Treatment Of Radiation-induced Fibrosis Research Articles

O166: Safety and Efficacy of Autologous Fat Grafting in the Treatment of Radiation-Induced Fibrosis and Contour Defects in Head and Neck Reconstruction

Abstract Background Multimodal treatment for head and neck cancer results in significant functional and cosmetic morbidity, often through contour deformity and radiation-induced skin fibrosis (RIF), affecting head and neck function and cosmesis. Autologous fat grafting is an emerging treatment for RIF. We conducted a retrospective cohort review of patient outcomes following autologous fat transfer for reconstruction of head and neck contour deformity and RIF. Methods A retrospective analysis was performed of patients treated at 2 UK centres between 2009-2022. Patient data collated included demographics, oncological treatment, reconstruction, operative details, and pre- and post-operative patient reported outcome measures (PROMs) including University of Washington Quality of Life Questionnaire (UW-QOL), Derriford Appearance Scale (DAS24) and Patient Outcomes of Surgery (POS). Patients were stratified by indication for AFG. Results A total of 45 patients were identified. 89% of patients (85% RIF, 92% contour deformity) reported cosmetic or functional improvement. Two patients (4%) reported no improvement, and three (7%) were lost to follow-up. Psychological health scores improved in patients following AFG for both RIF and contour deformity patients (DAS24, P< 0.0001). The UW-QOL scores revealed statistically significant improvements in multiple functional domains including appearance, activity, recreation, mood, and anxiety in both patients with RIF and contour deformities. Conclusion This study demonstrates that AFG is an effective technique for the correction of contour deformity and RIF in patients following treatment for head and neck cancer. Patients suffering from RIF demonstrated significant improvements in both functional and psychological domains.

Ab. No. 140 Non-Surgical Interventions for the Prevention and Treatment of Radiation-Induced Fibrosis and Its Associated Disability in Patients With Head and Neck Cancer: An ICF Framework-Based Systematic Review

Introduction: To outline non-surgical interventions effective in preventing or treating the effects of Radiation-induced fibrosis (RIF) in Head and Neck Cancer (HNC) Survivors across domains of International Classification of Functioning, Disability and Health (ICF). RIF is a debilitating, long term sequalae of radiotherapy in HNC survivors. ICF provides an opportunity to map limitation in body functions, activity and participation with interventions but has not been used in understanding the impact of RIF in HNC survivors. Methods: Studies reporting non-surgical interventions for prevention/treatment of RIF. The review was registered in PROSPERO. Using a systematic review framework, a comprehensive search was run in six databases, independently screened, and verified by authors. Risk-of-Bias was determined using NIH quality assessment tool. Qualitative descriptive analysis was performed for the included studies. Intervention targets and outcomes were mapped to ICF domains. Results: Fifteen of 7966 retrieved studies representing data of 603 participants were included for the review. Fourteen studies were of fair and one of good quality. Seven studies representing 294 participants aimed at prevention while eight representing 309 participants aimed at treatment of RIF. Interventions studied included- exercise, electrotherapy, orthotics, swallow therapy and pharmacotherapy. Studies weren’t mutually exclusive for ICF domains. Among prevention studies, four focused on body structure, six on body function, and one on activity and participation. Among treatment studies, five addressed body structure, seven on body function, and five on activity and participation. Conclusion: Non-surgical interventions for prevention or treatment of RIF are available across ICF domains. However, the studies are limited in numbers and are of fair quality. Implications: This review provides a summary of the current state of research evidence and could be useful in providing direction to future research for prevention/treatment of RIF in HNC survivors.

16. Single-cell RNA Sequencing in Mice Identifies Downregulation of Fra2-jun Signaling in Treatment of Radiation-induced Fibrosis by Fat Grafting

16. Single-cell RNA Sequencing in Mice Identifies Downregulation of Fra2-jun Signaling in Treatment of Radiation-induced Fibrosis by Fat Grafting

Adipose-Derived Stromal Cell-Based Therapies for Radiation-Induced Fibrosis.

