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Purpose: Although considered exceptional, radiation-induced arteriopathy in long-term breast cancer survivors involves three main arterial domains in the irradiated volume, namely axillary-subclavian, coronary, and carotid. Stenosis of medium-large arteries is caused by "accelerated" atherosclerosis, particularly beyond 10 years after long-forgotten radiotherapy. The present review aims at summarizing what is known about arteriopathy, as well as the state of the art in terms of diagnosis and therapeutic management., Diagnosis: Pauci-symptomatic over years, the usual clinical presentation of arteriopathy involves arm pain with coldness due to subacute or critical ischemia (arterial occlusion), wrongly attributed to an exclusive neurological disorder, and more rarely transient ischemic accident or angina. Evaluation of the supra-aortic trunks by computed tomography and/or magnetic resonance angiography visualizes artery lesions, while Doppler ultrasonography in expert hands assesses diagnosis and downstream functional impact. In severe cases, more invasive angiography directly visualizes long irregular arterial stenosis (full-field radiotherapy), allowing accurate prognosis and treatment., Management: Requires early diagnosis to enable initiation of medical treatment that increases blood flow (aspirin) as soon as moderate stenosis is detected, combined with correction of vascular risk factors. In intermediate cases, these therapeutic measures are completed by revascularization strategies using transluminal angioplasty-stenting (wall thickness). Antifibrotic treatment is useful in advanced cases with combined radiation injuries., Conclusion: In follow-up of long-term breast cancer survivors with node irradiation, myocardial infarction is treated even if radiotherapy is forgotten, while recognition and diagnosis of chronic arm ischemia due to subclavian artery stenosis needs to be improved for appropriate therapeutic management., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

A previously undescribed and robust miR210 overexpression is shown in intestinal samples obtained from patients with radiation enteropathy and fibrotic cultured cells. In addition, miR-210 overexpression is repressed by antifibrotic treatment combining pentoxifylline and α-tocopherol., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Radiation-induced fibrosis is a serious late complication of radiotherapy. Pentoxifylline-vitamin E has proven effective and safe in clinical trials in the treatment of fibrosis, while the molecular mechanism of its activity is yet unexplored., Methods: Ten patients suffering from radiation-induced enteropathy were treated with pentoxifylline-vitamin E combination with SOMA score as the primary endpoint. In parallel, primary smooth muscle cells isolated from intestinal samples isolated from humans with radiation enteropathy were incubated with pentoxifylline, trolox (vit. E hydrophilic analogous) or their combination. Activation of the TGF-β1/Smad and Rho/ROCK pathways was subsequently investigated using Q-RT-PCR, gene reporter, Western-blot, ELISA and immunohistochemistry., Results: Pentoxifylline-vitamin E combination induces regression of symptoms (SOMA) by -41% and -80% at 6 and 18months. In vitro, pentoxifylline and trolox synergize to inhibit TGF-β1 protein and mRNA expression. This inhibitory action is mediated at the transcriptional level and leads to subsequent inhibition of TGF-β1/Smad targets (Col Iα1, FN1, PAI-1, CTGF), while it has no effect on the Rho/ROCK pathway., Conclusions: The anti-fibrotic effect of combined pentoxifylline-vitamin E is at least in part mediated by inhibition of the TGF-β1 cascade. It strengthens previous clinical data showing pentoxifylline-vitamin E synergy and supports its use as a first-line treatment of radiation-induced fibrosis., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Radiation-induced peripheral neuropathy is a chronic handicap, frightening because progressive and usually irreversible, usually appearing several years after radiotherapy. Its occurrence is rare but increasing with improved long-term cancer survival. The pathophysiological mechanisms are not yet fully understood. Nerve compression by indirect extensive radiation-induced fibrosis plays a central role, in addition to direct injury to nerves through axonal damage and demyelination and injury to blood vessels by ischaemia following capillary network failure. There is great clinical heterogeneity in neurological presentation since various anatomic sites are irradiated. The well-known frequent form is radiation-induced brachial plexopathy (RIBP) following breast cancer irradiation, while tumour recurrence is easier to discount today with the help of magnetic resonance imaging and positron emission tomography. RIBP incidence is in accordance with the irradiation technique, and ranges from 66% RIBP with 60Gy in 5Gy fractions in the 1960s to less than 1% with 50Gy in 2Gy fractions today. Whereas a link with previous radiotherapy is forgotten or difficult to establish, this has recently been facilitated by a posteriori conformal radiotherapy with 3D-dosimetric reconstitution: lumbosacral radiculo-plexopathy following testicular seminoma or Hodgkin's disease misdiagnosed as amyotrophic lateral sclerosis. Promising treatments via the antioxidant pathway for radiation-induced fibrosis suggest a way to improve the everyday quality of life of these long-term cancer survivors., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The radiation-induced fibroatrophic process (RIF) constitutes a late, local and unavoidable sequela to high-dose radiotherapy, traditionally considered irreversible. Today, this process is partly reversible, thanks to recent progress in understanding the physiopathology of the lesions it causes and the results of recent clinical trials using antioxidant therapy. This review includes a synthetic description of the static and dynamic features of the RIF process, as reflected by its clinical, instrumental and histopathological characteristics, and by its cellular and molecular regulation. Schematically, three successive clinical and histopathological phases can be distinguished: a pre-fibrotic aspecific inflammatory phase, a constitutive fibrotic cellular phase, and a matrix densification and remodelling phase, possibly ending in terminal tissular necrosis. The respective roles of the chief actors in the RIF process are defined, as well as their development with time. A fibroblastic stromal hypothesis is suggested revolving around a 'gravitational effect' exerted by the couple ROS (reactive oxygen species)--fibroblasts, and partly mediated by TGF-beta1. A variety of strategies have been tested for the management of RIF. In the light of the mechanisms described, a curative procedure has been proposed via the antioxidant pathway. In particular, it was showed that superoxide dismutase and combined pentoxifylline-tocopherol treatment enables the process of established radiation-induced fibroatrophy to be greatly reduced or even reversed, both in clinical practice and animal experiments. The efficacy of combined pentoxifylline-tocopherol treatment in superficial RIF was confirmed in a randomised clinical trial, and then in successful phase II trials especially in uterine fibroatrophy and osteoradionecrosis. It is of critical importance to evaluate these new management approaches in larger clinical trials and to improve the recording of results for better outcome analysis. Mechanistic studies are always necessary to improve understanding of the RIF process and the antifibrotic drug action.

