Is radiation-induced arteriopathy in long-term breast cancer survivors an underdiagnosed situation?: Critical and pragmatic review of available literature.

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.

Medical treatment of osteoradionecrosis of the mandible by PENTOCLO: preliminary results.

INTRODUCTION: Osteoradionecrosis (ORN) is a severe, generally irreversible complication of radiotherapy due to failure of healing. The pentoxifylline-tocopherol combination decreases the superficial fibrosis induced by radiotherapy. Potentiation by Clodronate (PENTOCLO) appears to be effective in ORN of the mandible. The objectives of this study were to evaluate the efficacy and safety of PENTOCLO to treat osteoradionecrosis of the mandible. METHODS: Retrospective study of 27 patients with a mean age of 65±12 years, managed for ORN of the mandible secondary to irradiation for head and neck cancer, treated by the PENTOCLO protocol between January 2010 and March 2011. The primary endpoint was regression of exposed bone until complete healing. Assessment was both clinical (measurement of mucosal ulceration) and radiological (panoramic dental x-rays) before treatment, after antibiotic-corticosteroid combination therapy for one month (M1), and then after 3, 6, 12 months of PENTOCLO. RESULTS: An improvement of mucosal ulceration was observed in 16/21 patients after 3 months and in 12/17 patients after 6 months of PENTOCLO. Healing was obtained in 16 patients. Median healing time was 82 days (range: 32-266), and was shorter after surgery and radiotherapy (49 days) and longer after chemoradiotherapy (169 days). Radiological healing was achieved later than clinical healing with improvement in 9 out of 20 patients at 3 months. The safety and efficacy of treatment were evaluated by intraoral clinical examination, and assessment of feeding, weight and analgesic consumption. No patient discontinued treatment because of adverse effects. CONCLUSION: The PENTOCLO protocol achieved clinical and radiological regression of ORN with, in parallel, a reduction of the indications for major surgery. These preliminary results need to be confirmed by prospective studies comprising quality of life assessment.

[Radiation-induced neuropathies: collateral damage of improved cancer prognosis]. / Neuropathies post-radiques: un dommage collatéral chez les patients cancéreux long-survivants.

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.

[Post-operative fibrosis: pathophysiological aspects and therapeutical perspectives]. / Fibrose postopératoire : aspects physiopathologiques et perspectives thérapeutiques.

Postoperative fibrosis (POF) is a rare, localized, and irreversible delayed effect of surgery, described in numerous tissues and organs. Is this fibrotic process amenable to therapeutic intervention? A synthesis of various clinical and histopathological aspects, and of cellular and molecular process regulation is described. In summary, there exists a prefibrotic chronic inflammatory phase, a constituted and cellular phase, and lastly a matricial densification and remodelling phase. The respective phases and the roles played over time by the main protagonists, namely myofibroblasts, extracellular matrix and growth factor (TGFbeta1) are clarified. Understanding the mechanism of POF leads logically to treatments derived from our knowledge of the treatment of radiation-induced fibrosis: anti-inflammatory drugs help in the prefibrotic phase, pentoxifylline-tocopherol combination (PE) in the organized fibrotic phase, and pentoclo (PE-clodronate) in the late fibronecrotic phase. Randomized trials are necessary to validate the preliminary results of phase II trials.

[Uterus after irradiation]. / Utérus après irradiation.

Today, the good prognosis of girl's cancers raises the question of her future fertility. Several studies have focused on preservation of ovarian function, but the uterus, irradiated in childhood, is a crucial component to bear in mind because the somatic damages, in terms of endometrial and myometrial atrophy, scar fibrosis and hypovascularization, are negative factors for the establishment and maintenance of a pregnancy and for a convenient labour. Consequences for procreation are related to the morphologic uterine sequelae and its altered function: early miscarriages, abnormal placentation etc. In addition to some spontaneous pregnancies reported in literature, a few pregnancies, for women experiencing a premature iatrogenic ovarian failure due to mild irradiation, have been obtained after in vitro fertilization and oocyte donation with increased estrogen treatment. Recently, a real hope has surged in relation to the opportunity to reverse the radio-induced fibrosis and thus to obtain a better trophic uterus, using the antioxidant pathway. So, a treatment combining pentoxifylline 800 mg/d and tocopherol 1000 IU/d for 12 months allowed improvement of local uterine conditions such as endometrial thickness (x2), myometrial dimensions (x1.5) and uterine vascularization in all six sterile women studied, who have received high irradiation in childhood (>or=45 Gy). Moreover, two women mildly irradiated (#20 Gy) with endometrium resisting to physiological estrogen status, became spontaneously pregnant after using this combined treatment, and gave birth to healthy children. Further studies are in progress to assess, among other questions, the interest of this therapeutic direction.