Significance: Half of all cancer patients receive radiation therapy as a component of their treatment regimen, and the most common resulting complication is radiation-induced fibrosis (RIF) of the skin and soft tissue. This thickening of the dermis paired with decreased vascularity results in functional limitations and esthetic concerns and poses unique challenges when considering surgical exploration or reconstruction. Existing therapeutic options for RIF of the skin are limited both in scope and efficacy. Cell-based therapies have emerged as a promising means of utilizing regenerative cell populations to improve both functional and esthetic outcomes, and even as prophylaxis for RIF. Recent Advances: As one of the leading areas of cell-based therapy research, adipose-derived stromal cells (ADSCs) demonstrate significant therapeutic potential in the treatment of RIF. The introduction of the ADSC-augmented fat graft has shown clinical utility. Recent research dedicated to characterizing specific ADSC subpopulations points toward further granularity in understanding of the mechanisms driving the well-established clinical outcomes seen with fat grafting therapy. Critical Issues: Various animal models of RIF demonstrated improved clinical outcomes following treatment with cell-based therapies, but the cellular and molecular basis underlying these effects remains poorly understood. Future Directions: Recent literature has focused on improving the efficacy of cell-based therapies, most notably through (1) augmentation of fat grafts with platelet-rich plasma and (2) the modification of expressed RNA through epitranscriptomics. For the latter, new and promising gene targets continue to be identified which have the potential to reverse the effects of fibrosis by increasing angiogenesis, decreasing inflammation, and promoting adipogenesis.

Deferoxamine to Minimize Fibrosis During Radiation Therapy.

Significance: By 2030, there will be >4 million radiation-treated cancer survivors living in the United States. Irradiation triggers inflammation, fibroblast activation, and extracellular matrix deposition in addition to reactive oxygen species generation, leading to a chronic inflammatory response. Radiation-induced fibrosis (RIF) is a progressive pathology resulting in skin pigmentation, reduced elasticity, ulceration and dermal thickening, cosmetic deformity, pain, and the need for reconstructive surgery. Recent Advances: Deferoxamine (DFO) is a U.S. Food and Drug Administration (FDA)-approved iron chelator for blood dyscrasia management, which has been found to be proangiogenic, to decrease free radical formation, and reduce cell death. DFO has shown great promise in the treatment and prophylaxis of RIF in preclinical studies. Critical Issues: Systemic DFO has a short half-life and is cumbersome to deliver to patients intravenously. Transdermal DFO delivery is complicated by its high atomic mass and hydrophilicity, preventing stratum corneum penetration. A transdermal drug delivery system was developed to address these challenges, in addition to a strategy for topical administration. Future Directions: DFO has great potential to translate from bench to bedside. An important step in translation of DFO for RIF prophylaxis is to ensure that DFO treatment does not affect the efficacy of radiation therapy. Furthermore, after an initial plethora of studies reporting DFO treatment by intravenous and subcutaneous routes, a significant advantage of recent studies is the success of transdermal and topical delivery. Given the strong foundation of basic scientific research supporting the use of DFO treatment on RIF, clinicians will be closely following the results of the ongoing human studies.

MicroRNA-26 regulates the expression of CTGF after exposure to ionizing radiation.

Radiation-induced fibrosis (RIF) is a serious complication that occurs after irradiation and which is caused by the deposition of extracellular matrix (ECM) proteins such as collagen. However, the underlying mechanisms, including the expression of the cytokines, that promote the RIF process, are not yet fully understood. MicroRNAs (miRNAs) have recently been suggested to act as post-transcriptional repressors for many genes; however, their role in the process of RIF remains to be elucidated. Our previous study showed that ionizing radiation increased the type I collagen expression through the activation of transforming growth factor (TGF)-β, while miR-29 repressed this increase. This study aimed to investigate the mechanisms by which the expression of connective tissue growth factor (CTGF), a downstream mediator of TGF-β, is controlled by miRNAs post-transcriptionally after exposure to ionizing radiation. The expression of CTGF in NIH-3T3 cells and mouse embryonic fibroblasts was increased by ionizing radiation. However, this increase was suppressed with a specific inhibitor of TGF-β receptor. Among the predictable miRNAs that target the CTGF gene, the expression of miR-26a was downregulated after exposure to ionizing radiation and this regulation was negatively mediated by TGF-β signaling. miR-26a negatively regulated the CTGF expression at the post-transcriptional level; however, ionizing radiation suppressed this negative regulation. In addition, the overexpression of miR-26a inhibited the expression of CTGF and type I collagen after irradiation. In conclusion, miR-26a modulates the expression of CTGF via TGF-β signaling in irradiated fibroblasts. The results suggest the potential application of miR-26a in the treatment of RIF.

