Scar Fibrosis Research Articles

Thorax CT Findings in Symptomatic Hemodialysis Patients

The goal of the present study was to discuss thoracic problems in symptomatic hemodialysis patients based on the CT findings among 64 uremic patients including 34 females and 30 males of age range 14 to 83 years (mean = 61 years). We retrospectively documented complaints of cough, dyspnea, low-grade pyrexia, malaise, and weight loss. Atelectasis (79.7%), cardiomegaly (59.3%), parenchymal fibrosis–scar (50%), pleural effusion (45.3%), and ground-glass opacity (45.3%) were the most common findings. Pulmonary artery caliber was greater than 32 mm in 19 (29.7%) patients. Staphylococcus aureus (26.6%) and Mycobacterium tuberculosis (13.3%) were the most common infectious agents in patients who had parenchymal infiltrations, respectively. Chronic renal failure patients may display many thoracic and extrathoracic complications. The radiologic findings in these patients were multiple and complex, but, in most of cases, imaging techniques (predominantly CT) offered an accurate, noninvasive diagnostic approach.

Treatment of Obturator Neuralgia With Laparoscopic Neurolysis

Obturator neuralgia is a cause of pelvic and perineal pain that is rarely suggested, probably because it is poorly understood. We report the results of a pilot study of laparoscopic treatment for obturator neuralgia. Seven patients (8 nerves) with obturator neuralgia were treated at our department. The etiology was idiopathic in 3 cases and iatrogenic following inguinal hernia surgery in 3 and TVT(R) repair in 2. The diagnosis was based on allodynic pain of the anterior and internal surface of the thigh, which was associated with limping with a sidestepping gait. It was confirmed by an anesthetic block under computerized tomography monitoring using a posterior approach. Treatment consisted of transperitoneal laparoscopic neurolysis with dissection of the nerve and section of the scarring fibrosis or prosthetic mesh in contact with it. In idiopathic cases nerve release was performed by sectioning the internal obturator muscle and the obturator membrane, causing compression and making it possible to widen the obturator foramen. At a mean followup of 16 months the rate of an at least 50% improvement in pain was 87.5% (7 of 8 cases), including complete disappearance of pain in 50% (4 of 8). Minimally invasive treatment with laparoscopic truncular release of obturator neuralgia yielded encouraging and good results.

Tissue reaction and surface morphology of absorbable sutures after in vivo exposure

Tissue reaction to suture materials depends mainly on how the polymer they are composed of interacts with the tissues. There are few in vivo studies evaluating the suture material modifications resulting from its interaction with tissues. This paper aimed to study rat subcutaneous tissue reaction to irradiated polyglactin 910, polydioxanone, poliglecaprone 25 and chromic gut and its correlation with the ultra-structural alterations the materials undergo. The histological alterations were studied on the 1st, 2nd, 3rd, 7th and 14th day after suture implantations. In these periods, the materials were removed from the tissues and their surfaces were analyzed by scanning electron microscopy. Irradiated polyglactin 910 stimulated the formation of multinucleated giant cells and its filaments underwent cleavage and dissolution. In potydioxanone, a few inflammatory cells and scar fibrosis was observed, and triangular cracks appeared on its surface. Around the poliglecaprone 25, a diffused infiltration of a few mononuclear cells and fibrosis was recorded and formation of craters was observed on its surface. Chromic gut induced necrosis and granulation tissue and underwent dissolution in the tissues during the studied periods. In this study, it was observed that suture materials induced differentiated tissue reactions and morphologic surface changes, suggesting that indications should be individualized.

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.

Cellular cardiomyoplasty for myocardial support and regeneration

BACKGROUND: Cell-based regenerative therapy is undergoing different experimental and clinical trials in order to limit the consequences of decreased contractile function and compliance of damaged ventricles following myocardial infarction. METHODS: An overview of the actual status quo. RESULTS: Over 200 patients have been treated worldwide with cell-based procedures for myocardial regeneration. Results are preliminary. CONCLUSIONS: Cellular cardiomyoplasty seems to reduce the size and fibrosis of infarct scars, limit postischemic remodelling, and restore regional myocardial contractility.

