also more effective treatments 20,24,25 …”

“…Therefore, investigators are aiming to develop novel treatment strategies that could accelerate healing of PCF 28 . Cohen et al reported that octreotide‐induced downregulation of cystatins could improve healing of PCF by promoting an angiogenic response as well as proliferation and migration of cells 24 . Rani et al also showed that hyperbaric oxygen therapy could be helpful for patients with PCF who have failed conservative treatment 30 …”

“…31,32 However, in terms of head and neck cancer, saliva is always considered an obstacle to wound healing, considering that healing is always delayed in patients with PCF. 24,33,34 Many laryngologists are now focused on development of new strategies to prevent formation of PCF or accelerate its healing by decreasing the flow of saliva. Use of salivary bypass tubes to prevent PCF was described by Montgomery as far back as 1978.…”

“…22,23 An increasing amount of research attention is now focused on not only early detection and prevention of PCF but also more effective treatments. 20,24,25 In this study, we investigated the clinical value of TNPT in the management of PCF. Currently, there are no guidelines for the treatment of these patients.…”

“…28 Cohen et al reported that octreotideinduced downregulation of cystatins could improve healing of PCF by promoting an angiogenic response as well as proliferation and migration of cells. 24 Rani et al also showed that hyperbaric oxygen therapy could be helpful for patients with PCF who have failed conservative treatment. 30 We have found that the major clinical issue when treating PCF is how to deal with an internal fistula orifice that is soaked in excessive saliva, although the external fistula can often be managed well by the abovementioned conservative measures.…”