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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.)

Although the peripheral nerve has often been considered as radioresistant, clinical practice demonstrates the occurrence of radiation-induced peripheral neuropathies. Because these complications appear late, usually several years after the course of radiotherapy, their occurrence is explained by improvement in the prognosis of several cancers. Their physiopathology is not fully understood. Compression by radio-induced fibrosis probably plays a central role but direct injury to nerves and blood vessels is probably also involved. The most frequent and best known form of postradiation neuropathy is brachial plexopathy, which may follow irradiation for breast cancer. Recent reports demonstrate that postradiation neuropathies show a great heterogeneity, particularly in the anatomical sites, but also in the clinical, electrophysiological, and neuroimaging features. The link with radiotherapy may be difficult for the clinician to establish. Patients with radiation-induced lumbosacral radiculoplexopathy may be misdiagnosed with amyotrophic lateral sclerosis as they often present with pure lower motor neuron syndrome, or with leptomeningeal metastases since nodular MRI enhancement of the nerve roots of the cauda equina and increased CSF protein content can be observed. From a pathophysiological perspective, radiation-induced neuropathy offers an interesting model for deciphering the mechanisms of peripheral neuropathies due to environmental factors. Recent developments show promising strategies for the prevention and treatment of these complications, which have a considerable impact on a patient's quality of life., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Introduction: Because of the improvement of cancer prognosis, long-term damages of treatments become a medical and public health problem. Among the iatrogenic complications, neurological impairment is crucial to consider since motor disability and pain have a considerable impact on quality of life of long cancer survivors. However, radiation-induced neuropathies have not been the focus of great attention. The objective of this paper is to provide an updated review about the radiation-induced lesions of the peripheral nerve system., State of the Art: Radiation-induced neuropathies are characterized by their heterogeneity in both symptoms and disease course. Signs and symptoms depend on the affected structures of the peripheral nerve system (nerve roots, nerve plexus or nerve trunks). Early-onset complications are often transient and late complications are usually progressive and associated with a poor prognosis. The most frequent and well known is delayed radiation-induced brachial plexopathy, which may follow breast cancer irradiation. Radiation-induced lumbosacral radiculoplexopathy is characterized by pure or predominant lower motor neuron signs. They can be misdiagnosed, confused with amyotrophic lateral sclerosis (ALS) or with leptomeningeal metastases since nodular MRI enhancement of the nerve roots of the cauda equina and increased cerebrospinal fluid protein content can be observed. In the absence of specific markers of the link with radiotherapy, the diagnosis of post-radiation neuropathy may be difficult. Recently, a posteriori conformal radiotherapy with 3D dosimetric reconstitution has been developed to link a precise anatomical site to unexpected excess irradiation., Perspectives and Conclusion: The importance of early diagnosis of radiation-induced neuropathies is underscored by the emergence of new disease-modifying treatments. Although the pathophysiology is not fully understood, it is already possible to target radiation-induced fibrosis but also associated factors such as ischemia, oxidative stress and inflammation. A phase III trial evaluating the association of pentoxifylline, tocopherol and clodronate (PENTOCLO, NCT01291433) in radiation-induced neuropathies is now recruiting., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

In this study we report a progressive sciatic mononeuropathy occurring 13 years after radiotherapy (56-Gy prescribed dose) for a synovial sarcoma of the thigh. Conformal dosimetric reconstitution showed that irradiation was heterogeneous and that the sciatic nerve received 66 Gy over a 25-cm length. Magnetic resonance imaging (MRI) showed muscle fibrosis and increased sciatic nerve diameter. Our observation suggests that the risk of late mononeuropathy should be considered when large-volume and high-dose radiotherapy includes a nerve trunk.

Radiation-induced fibrosis (RIF) and radionecrosis (RN) are late complications that are usually considered irreversible. Usual management strategy includes eliminating local and general aggravating factors and controlling acute and chronic inflammation with steroids. Thanks to progress in understanding the pathophysiology of these lesions, several lines of treatment have been developed in clinical practice. However, results of clinical studies are difficult to compare because of variations in severity of RIF, method of RIF assessment, availability of efficient therapeutic drugs, treatment duration, and quality of trial design. For moderate established RIF, current management strategy mainly includes (1) anti-inflammatory treatment with corticosteroids or interferon gamma; (2) vascular therapy with pentoxifylline (PTX) or hyperbaric oxygen (HBO); and (3) antioxidant treatment with superoxide dismutase, tocopherol (vitamin E), and, most successfully, with a PTX-vitamin E combination. On the basis of etiology, RN can be managed by (1) anti-inflammatory treatment with corticosteroids and possibly clodronate, (2) vascular therapy with HBO and PTX, (3) antioxidant treatment with a PTX-vitamin E combination, and (4) a PTX-vitamin E-clodronate combination. Controlled randomized trials are now necessary to identify the best treatment at each step of RIF. In the future, these treatments of fibrosis and necrosis should include targeted drugs (such as growth factors) to take organ specificities into account.

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.