Cellular cardiomyoplasty: clinical application

Myocardial regeneration can be induced with the implantation of a variety of myogenic and angiogenic cell types. More than 150 patients have been treated with cellular cardiomyoplasty worldwide, 18 patients have been treated by our group. Cellular cardiomyoplasty seems to reduce the size and fibrosis of infarct scars, limit postischemic remodelling, and restore regional myocardial contractility. Techniques for skeletal myoblasts culture and ex vivo expansion using autologous patient serum (obtained from plasmapheresis) have been developed by our group. In this article we propose (1) a total autologous cell culture technique and procedures for cell delivery and (2) a clinical trial with appropriate endpoints structured to determine the efficacy of cellular cardiomyoplasty.

SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7.

Clinically, there is a great need for small molecule inhibitors that could control pathogenic effects of transforming growth factor (TGF-beta) and/or modulate effects of TGF-beta in normal responses. Inhibition of TGF-beta signaling would be predicted to enhance re-epithelialization of cutaneous wounds and reduce scarring fibrosis. Selective small molecule inhibitors of the TGF-beta signaling pathway developed for therapeutics will also be powerful tools in experimentally dissecting this complex pathway, especially its cross-talk with other signaling pathways. In this study, we characterized 2-(5-benzo[1,3]dioxol-5-yl-2-tert-butyl-3H-imidazol-4-yl)-6-methylpyridine hydrochloride (SB-505124), a member of a new class of small molecule inhibitors related to imidazole inhibitors of p38, which inhibit the TGF-beta type I receptor serine/threonine kinase known as activin receptor-like kinase (ALK) 5. We demonstrate that this compound selectively and concentration-dependently inhibits ALK4-, ALK5-, and ALK 7-dependent activation of downstream cytoplasmic signal transducers, Smad2 and Smad3, and of TGF-beta-induced mitogen-activated protein kinase pathway components but does not alter ALK1, ALK2, ALK3 or ALK6-induced Smad signaling. SB-505124 also blocks more complex endpoints of TGF-beta action, as evidenced by its ability to abrogate cell death caused by TGF-beta1 treatment. SB-505124 is three to five times more potent than a related ALK5 inhibitor described previously, SB-431542.

Interference with Transforming Growth Factor-β/ Smad3 Signaling Results in Accelerated Healing of Wounds in Previously Irradiated Skin

Transforming growth factor (TGF)-beta regulates many aspects of wound repair including inflammation, chemotaxis, and deposition of extracellular matrix. We previously showed that epithelialization of incisional wounds is accelerated in mice null for Smad3, a key cytoplasmic mediator of TGF-beta signaling. Here, we investigated the effects of loss of Smad3 on healing of wounds in skin previously exposed to ionizing radiation, in which scarring fibrosis complicates healing. Cutaneous wounds made in Smad3-null mice 6 weeks after irradiation showed decreased wound widths, enhanced epithelialization, and reduced numbers of neutrophils and myofibroblasts compared to wounds in irradiated wild-type littermates. Differences in breaking strength of wild-type and Smad3-null wounds were not significant. As shown previously for neutrophils, chemotaxis of primary dermal fibroblasts to TGF-beta required Smad3, but differentiation of fibroblasts to myofibroblasts by TGF-beta was independent of Smad3. Previous irradiation-enhanced induction of connective tissue growth factor mRNA in wild-type, but not Smad3-null fibroblasts, suggested that this may contribute to the heightened scarring in irradiated wild-type skin as demonstrated by Picrosirius red staining. Overall, the data suggest that attenuation of Smad3 signaling might improve the healing of wounds in previously irradiated skin commensurate with an inhibition of fibrosis.

Increased vascular endothelial growth factor may account for elevated level of plasminogen activator inhibitor-1 via activating ERK1/2 in keloid fibroblasts.