Case report: resolution of symptomatic epidural fibrosis following treatment with combined pentoxifylline-tocopherol.

Epidural fibrosis (EF) is a major cause of failed back surgery syndrome (FBSS), which induces disabling radiculopathy for which no effective medical treatment exists. Our understanding of the fibrosis mechanisms and our clinical and experimental results for the treatment of radiation-induced fibrosis prompted us to postulate that EF might respond to treatment with combined pentoxifylline (PTX)-tocopherol (Vit.E). 6 weeks after lumbar spine surgery, a 28-year-old man presented with recurrent left L5 sciatica without disc herniation on MRI in December 1993. From 1993 to 1997, he had unrelieved back and leg pain, which became increasingly resistant to intensive medical treatment and to a spinal cord stimulator, and confined him to bed as from December 1997. In 1998, a lumbar CT-scan showed an area of left L4-L5 EF measuring 12 mm x 12 mm, without disc herniation. From April 1998, oral PTX (800 mg day(-1)) and Vit.E (1000 IU day(-1)) were administered daily for 3.5 years and well tolerated. Clinical improvement began during the third month of treatment and continued until total regression of clinical symptoms April 2001. Lumbar MRI in November 2001 showed a surface area of residual EF half the size of the initial area. This is the first report to indicate that antifibrotic treatment using combined PTX-Vit.E may be of potential benefit in the treatment of post-operative EF. Additional studies are required to confirm this potential.

Combined treatment by pentoxifylline and tocopherol for recipient women with a thin endometrium enrolled in an oocyte donation programme.

BACKGROUND: To evaluate the effect of an antifibrotic treatment by a combination of pentoxifylline (PTX) and tocopherol (vitamin E) in patients with a thin endometrium who were enrolled in an oocyte donation programme. METHODS: Eighteen oocyte recipients who failed to develop a pre-ovulatory endometrial thickness of at least 6 mm after receiving vaginal micronized estradiol were enrolled in the study. The patients received a combination of PTX (800 mg/day) and vitamin E (1000 IU/day) for 6 months. The main outcome measurements were the change in endometrial thickness and the pregnancy and delivery rates after treatment. RESULTS: Endometrial thickness increased significantly (P <0.001), with a mean of (+/-SD) 4.9 +/-0.6 mm before and 6.2 +/- 1.4 mm after treatment, with 72% (13/18) of patients being good responders. Five patients either did not respond to the treatment or responded only slightly. Three patients, of which two had received previous radiotherapy, became spontaneously pregnant, and two became pregnant after embryo transfer. Three patients did not have embryo transfer. A total of four babies were delivered. The pregnancy rate was thus 33% and the delivery rate 27%. CONCLUSION: Treatment by combination of PTX and vitamin E appears to improve the pregnancy rate in patients with a thin endometrium by increasing the endometrial thickness and improving ovarian function. This was especially noticeable in patients who had previously received total body irradiation.

Complete healing of severe osteoradionecrosis with treatment combining pentoxifylline, tocopherol and clodronate.

Osteoradionecrosis (ORN) is a late terminal sequela of irradiation that does not resolve spontaneously. In a preliminary study, a combination of pentoxifylline (PTX), tocopherol (Vit-E) and clodonate has been shown to be of clinical benefit with more than 50% regression of progressive ORN observed at 6 months in 12 patients. A 68-year-old woman presenting with severe exteriorized osteoradionecrosis had received radiotherapy for breast cancer 29 years previously. She had palpable breast fibrosis, including the sternum (15 cm x 11 cm) and a painful fistulous track in the upper part of the bone (orifice diameter 10 mm) surrounded by local inflammatory signs, and chronic osteitis with sequestra extrusion. MRI showed deep radiation-induced fibrosis below this area without cancer recurrence, and complete bone destruction over an area of 7 cm x 4 cm. Oral PTX (800 mg day(-1)), Vit.E (1000 IU day(-1)) and clodronate (1600 mg day(-1)) were administered daily for 3 years and were well tolerated. The patient exhibited regular clinical improvement until complete closure of the fistula and total regression of the clinical fibrosis. MRI confirmed the good response and showed heterogeneous restoration of the sternum, which was filled with new tissue. This is the first time that antifibrotic treatment with combined PTX-Vit.E plus clodronate has been shown to have a significant effect on necrosis, by completely reversing severe progressive ORN and the associated radiation-induced fibrosis.

