[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.

Cobalt toxicity: chemical and radiological combined effects on HaCaT keratinocyte cell line.

Cobalt (Co) is an essential trace element well known as a constituent of vitamin B(12), but different compounds of Co are also described as highly toxic and/or radiotoxic for individuals or the environment. In nuclear power plants, (58)Co and (60)Co are radioactive isotopes of cobalt present as activation products of stable Co and Ni used in alloys. Skin exposure is a current occupational risk in the hard metal and nuclear industries. As biochemical and molecular cobalt-induced toxicological mechanisms are not fully identified, we investigated cobalt toxicity in a model human keratinocyte cell line, HaCaT. In this study, we propose a model to determine the in vitro chemical impact on cell viability of a soluble form of cobalt (CoCl(2)) with or without gamma-ray doses to mimic contamination by (60)Co, to elucidate the mechanisms of cobalt intracellular chemical and radiological toxicity. Intracellular cobalt concentration was determined after HaCaT cell contamination and chemical toxicity was evaluated in terms of cellular viability and clonogenic survival. We investigated damage to DNA in HaCaT cells by combined treatment with chemical cobalt and a moderate gamma-ray dose. Additive effects of cobalt and irradiation were demonstrated. The underlying mechanism of cobalt toxicity is not clearly established, but our results seem to indicate that the toxicity of Co(II) and of irradiation arises from production of reactive oxygen species.

A comparison of cellular irradiation techniques with alpha particles using the Geant4 Monte Carlo simulation toolkit.

A comparison of three cellular irradiation techniques using the Monte Carlo simulation toolkit Geant4 is presented in this paper. They involve electrodeposited source of alpha particle-emitting radionuclides, random classical alpha beam irradiation and single cell targeted irradiation using a focused alpha microbeam line. The simulation allows the calculation of hit distributions among the cellular population as well as the absorbed dose for two typical cellular geometries.

An interdisciplinary approach to investigate the impact of cobalt in a human keratinocyte cell line.

Since in nuclear power plants, risks of skin contact contamination by radiocobalt are significant, we focused on the impact of cobalt on a human cutaneous cell line, i.e. HaCaT keratinocytes. The present paper reports an interdisciplinary approach aimed at clarifying the biochemical mechanisms of metabolism and toxicity of cobalt in HaCaT cells. Firstly, a brief overview of the used instrumental techniques is reported. The following parts present description and discussion of results concerning: (i) toxicological studies concerning cobalt impact towards HaCaT cells (ii) structural and speciation fundamental studies of cobalt-bioligand systems, through X-ray absorption spectroscopy (XAS), ab initio and thermodynamic modelling (iii) preliminary results regarding intracellular cobalt speciation in HaCaT cells using size exclusion chromatography/inductively coupled plasma-atomic emission spectroscopy (SEC/ICP-AES) and direct in situ analysis by ion beam micropobe analytical techniques.

[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.

[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.

[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.

Promoter sequences involved in transforming growth factor beta1 gene induction in HaCaT keratinocytes after gamma irradiation.

Transforming growth factor beta 1 (TGFB1) is a cytokine involved in the development of both acute and late cutaneous radiation syndromes. We previously demonstrated that ionizing radiation induces TGFB1 expression in vivo in pig skin within a few hours. The purpose of the present study was to develop an in vitro human model to identify the mechanisms of this early activation. Accordingly, human HaCaT keratinocytes were irradiated with a single dose of 20 Gy. First, radiation-induced TGFB1 overexpression was checked at both the transcriptional and transductional levels in HaCaT cells. Then electrophoretic mobility shift assays (EMSA) and transient transfection with various TGFB1 promoter constructs were used to identify the sequences involved in regulating this promoter. EMSA analysis showed the induction of nuclear protein binding activity by gamma irradiation to the -365 AP1 sequence (TGTCTCA), suggesting the involvement of AP1 sequences in the regulation of TGFB1 transcription. In gene reporter assays, maximal TGFB1 promoter activation was found for the longest construct, which contains two AP1 sequences. However, assays with constructs including deletions showed that these two AP1 sequences were not sufficient to confer TGFB1 inducibility. These results showed for the first time, to our knowledge, that transcriptional regulation is involved in radiation-induced activation of TGFB1 gene expression.

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.

In vivo K-edge imaging with synchrotron radiation.

We present in this paper two imaging techniques using contrast agents assessed with in vivo experiments. Both methods are based on the same physical principle, and were implemented at the European Synchrotron Radiation Facility medical beamline. The first one is intravenous coronary angiography using synchrotron radiation X-rays. This imaging technique has been planned for human studies in the near future. We describe the first experiments that were carried out with pigs at the ESRF. The second imaging mode is computed tomography using synchrotron radiation on rats bearing brain tumors. Owing to synchrotron radiation physical properties, these new imaging methods provide additional information compared to conventional techniques. After infusion of the contrast agent, it is possible to derive from the images the concentration of the contrast agent in the tumor area for the computed tomography and in any visible vessel for the angiography method.

[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.

Imaging radiation induced muscular necrosis with antimyosin-scintigraphy and computed tomography.

Radiations accidents involving high exposures require accurate assessment of radiation dose for correct surgical or medical management. Techniques involving computed tomography and antimyosin-antibody scintigraphy were evaluated in an experimental model of acute localized irradiation overexposure to 192Ir. Ten rabbits were exposed to a single dose of 192Ir gamma irradiation (120 Gy) on the back (right iliospinal muscle). Computed tomography and antimyosin-antibody scintigraphy results were compared with those in four control animals. Planar scintiscans (posterior views) were performed 48 h post-injection of antimyosin-antibody each week for 2 mo after exposure. An antimyosin uptake was observed in irradiated muscle five weeks after exposure and correlated with computed tomography and histopathology results, showing muscle necrosis. Biodistribution assessed at 7 and 9 wk post exposure confirmed antimyosin-antibody accumulation in damaged muscle. A semi-quantitative analysis of a region of interest over the uptake area in the irradiated muscle (on the right side) and a contralateral non-irradiated region of interest used as control showed that uptake was significantly higher in irradiated animals than in control animals (p < 0.02). Antimyosin-antibody scintiscans used in nuclear cardiology to explore ischemic heart disease, myocarditis or heart transplant rejection could be realized to assess the extent of muscle necrosis after trauma or radiation induced injury.

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.

Histopathological and cellular studies of a case of cutaneous radiation syndrome after accidental chronic exposure to a cesium source.

This study was designed for the histopathological, cellular and biochemical characterization of a skin lesion removed surgically from a young male several months after accidental exposure to cesium-137, with an emphasis on expression of transforming growth factor beta1 (TGFB1) and tumor necrosis factor alpha (TNFA) and the occurrence of apoptosis. Under a hypertrophic epidermis, a highly inhomogeneous inflammatory dermis was observed, together with fibroblastic proliferation in necrotic areas. Immunostaining revealed overexpression of TGFB1 and TNFA inside the keratinocytes of the hypertrophic epidermis as well as in the cytoplasm of the fibroblasts and connective tissue of the mixed fibrotic and necrotic dermis. Inside this dermis, the TUNEL assay revealed areas containing numerous apoptotic fibroblasts next to areas of normal viable cells. Overexpression of TGFB1 was found in the conditioned medium and cellular fractions of both hypertrophic keratinocytes and fibrotic fibroblasts. This overexpression lasted for at least three passages in tissue culture. The present observations were consistent with the central role of TGFB1 in the determination of chronic radiation-induced damage to the skin and a significant involvement of TNFA. In addition, programmed cell death appeared to take place during the remodeling of the mixed fibrotic and necrotic tissue.