Keloids are characterized as an "overexuberant" healing response in which disequilibrium between production and catabolism of extracellular matrix (ECM) occurs. Previous studies from our laboratory and others demonstrate an intrinsically higher level of plasminogen activator inhibitor-1 (PAI-1) expression in keloid tissues and cultured fibroblasts compared with normal bordering skin. These findings support the concept that an altered balance of activator and inhibitor activities in the plasminogen system, in particular, an overexpression of PAI-1, may partly contribute to keloid formation and tissue fibrosis. Vascular endothelial growth factor (VEGF) has been implicated as a critical factor in regulating angiogenesis and inflammation under both physiological and pathological conditions. This study was designed to assess whether VEGF plays a role in keloid fibrosis. We report that VEGF was expressed at higher levels in keloid tissues and their derived fibroblasts compared with their associated normal skin. We have further demonstrated that VEGF stimulated the expression of PAI-1, but not urokinase plasminogen activator (uPA), in keloid fibroblasts at both mRNA and protein levels, in a dose- and time-dependent manner. However, treatment of normal skin fibroblasts with VEGF exerted little effects on PAI-1 gene expression. Additionally, we have characterized for the first time that the extracellular signal-regulated kinase (ERK)1/2 signaling pathway is mainly involved in VEGF-induced PAI-1 expression and have demonstrated its potential as a target molecule for modulation of scar fibrosis. These findings suggest that VEGF may play an important role in keloid formation by altering ECM homeostasis toward a state of impaired degradation and excessive accumulation.

Mechanisms of Hypoxic Regulation of Plasminogen Activator Inhibitor-1 Gene Expression in Keloid Fibroblasts

Keloids are an excessive accumulation of extracellular matrix. Although numerous studies have shown elevated plasminogen activator inhibitor-1 (PAI-1) levels in keloid fibroblasts compared with those of normal skin. Their specific mechanisms involved in the differential expression of PAI-1 in these cell types. In this study, the upregulation of PAI-1 expression is demonstrated in keloid tissues and their derived dermal fibroblasts, attesting to the persistence, if any, of fundamental differences between in vivo and in vitro paradigms. We further examined the mechanisms involved in hypoxia-induced regulation of PAI-1 gene in dermal fibroblast derived from keloid lesions and associated clinically normal peripheral skins from the same patient. Primary cultures were exposed to an environmental hypoxia or desferroxamine. We found that the hypoxia-induced elevation of PAI-1 gene appears to be regulated at both transcriptional and post-transcriptional levels in keloid fibroblasts. Furthermore, our results showed a consistent elevation of HIF-1alpha protein level in keloid tissues compared with their normal peripheral skin controls, implying a potential role as a biomarker for local skin hypoxia. Treatment with antisense oligonucleotides against hypoxia-inducible factor 1alpha (HIF-1alpha) led to the downregulation of steady-state levels of PAI-1 mRNA under both normoxic and hypoxic conditions. Conceivably, our results suggest that HIF-1alpha may be a novel therapeutic target to modulate the scar fibrosis process.

Synthetic Vitreous Fibers: A Review of Toxicology Research and Its Impact on Hazard Classification