[Reversibility of radiation-induced fibroatrophy]. / Réversibilité de la fibroatrophie radio-induite.

PURPOSE: The radiation-induced fibro-atrophic process described in numerous tissues and organs is a localized and irreversible late effect of high-dose radiation therapy. Our purpose is to show that this process is today reversible. CURRENT KNOWLEDGE AND KEY POINTS: This review describes a synthesis of various clinical, paraclinical and histopathological aspects of radiation-induced fibro-atrophic process, and of cellular and molecular process regulation. Schematically, there exists a prefibrotic aspecific inflammatory phase, then a constituted and cellular phase, then a matricial densification and remodeling phase, associated in some cases with a tissular terminal necrosis. The respective parts and their evolution during time of the main protagonists as myofibroblast, extracellular matrix and growth factor TGF beta 1 are clarified. From the pathophysiological mechanisms described, curative therapeutic attitudes are proposed for the different progressive phases. Especially, superoxide dismutase (not available) and the pentoxifylline-tocopherol combination seem to allow reduction and reversibility of the fibro-atrophic radiation-induced established process, in clinics as in animal experiments. FUTURE PROSPECTS AND PROJECTS: Some phase II trials try to assess the therapeutic interest of combined pentoxifylline-tocopherol in various radiation-induced sequelae, as in osteo-radionecrosis. A clinical randomized trial phase III has just been achieved and could support the results of these experimental and retrospective clinical trials.

[Mature bone radionecrosis: from recent physiopathological knowledge to an innovative therapeutic action]. / Radionécrose de l'os mature: connaissance physiopathologique récente motrice d'une thérapeutique médicale innovante.

Osteoradionecrosis is a severe radiotherapy (RT) injury by healing failure, late effect and spontaneously irreversible by tissue death. Histologically, it consists in a pagetoid mosaic that combines a defective osteogenesis with an osteoclastic osteolysis and more marginally an osteolytic osteolysis, turned to account to fibroblastic and collagenic fibrosis. Several pathogenic hypotheses favor sometimes a vascular hypoxic hypotheses, sometimes a fibro-atrophic hypothesis. Various events start up or favour ORN as traumatisms (dental extraction, surgery,...) or bacterian infection on fistula. In clinic, adult mature bone concerned is the mandible after head and neck RT by septic ORN, and the hip after pelvic RT by aseptic ORN. For each, epidemiology, clinic and therapeutic aspects are developed. Usual therapeutic attitudes consisted in restriction of defavorable associated events (dental extraction, infection, RT dose, chemotherapy,...) and devitalized tissue removal. Physiopathological therapeutic innovatives aspects are proposed to struggle against radiation-induced fibrosis associated and to limit bone destruction.

Cu/Zn superoxide dismutase modulates phenotypic changes in cultured fibroblasts from human skin with chronic radiotherapy damage.

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.

Antifibrotic action of Cu/Zn SOD is mediated by TGF-beta1 repression and phenotypic reversion of myofibroblasts.

Skin fibrosis is characterized by the proliferation and accumulation of activated fibroblasts called myofibroblasts. They exhibit specific cytoskeletal differentiation, overexpress the fibrogenic cytokine TGF-beta1, synthesize excess extracellular matrix compounds and exhibit a depleted antioxidant metabolism. Recently, SOD was successfully used as an antifibrotic agent in vivo, thus challenging the postulate of established fibrosis irreversibility. We postulated that myofibroblasts could be a direct target for this therapeutic effect. To test this hypothesis, we used three-dimensional co-culture models of skin, in which specific phenotypes of normal fibroblasts versus myofibroblasts are retained. These 3-D models were treated with liposomal and carrier-free Cu/Zn SOD, and examined for their effects on cell number, cell death, and phenotypic differentiation. The results show that SOD did not induce myofibroblast cell death, whereas it significantly reduced TGF-beta1 expression, thus demonstrating that SOD might be proposed as a potent antagonist of this major fibrogenic growth factor. We also found that SOD significantly lowered the levels of the myofibroblast marker alpha-sm actin, of beta-actin, and of the extracellular matrix components alpha1(I) collagen and tenascin-C. In conclusion, our results suggest that SOD antifibrotic action occurred in vitro through the reversion of myofibroblasts into normal fibroblasts.

