Elucidating interactions between the dermal fibroblast phenotype, inflammatory signals and extra-cellular matrix components

The study of dermal wound healing has long been used to elucidate the cellular and molecular processes guiding the connective tissue response to injury. Of particular interest are the mechanisms by which soluble mediators, including inflammatory signals, guide fibroblast activity within the wound bed. This thesis addresses the role of prostaglandin E2 (PGE2) in the regulation of fibroblast activities relevant to restoration of tissue structure and function. Although PGE2 has been previously shown to play an important role in various wound healing steps, its precise contribution to the overall outcome of dermal repair is unclear. Using three well defined human dermal fibroblast phenotypes this study demonstrates that while PGE2 signaling during dermal repair triggers pro-inflammatory cascades, its effects on fibroblast activities are putatively anti-fibrotic. Specifically, exogenous PGE2 decreases the migratory and contractile potential of dermal fibroblasts through destabilization of the actin cytoskeleton and inhibits endogenous collagen synthesis. While PGE2 effects on fibroblast activity are largely conserved across phenotypes, fetal fibroblasts maintain a quantitatively diminished response to PGE2-induced alterations of cytoskeletal dynamics.Upon further analysis, this effect was shown to be representative of a larger intrinsic fibroblast phenotype. Fetal dermal fibroblasts were shown to maintain elevated rates of migration and contraction, as part of a generalized hyperactive dynamic state. Surprisingly, this phenotype was found to be sufficiently robust so as to persist despite changes in substrate and environmental constraints. In light of this finding, one additional approach was used to ascertain the robustness of the fetal fibroblast. Transplantation of fetal dermal fibroblasts into an adult wound environment was used to assess whether the intrinsic fetal fibroblast phenotype can survive the multitude of events comprising adult wound healing. While results are preliminary, this approach does present a useful tool for future studies aimed at elucidating the precise fetal fibroblast phenotype and its contribution to overall wound healing response

Early Detection of Mandible Osteoradionecrosis Risk in a High Comorbidity Veteran Population

OBJECTIVE: Osteoradionecrosis (ORN) of the mandible is a devastating complication of external beam radiation therapy (EBRT) for head and neck squamous cell carcinoma (HNSCC). We sought to ascertain ORN risk in a Veteran HNSCC population treatment with definitive or adjuvant EBRT and followed prospectively. STUDY DESIGN: Retrospective analysis of prospective cohort. SETTING: Tertiary care Veterans Health Administration (VHA) medical center. METHODS: Patients with HNSCC who initiated treatment at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) are prospectively tracked for quality of care purposes through the end of the cancer surveillance period (5 years post treatment completion). We retrospectively analyzed this patient cohort and extracted clinical and pathologic data for 164 patients with SCC of the oral cavity, oropharynx, larynx, and hypopharynx who received definitive or adjuvant EBRT (2016-2020). RESULTS: Most patients were dentate and 80 % underwent dental extractions prior to EBRT of which 16 (16 %) had complications. The rate of ORN was 3.7 % for oral cavity SCC patients and 8.1 % for oropharyngeal SCC patients. Median time to ORN development was 156 days and the earliest case was detected at 127 days post EBRT completion. All ORN patients were dentate and underwent extraction prior to EBRT start. CONCLUSION: ORN development can occur early following EBRT in a Veteran population with significant comorbid conditions but overall rates are in line with the general population. Prospective tracking of HNSCC patients throughout the post-treatment surveillance period is critical to early detection of this devastating EBRT complication