Purpose: As we previously observed that bovine liposomal Cu/Zn SOD (LipSOD) reduces cutaneous radiation-induced fibrosis (RIF) in human therapeutic assays the mechanisms involved were investigated here by an in vitro study of the LipSOD effects on cellular antioxidant metabolism and regulation of matrix degradation., Methods: Primary cultures of human fibroblasts harvested from normal or RIF skin were treated with various doses of LipSOD. Catalase, Cu/Zn and Mn SOD endogenous cell enzyme activities and protein amounts were assayed by polyacrylamide gel electrophoresis and western blotting. Gene expressions of tissue inhibitor of metalloproteinases (TIMP) and TGF-beta1 was investigated by northern blot analysis., Results: A deficiency of endogenous Mn SOD, considered to favour cell proliferation, was observed in cultured RIF cell. The present study showed that bovine Cu/Zn SOD entered the cells. Exposure to LipSOD (a) enhanced endogenous Mn SOD activity and protein level, without changes of endogenous Cu/Zn SOD and catalase, and (b) significantly reduced TIMP and TGF-beta1 gene expression, in RIF cells. No changes in these parameters were noted in treated control skin fibroblasts., Conclusion: Modulation of RIF skin fibroblasts by LipSOD seems effective via indirect endogenous Mn SOD activation, which might explain the cell phenotype reversion observed. TIMP reduction accounts for the elimination of collagenase activity inhibition and the subsequent digestion of excess extracellular matrix deposition, as well as RIF reversibility in vivo. The reduction of TGF-beta1 expression might explain the breaking of maintaining fibrotic cell activation connected with this growth factor.

Purpose: The pathophysiological aspects of radiation-induced fibrosis (RIF) have not been well characterized. We therefore cultured human fibroblasts from samples of skin with RIF to investigate the long-term effects of therapeutic irradiation., Materials and Methods: Biopsies of normal and RIF skin were obtained from patients previously irradiated for cancer, without recurrence. Cells were extracted from dermis samples by the outgrowth technique, seeded as monolayers and cultured at confluence. Enzyme activities and proteins were assayed, RNA was isolated and Northern blot analysis was performed on surviving cells between passages 2 and 5., Results: RIF cell cultures displayed heterogeneous fibroblasts populations. The initial outgrowth consisted of one-third small cells that floated rapidly, one-third spindle-shaped cells migrating far from the explant to form islets and one-third large pleiomorphic cells. In subsequent subcultures, surviving cells exhibited either myofibroblastic characteristics with a normal proliferative capacity or senescent morphology with a reduced proliferative capacity. These RIF cells had a brief finite lifespan, with dramatically reduced growth rate during their initial outgrowth and the following passages. Study of the antioxidant metabolism showed that Mn superoxide dismutase and catalase activities were significantly weaker in surviving RIF cells than healthy fibroblasts. These exhausted RIF cells exhibited no overexpression of transforming growth factor beta or tissue inhibitor of metalloproteinase., Conclusion: Irradiation may lead to apparently contradictory effects such as fibrosis and necrosis in clinical practice. In cell culture, we observed two main cellular phenotypes which may be related to both processes, i.e. myofibroblast-like cells and fibrocyte-like cells. These two phenotypes may represent two steps in the differentiation induced as a long-term effect of therapeutic irradiation of the skin. Cell culture probably accelerates the induction of the terminal differentiation in RIF fibroblasts.

Based on experimental and clinical evidence indicating that the anti-oxidant agent liposomal Cu/Zn superoxide dismutase (Lipsod) is an effective anti-inflammatory drug and possibly might be effective in reducing late radiation-induced tissue injury, a clinical trial using Lipsod to treat long-standing radiation-induced fibrosis (RIF) was begun at the Necker Hospital, Paris in May 1984. Thirty-four patients presenting 42 distinct palpable zones of RIF involving the skin and underlying tissues were treated from May 1984 to January 1986 and followed for an average of 5 years (range, 14-89 months). Lipsod was administered over 3 weeks in twice weekly i.m. injections of 5 mg for a total of 30 mg. Patients underwent two physical examinations by independent physicians at each check-up. Parameters noted included determination of the density of the palpated fibrotic block and the dimensions of the projected cutaneous surface. The extent of change in the fibrotic zone was expressed as the ratio of the sum of the dimensions (L + W) and the ratio of the uncorrected areas (L x W) of the projected cutaneous surface before and after treatment. Changes in density were noted and scored. All patients showed some clinical regression of fibrosis. In most patients, clinically assessable regression begun during the third week of treatment and was maximum by 2 months. The mean decreases in the linear dimensions (L + W) and in the area (L x W) of the projected cutaneous surface were 41 +/- 30% and 57 +/- 26%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)