[Radiation-induced superficial fibrosis and TGF-alpha 1]. / Fibrose superficielle radio-induite et TGF-beta 1.

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.

TGF-beta1 and radiation fibrosis: a master switch and a specific therapeutic target?

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.

[Evaluation of late radiation-induced changes in superficial microcirculation after acute beta-irradiation. II. Prognostic importance of cutaneous Doppler laser]. / Evaluation des modifications radio-induites tardives de la microcirculation superficielle après irradiation aiguë beta. II. Intérêt pronostique du laser doppler cutané.

OBJECTIVE: The changes that occur in the tissular microcirculation after accidental acute irradiation account for some of the early effects of such irradiation, especially at the cutaneous level. The prognostic importance of the cutaneous laser doppler was tested in an experimental model of acute beta-irradiation. METHODS: Ten pigs were given beta-irradiation with a high single localized dose of 90Sr/90Y (32 or 64 Gy, 7 mg/cm2) delivered to the flank, and were evaluated 2, 7, 14, 21 and 28 days thereafter. Each individual was its own control. The local microcirculation was measured in the resting state and during thermal stimulation at 42 degrees C, using a Periflux cutaneous Doppler laser with p413 probes. Three periods of six minutes each were continuously recorded: period 1 (P1) represented basal resting cutaneous perfusion, with the slope p corresponding to the increase in perfusion when two minutes of thermal stimulation at 42 degrees C began; P2 to plateau perfusion during this stimulation; and P3 to perfusion on the return to equilibrium. RESULTS: After acute beta-irradiation in the pig, all the cutaneous microcirculation parameters measured (P1, p, P2 and P3) had risen at day 2 in the irradiated area by a factor of 2 to 4, depending on the dose (p < 0.001), compared to the adjacent control area. On the other hand, as from day 7, the resting and the stimulated microcirculation varied little, except for a reduction of the slope p by a factor of 2 (p < 0.05) after the strongest radiation dose. CONCLUSION: After acute irradiation, the increase in the resting cutaneous microcirculation may correspond to immediate but transitory capillary vasodilatation that accompanies the initial erythema in accidental irradiation. The absence of vascular response to thermal stimulation seems to be a good means of reaching an early diagnosis of delayed cutaneous radiation necrosis.

[Evaluation of late radiation-induced changes in superficial microcirculation. I. Clinical benefit of the cutaneous Doppler laser]. / Evaluation des modifications radio-induites tardives de la microcirculation superficielle. I. Apport clinique du laser doppler cutané.

OBJECTIVE: The changes that occur in the tissular microcirculation after therapeutic irradiation (RT) account for some of the late effects of irradiation, especially on the cutaneous level. As a rule, the methods of exploring the superficial microcirculation only measure blood flow indirectly. Only the Doppler laser can provide direct measurements of blood parameters in vivo in man. METHODS: Thirty women who had been irradiated with 45 + 20 Gy of locoregional fractionated adjuvant RT for breast cancer developed local radiation-induced fibrosis six years later (+/- 5). The local microcirculation was measured in the resting state and during thermal stimulation at 42 degrees C, using a Periflux cutaneous Doppler laser with p413 probes. Three periods of six minutes each were continuously recorded: period 1 (P1) represented basal resting cutaneous perfusion, with the slope p corresponding to the increase in perfusion when two minutes of thermal stimulation at 42 degrees C began; P2 to plateau perfusion during this stimulation; and P3 to perfusion on the return to equilibrium. Each individual was its own control. RESULTS: In the women treated by RT, the resting microcirculation in the skin underlying an area of late fibrosis rose by a factor of 2 during P1 (p < 0.001), and the P2/P1 ratio decreased by a factor of 2 (p < 0.001), compared to the control area. After thermal stimulation, there was no change in p, P2 or P3. CONCLUSION: Although a hypovascularization is frequently found in late sequelae of RT, we observed an increase of the cutaneous microcirculation associated with a maladjustment of the endothelial response to a thermal stimulation. These observations seem to reflect the presence of dilated new capillaries of the telangiectatic type, which are macroscopically undetectable.

Striking regression of chronic radiotherapy damage in a clinical trial of combined pentoxifylline and tocopherol.

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.

Striking regression of subcutaneous fibrosis induced by high doses of gamma rays using a combination of pentoxifylline and alpha-tocopherol: an experimental study.

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.

Striking regression of radiation-induced fibrosis by a combination of pentoxifylline and tocopherol.

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.

Abnormal phenotype of cultured fibroblasts in human skin with chronic radiotherapy damage.

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.