Because the inhalation of asbestos, a naturally occurring, inorganic fibrous material, is associated with lung fibrosis and thoracic cancers, concerns have been raised about the possible health effects of synthetic vitreous fibers (SVFs). SVFs include a very broad variety of inorganic fibrous materials with an amorphous molecular structure. Traditionally, SVFs have been divided into three subcategories based on composition: fiberglass, mineral wool (rock, stone, and slag wools), and refractory ceramic fiber. For more than 50 years, the toxicologic potential of SVFs has been researched extensively using human epidemiology and a variety of laboratory studies. Here we review the research and its impact on hazard classification and regulation of SVFs.Large, ongoing epidemiology studies of SVF manufacturing workers have provided very little evidence of harmful effects in humans. Several decades of research using rodents exposed by inhalation have confirmed that SVF pulmonary effects are determined by the “Three D's”, fiber dose (lung), dimension, and durability. Lung dose over time is determined by fiber deposition and biopersistence in the lung. Deposition is inversely related to fiber diameter. Biopersistence is directly related to fiber length and inversely related to fiber dissolution and fragmentation rates. Inhaled short fibers are cleared from the lung relatively quickly by mobile phagocytic cells, but long fibers persist until they dissolve or fragment. In contrast to asbestos, most of the SVFs tested in rodent inhalation studies cleared rapidly from the lung (were nonbiopersistent) and were innocuous. However, several relativley biopersistent SVFs induced chronic inflammation, lung scarring (fibrosis), and thoracic neoplasms. Thus, biopersistence of fibers is now generally recognized as a key determinant of the toxicologic potential of SVFs. In vitro dissolution of fibers in simulated extracellular fluid correlates fairly well with fiber biopersistence in the lung and pulmonary toxicity, but several exceptions suggest that biopersistence involves more than dissolution rate.Research demonstrating the relationship between biopersistence and SVF toxicity has provided a scientific basis for hazard classification and regulation of SVFs. For a nonhazardous classification, legislation recently passed by the European Union requires a respirable insulation wool to have a low lung-biopersistence or be noncarcinogenic in laboratory rats. U.S. fiberglass and mineral wool industries and the Occupational Health and Safety Administration (OSHA) have formed a voluntary Health and Safety Partnership Program (HSPP) that include: a voluntary permissible exposure level (PEL) in the workplace of 1 fiber/cc, a respiratory protection program for specified tasks, continued workplace air monitoring, and, where possible, the development of fiber formulations that do not persist in the lung. RCF manufacturers have implemented a Product Stewardship Program that includes: a recommended exposure guideline of 0.5 fibers/cc; a 5-year workplace air monitoring program; and research into the development of high-temperature-resistant, biosoluble fibers.

Characterization of a macrophage-based system for studying the activation of latent TGF-beta.

TGF-beta has been implicated in scarring and tissue fibrosis. Most cells secrete TGF-beta as a high molecular weight, latent complex that must be processed to a lower molecular weight, biologically active form. A number of molecules are involved in this activation step including the mannose 6-phosphate/insulin-like growth factor-II receptor, tissue transglutaminase, thrombospondin, plasmin, and others. Here we describe a rapid macrophage-based system for TGF-beta1 activation, which could be used for screening potential anti-fibrotic agents. The system employs transformed mouse peritoneal macrophages treated with lipopolysaccharide as a cell line capable of activating latent TGF-beta. The activation mechanism in our system involves mannose 6-phosphate/insulin-like growth factor-II receptor and transglutaminase. The activation of latent TGF-beta in this system can be prevented by the addition of mannose-6-phosphate but not mannose-1-phosphate. In addition, transglutaminase inhibitors, antibodies to thrombospondin, insulin-like growth factor-II in the presence of its binding protein IGFBP-2, but not IGFBP-1, suppressed the activation of TGF-beta. Anti-inflammatory molecules, such as hydrocortisone, when added to LPS-treated macrophages, inhibited TGF-beta activation by a mechanism, that may involve downregulation of transglutaminase expression. In summary, this new, rapid and reproducible system allows testing molecules for their ability to inhibit TGF-beta activation, thus providing a screening method for potential anti-scarring molecules.

Arthroscopic surgery of the metatarsophalangeal first joint

Arthroscopic surgery of the metatarsophalangeal first joint was used to treat a dorsal impingement syndrome of the hallux by removing the dorsally located osteophytes. Also, osteochondritis dissecans, painful sesamoid bones resistant to conservative therapy, and hallux rigidus were arthroscopically treated in a prospective study enrolling 24 consecutive patients. Seventeen patients were high-level athletes. Pain, swelling, sports, and work involvement were recorded. The operative technique is described. There was one persistent loss of sensitivity of the hallux. In the dorsal impingement group, 8 of 12 patients had a good or excellent result after a minimum follow-up of 2 years. In patients with osteochondritis dissecans, 3 of 4 showed good or excellent results. In hallux rigidus and sesamoid bone removal the results were less favorable. As in all arthroscopic procedures there was a fast rehabilitation and work resumption. Especially in athletes arthroscopically, treatment of a dorsal impingement syndrome or osteochondritis dissecans can be recommended because of the diminished chance of scar fibrosis. (Arthroscopy 1998 Nov-Dec;14(8):851-5.)