The Pathway from Radiation to Fibrosis: LET Dependence

It is well-known that Radiation-induced fibrosis (RIF) is a late event occurring months to years after the initial radiation exposure. Fibrotic lesions have been shown to manifest in many tissues including the skin, heart, lung, liver and kidney. Fibrosis occurs due to abnormal accumulation of extracellular matrix (ECM) proteins that result in loss of normal tissue and organ function. The cell type involved in RIF is myofibroblasts, which do not undergo apoptosis after healing but instead continue to accumulate, producing excessive amounts of ECM proteins, thereby damaging the tissues and organs. Reactive oxygen species, generated in response to radiation, is one signal that helps maintain the myofibroblast phenotype. In this review, we discuss molecular mechanisms leading to this late radiation event, known biomarkers for prediction, preclinical animal models of radiation-induced toxicity and current clinical trials designed for mitigation and treatment of radiation-induced fibrosis. We also discuss other physical properties such as linear energy transfer (LET) than the ones used in the clinics today which may have the potential to change our understanding on this inevitable pathway from radiation treatment to organ fibrosis.

Autologous fat transplantation alters gene expression patterns related to inflammation and hypoxia in the irradiated human breast.

Radiation-induced fibrosis, an adverse effect of breast cancer treatment, is associated with functional and cosmetic impairment as well as surgical complications. Clinical reports suggest improvement following autologous fat transplantation, but the mechanisms underlying this effect are unknown. A global gene expression analysis was undertaken to identify genetic pathways dysregulated by radiation and evaluate the impact of autologous fat transplantation on gene expression. Adipose tissue biopsies were taken synchronously from irradiated and contralateral non-irradiated breasts, before and 1 year after autologous fat transplantation. Whole-genome gene expression analyses were performed, and Hallmark gene set analysis used to explore the effect of radiotherapy and autologous fat transplantation on gene expression. Forty microarrays were analysed, using bilateral biopsies taken from ten patients before and after autologous fat transplantation. Forty-five pathways were identified among the 3000 most dysregulated transcripts after radiotherapy in irradiated compared with non-irradiated breast (P ≤ 0·023; false discovery rate (FDR) no higher than 0·026). After autologous fat transplantation, 575 of the 3000 genes were again altered. Thirteen pathways (P ≤ 0·013; FDR 0·050 or less) were identified; the top two canonical pathways were interferon-γ response and hypoxia. Correlative immunohistochemistry showed increased macrophage recruitment in irradiated tissues. The present findings contribute to understanding of how autologous fat transplantation can ameliorate radiation-induced fibrosis. This further supports the use of autologous fat transplantation in the treatment of radiation-induced fibrosis. Surgical relevance Clinical studies have indicated that autologous fat transplantation (AFT) stimulates regression of chronic inflammation and fibrosis caused by radiotherapy in skin and subcutaneous fat. However, there is a paucity of biological evidence and the underlying processes are poorly understood. Human data are scarce, whereas experimental studies have focused mainly either on the effect of irradiation or AFT alone. The present results indicate that radiotherapy causes dysregulated gene expression in fibrosis-related pathways in adipose tissues in humans. They also show that AFT can cause a reversal of this, with several dysregulated genes returning to nearly normal expression levels. The study provides biological evidence for the impact of AFT on radiation-induced dysregulated gene expression in humans. It supports the use of AFT in the treatment of radiation-induced fibrosis, associated with severe morbidity and surgical challenges.

Radiation-Induced Fibrosis: Mechanisms and Opportunities to Mitigate. Report of an NCI Workshop, September 19, 2016.

A workshop entitled "Radiation-Induced Fibrosis: Mechanisms and Opportunities to Mitigate" (held in Rockville, MD, September 19, 2016) was organized by the Radiation Research Program and Radiation Oncology Branch of the Center for Cancer Research (CCR) of the National Cancer Institute (NCI), to identify critical research areas and directions that will advance the understanding of radiation-induced fibrosis (RIF) and accelerate the development of strategies to mitigate or treat it. Experts in radiation biology, radiation oncology and related fields met to identify and prioritize the key areas for future research and clinical translation. The consensus was that several known and newly identified targets can prevent or mitigate RIF in pre-clinical models. Further, basic and translational research and focused clinical trials are needed to identify optimal agents and strategies for therapeutic use. It was felt that optimally designed preclinical models are needed to better study biomarkers that predict for development of RIF, as well as to understand when effective therapies need to be initiated in relationship to manifestation of injury. Integrating appropriate endpoints and defining efficacy in clinical trials testing treatment of RIF were felt to be critical to demonstrating efficacy. The objective of this meeting report is to (a) highlight the significance of RIF in a global context, (b) summarize recent advances in our understanding of mechanisms of RIF,

Pentoxifylline in the Treatment of Radiation-Induced Fibrosis

Pentoxifylline in the Treatment of Radiation-Induced Fibrosis