Objective: To determine whether combined pentoxifylline (PTX) and tocopherol (vitamin E) treatment can improve uterine radiation-induced sequelae, resulting in an improved embryo implantation rate., Design: Retrospective phase II clinical trial., Setting: Volunteers in an oocyte donation program in a public hospital., Patient(s): Six women aged 31 +/- 4 years, who were irradiated 25 years previously for childhood cancer with 20 to 40 Gy including the pelvic area., Intervention(s): Four women had taken hormone replacement therapy for primary amenorrhea, and two had retained their natural cycle. Treatment consisted of at least 12 months of pentoxifylline at 800 mg/day combined with 1000 IU/day of tocopherol., Main Outcome Measure(s): Endometrial thickness, uterine volume, and uterine artery blood flow were assessed by ultrasonography before and after pentoxifylline-tocopherol treatment, under usual estrogen-progesterone (OP) administration., Result(s): This treatment was well tolerated. All six patients improved significantly in endometrial thickness (6.2 +/- 0.6 vs. 3.2 +/- 1.1 mm), myometrial dimensions (44 [+/- 5] x 30 [+/- 3] x 20 [+/- 2] vs. 30 [+/- 7] x 22 [+/- 3] x 16 [+/- 2] mm), and diastolic uterine artery flow., Conclusion(s): In young women who want to bear children, the combination of pentoxifylline and vitamin E can reduce fibroatrophic uterine lesions after childhood irradiation.

Radiation-induced fibrosis is a late sequela of both therapeutic and accidental irradiations, which has been described in various tissues, including the lung, liver, kidney and skin. This review presents different aspects of superficial radiation-induced fibrosis, such as clinical observations, histological changes, cellular and molecular regulations, and medical management. Recent evidence on the critical role played by TGF-beta 1 in the initiation, development and persistence of fibrosis are discussed, as well as the possibility that this cytokine may constitute a specific target for antifibrotic agents.

Radiation fibrosis is a frequent sequel of therapeutic or accidental radiation overexposure in normal human tissues. One of the main fundamental problems yet unsolved in fibrotic tissues is the origin of the chronic activation of myofibroblasts within these tissues. It has been postulated that this chronic activation results from a continuous production of activating factors. In this context, fibrosis could be defined as a wound where continuous signals for tissue repair are emitted. Cytokines and growth factors probably play a central role in this process. Among them, transforming growth factor-beta1 (TGF-beta1) is considered as a master switch for the fibrotic program. This review discusses recent evidence on the critical role played by TGF-beta in the initiation, development, and persistence of radiation fibrosis. It summarizes the results concerning this factor after irradiation of various tissues and cells, with an emphasis on superficial fibrosis, including skin and subcutaneous tissues. Finally, recent data concerning the treatment of established fibrotic disorders of various etiology are presented, as well as the possible mechanisms involved in fibrosis regression, which show that the TGF-beta pathway may constitute a specific target for antifibrotic agents.

Purpose: Radiation-induced fibrosis (RIF) remains the most morbid complication of radiotherapy because of the absence of spontaneous regression and the difficulty of patient management. RIF treatment with combined pentoxifylline (PTX) and tocopherol (Vit E) was prompted by recent advances in cellular and molecular biology that have improved researchers' understanding of radiation-induced late-injury mechanisms and by the excellent results from our previous human and animal studies., Patients and Methods: Forty-three patients (mean [+/- SD] age, 59 +/- 10 years) presenting with 50 symptomatic RIF areas involving the skin and underlying tissues were treated from April 1995 to September 1997. Patients had had radiotherapy for head and neck or breast cancer a mean period of 8.5 +/- 6.5 years previously. RIF developed in the first year after irradiation and gradually worsened, without spontaneous regression. The mean measurable surface area of RIF ([S]) at the time of this study ([S(0)]) was 42 +/- 34 cm(2). The initial Subjective Objective Medical management and Analytic (SOMA) injury evaluation score was 13.2 +/- 5.9 and included evidence of edema, plexitis, restricted movement, and local inflammatory signs. A combination of PTX (800 mg/d) and Vit E (1,000 IU/d) was administered orally for at least 6 months., Results: Treatment was well tolerated. All assessable injuries exhibited continuous clinical regression and functional improvement. Mean RIF surface area and SOMA scores improved significantly (P <.0001) at 3 months ([S(3)], -39%; [SOMA(3)], -22%), 6 months ([S(6)], -53%; [SOMA(6)], -35%), and 12 months ([S(12)], -66%; [SOMA(12)], -48%), and mean linear dimensions ([D]) diminished from the start of the study ([D(0)], 6.5 +/- 2.5 cm) to the end of treatment 12 months later ([D(12)], 4 +/- 2 cm). At the time of the treatment, we did not attempt to achieve the maximum effect, and the study was continued., Conclusion: The PTX-Vit E combination reversed human chronic radiotherapy damage and, because no other treatment is presently available for RIF, should be considered as a therapeutic measure.