Ludwig symposium on biliary disorders--part I. Pathogenesis of ductal plate abnormalities.

Intrahepatic bile ducts (IHBDs) develop from bipotential liver progenitor cells in contact with the mesenchyme of the portal vein and thus form the "ductal plates." The ductal plates are remodeled into mature tubular ducts. Lack of remodeling results in the persistence of periportal epithelial sleeves or "ductal plate malformation" (DPM). A proposal is that virtually all congenital diseases of IHBDs represent examples of DPM. Some early, severe types of extrahepatic bile duct atresia are characterized by DPM, a suggestion of a prenatal beginning of the disease. Several congenital diseases are characterized by dilatation of segments of IHBDs and variable degrees of fibrosis. Such "fibrocystic diseases" represent DPM at different levels of the biliary tree. Autosomal recessive polycystic kidney disease represents DPM of interlobular bile ducts, associated with tubular dilatation of collecting renal tubules. Congenital hepatic fibrosis may derive from the same type of liver lesion, through a superimposed destructive type of cholangiopathy associated with scarring fibrosis. Caroli's disease represents DPM of the larger IHBDs, whereas Caroli's syndrome combines the lesions of Caroli's disease and congenital hepatic fibrosis. von Meyenburg complexes represent DPM of smaller interlobular ducts; their dilatation gives rise to the liver cysts in autosomal dominant polycystic kidney disease. Finally, DPM is a component of the tissue abnormalities in so-called mesenchymal hamartoma.

Pathogenesis of Ductal Plate Abnormalities

Intrahepatic bile ducts (IHBDs) develop from bi-potential liver progenitor cells in contact with themesenchyme of the portal vein and thus form the plates. The ductal plates are remodeled into mature tubular ducts. Lack of remodeling results in the persistence of periportal epithelial sleeves or plate malformation (DPM). A proposal is that virtually all congenital of IHBDs represent examples of DPM. Some early, severe types of extra-hepatic bile duct atresia are characterized by DPM, a suggestion of a prenatal beginning of the disease. Several congenital are characterized by dilatation of segments of IHBDs and variable degrees of fibrosis. Such fibrocystic diseases represent DPM at different levels of the biliary tree. Autosomal recessive polycystic kidney disease represents DPM of interlobular bile ducts, associated with tubular dilatation of collecting renal tubules. Congenital hepatic fibrosis may derive from the same type of liver lesion, through a superimposed destructive type of cholangiopathy associated with scarring fibrosis. Caroliapos;sdisease represents DPM of the larger IHBDs, whereas Caroliapos;s syndrome combines the lesions of Caroliapos;sdisease and congenital hepatic fibrosis, von Meyenburg complexes represent DPM of smaller interlobular ducts; their dilatation gives rise to the liver cysts in autosomal dominant polycystic kidney disease. Finally, DPM is a component of the tissue abnormalities in socalled mesenchymal hamartoma.

863 Clinical applications of FDG positron emission tomography in patients with soft tissue sarcoma

Various applications of positron emission tomography (PET) were studied in patients with soft tissue sarcoma: depiction of primary and recurrent lesions, determination of malignancy grade and evaluation of response to regional isolation perfusion. Twenty-nine patients with various types of soft tissue sarcoma were studied, 17 with a primary tumor and 12 patients with a local recurrence. The tumor size ranged from 1.0 to 31 cm. An IV dose of 370 MBq 18F-fluoro-deoxy-D-glucose (FDG) was administered. PET studies were performed in a dynamic and a “whole body” mode using a Siemens ECAT 951 camera. All 17 primary tumors and 11 of the 12 recurrent sarcomas were well visualized on the PET studies. The location of the recurrent lesions was clearly depicted in the presence of surrounding scar tissue and fibrosis. The glucose metabolic rate in the lesions was found to increase with increasing malignancy grade (P The decrease in glucose metabolic rate after TNF perfusion (20 patients) was found to provide information about the tumor response. In summary, several clinical applications of PET with FDG were established in patients with soft tissue sarcoma.