Purpose: To establish a successful treatment of subcutaneous fibrosis developing after high doses of gamma rays, suitable for use in clinical practice., Methods and Materials: We used an animal model of acute localized gamma irradiation simulating accidental overexposure in humans. Three groups of 5 Large White pigs were irradiated using a collimated 192Ir source to deliver a single dose of 160 Gy onto the skin surface (100%) of the outer side of the thigh. A well-defined block of necrosis developed within a few weeks which had healed after 26 weeks to leave a block of subcutaneous fibrosis involving skin and skeletal muscle. One experimental group of 5 pigs was dosed orally for 26 weeks starting 26 weeks after irradiation with 1600 mg/120 kg body weight of pentoxifylline (PTX) included in the reconstituted food during its fabrication, and another group of 5 was dosed orally for the same period with a daily dose of 1600 mg/120 kg body weight of PTX combined with 2000 IU/120 kg body weight of alpha-tocopherol. Five irradiated control pigs were given normal food only. Animals were assessed for changes in the density of the palpated fibrotic block and in the dimensions of the projected cutaneous surface. Depth of scar tissue was determined by ultrasound. Physical and sonographic findings were confirmed by autopsy 26 weeks after treatment started. The density, length, width, and depth of the block of fibrotic scar tissue, and the areas and volume of its projected cutaneous surface, were compared before treatment, 6 and 13 weeks thereafter, and at 26 weeks., Results: The experimental animals exhibited no change in behavior and no abnormal clinical or anatomic signs. No modifications were observed in the block of fibrotic scar tissue of pigs dosed with PTX alone. However, significant softening and shrinking of this block were noted in the pigs dosed with PTX + alpha-tocopherol 13 weeks after treatment started and at autopsy, when mean regression was approximately 30% for length, approximately 50% for width and depth, and approximately 70% for area and volume. Histologic examination showed completely normal muscle and subcutaneous tissue surrounding the residual scar tissue. The 50% decrease in the linear dimensions of the scar tissue, were comparable to the results obtained in our previous clinical studies, and were highly significant compared to the clinical and autopsy results for the controls. Histologic examination of the residual scar tissue revealed tissue which was more homogenous and less cellular and inflammatory than in control and PTX-dosed pigs. The tissular and cellular immunolocalization of tumor necrosis factor alpha (TNFalpha) was similar in the residual fibrotic tissues of all three groups of pigs, whereas the immunostaining of transforming growth factor beta-1(TGFbeta-1) diminished much more in the residual fibrotic scar tissue of the PTX + alpha-tocopherol-dosed pigs than in the two other groups., Conclusions: The present results showed a striking regression of the subcutaneous fibrotic scar tissue that develops as a consequence of high doses of gamma rays.

Radiation-induced fibrosis (RIF) is a terminal sequela to irradiation that does not regress spontaneously. A preliminary study of a combination of pentoxifylline (PTX) and tocopherol (vit-E) has shown clinical activity with 50% superficial RIF regression at 6 months in half of the patients studied. The present report is of a 67-year-old woman presenting with bulky cervicothoracic RIF who, 10 years previously, had received radiochemotherapy for a small cell thyroid carcinoma to a dose of 50 Gy, with severe acute side-effects. She had palpable cervicosternal fibrosis measuring 10 x 8 cm, with local inflammatory signs and functional consequences (cough, restricted cervical movement, dyspnoea and bronchitis) with a SOMA scale for grading the long-term side effects of radiation therapy of 19/14. CT showed deep RIF extending from the vocal cords to the carina, with laryngotracheal compression but without cancer recurrence. PTX (800 mg d-1) and vit-E (1000 U d-1), orally administered daily for 18 months, were well tolerated. The patient exhibited clinical regression and functional improvement. The linear dimensions and SOMA scale were, respectively, 8 x 6 cm and 11 at 6 months; 4 x 4 cm and 7 at 12 months; and complete response with no measurable RIF and 1 at 18 months. This is the first time that the combination of PTX and vit-E has had a significant antifibrotic effect by completely reversing deep RIF as shown by CT scan normalization.

The radiation-induced fibrosis is a late sequela of both therapeutic and accidental irradiations, and has been described in several tissues such as skin and underlying sub-cutaneous tissues, and lung. Based on the newest findings arising from cellular and molecular radiobiology, this review synthesis different aspects of the human superficial radiation-induced fibrosis: clinical and paraclinical observations, radiobiological aspects, gross histological changes, cellular and molecular regulations, and medical management. However, the underlying mechanisms of the superficial radiation-induced fibrosis still remain to be resolved.

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)

Fibrosis in oncology concerns iatrogenic pathology, after radiotherapy or bleomycin, and also after surgery or neoadjuvant chemotherapy. Specificity of certain etiologic conditions are described in detail. Some therapeutic attitudes are discussed. Corticoids are useful in the management of inflammatory fibrosis attacks. Other drugs under study are used in an attempt to reduce the late fibrotic process, namely liposomal superoxide dismutase.

Tissue fibrosis is a non specific proliferation of connective tissue, overriding the limits of normal wound healing and essentially encountered in oncological practice as an iatrogenic pathology. This study reviews the data pertaining to the cellular and extracellular components of fibrosis and their regulation. Regulation of the fibrotic process is studied in several steps: chemotaxis and proliferation of fibroblasts, collagen metabolism, and interactions between inflammatory cells and the extracellular matrix.