In Utero Cleft Palate Repair in the Ovine Model

Cleft lip and palate defects assume many forms from mild to severe, but all may be associated with abnormal craniofacial development. Even the most expert and sophisticated methods of surgical repair are followed by scar contraction and fibrosis, which result in skeletal defects, dental abnormalities, cosmetic disfigurement, and speech impairment. Recent clinical and experimental observations that fetal cutaneous wounds heal without scarring are of great potential interest in the management of cleft lip and palate. The objective of this study was to investigate the effect of prenatal repair of iatrogenically produced cleft palate on scar formation in the fetal lamb model. Ten ewes were operated on ranging in gestation from 70 to 133 days. Fifteen lambs were studied (nine cleft palates produced and repaired in utero; one cleft produced in utero and not repaired, four normal, unoperated palates; and one cleft palate produced and repaired 1 week postnatally). The lambs were delivered normally at 145 to 147 days gestation and maintained with the ewe until 1 month of age. The lambs were euthanized, and the surgical area of the palates studied grossly and histologically. Animals operated at 112 days or later in gestation exhibited scars both clinically and histologically. The animals that had cleft palate produced and repaired at 70 days gestation did not have a visible palatal scar at 1 month of age. Histologically, there was evidence of minimal scarring without disruption of normal architecture. Studies are underway to determine the impact of reduced scarring on craniofacial growth after palatal repair during mid gestation in the ovine model.

Role of In-111 Labeled CYT-103 Immunoscintigraphy in the Evaluation of Patients With Recurrent Colorectal Carcinoma

An immunoconjugate of the whole antibody, B72.3, has been approved by the FDA. It is labeled with indium-111, which allows imaging studies intended for the diagnosis and staging of colorectal and recurrent ovarian carcinoma. The new diagnostic imaging agent (CYT-103), Oncoscint CR/OV, has found particular use in evaluating patients with recurrent carcinoma. The three major indications for the study are: 1) occult disease--unexplained rise in serum tumor markers (e.g. CEA), with negative work-up including CT; 2) known local recurrence (e.g. liver or rectal area)--surgery is planned, but there is a need to rule out other areas of involvement; 3) clarify equivocal CT or MRI finding--to distinguish whether an abnormality is due to recurrent tumor or scar tissue, fibrosis, or unopacified bowel loop. Oncoscint has proven to be more sensitive than CT in the detection of disease in the pelvis and extrahepatic abdomen. CT remains the modality of choice for the detection of liver metastases. The combined sensitivity of the two modalities is 88% on a per-patient basis.

Obtaining rigidity in the neophallus of female-to-male transsexuals: a review of the literature.

In phalloplasty, the use of transplants and implants to obtain sufficient rigidity allowing for sexual penetration is difficult and often has resulted in complications and failure. Resorption, curving, and fracture of autologous cartilage and bone transplants are reported, and rigid implants have a tendency to erode and extrude. Besides, a constantly rigid phallus may serve as a source of embarrassment to the patient. On the other hand, hydraulic prostheses frequently show mechanical failure compared with nonhydraulic implants. For these reasons, some authorities have their patients use external devices for erection. Others fully rely on edema, scar fibrosis, or congestion to give sufficient rigidity. In this review, the literature on baculum implantation--on the use of external devices as well as on the use of no stiffener at all--is discussed.

The place of mammography following breast-conserving therapy of breast cancer

This study evaluates the radiographical signs of the breast in 168 patients with breast carcinoma who were treated with lumpectomy and radiation therapy. Two thirds of the postsurgical scars were radiologically seen only up to two years after operation. One-third showed only discrete scarred tissue after this period. The most characteristic sign was the continuous diminution of the post-surgical and post-radiation lesions in the follow-up mammograms (scar densities, fibrosis and architectural distortions). Microcalcification highly suspicious of malignancy developed in 6%; one-third, however, proved to be benign. Acute and chronic edema were the most striking symptoms up to one year after radiotherapy; the final stage of the post-radiation alterations was breast fibrosis which demonstrated in 60% of the cases rather discretely. The recurrence rate was 7%.