[Subcutaneous and intramuscular heterotopic calcification of the neck 42 years after radiotherapy]. / Subcutan és intramuscularis heterotop kalcifikáció a nyakon 42 évvel a sugárkezelést követoen.

Radiotherapy-induced heterotopic tissue calcification is an exceedingly rare complication in the head and neck region. We report a patient with extensive, radiotherapy-induced, combined subcutaneous and intramuscular, heterotopic calcification of the neck. An 80-year-old male presented with a 2-month history of severe dysphagia and a painful ulcer on the neck 42 years after salvage total laryngectomy following radiotherapy (total dose: 80 Gy) for a T3N0M0 glottic squamous cell carcinoma. We excluded recurrence or secondary malignancy by biopsy and performed computed tomography, which revealed subcutaneous and intramuscular calcification in the area of the skin ulcer and close to the hypopharyngeal wall, moreover, total occlusion of the common carotid and vertebral arteries bilaterally. Surgical correction involved removing the calcified lesions and closure using fasciocutaneous flap transposition. The patient has been asymptomatic for the past 48 months. Radiotherapy plays an essential role in the treatment of patients with head and neck squamous cell carcinoma. Distorted postoperative anatomy, excessive scar formation, radiotherapy-induced fibrosis as well as skin and subcutaneous tissue calcification can present as atypical findings. Orv Hetil. 2023; 164(10): 383-387.

Assessment of Mechanical Stress Induced by Radiofrequency Currents on Skin Interfaces.

The epidermal-dermal (ED) and dermal-subcutaneous (DS) junctions are the most prominent skin interfaces, which are known to be of primary importance in different dermatological and aesthetic conditions. These interfaces are strongly modified in aging skin, and their effective targeting can lead to improvement of skin appearance in aging and by cellulite. Application of radiofrequency (RF) currents to the skin can selectively produce mechanical stress on these interfaces. Here, we assess the stresses induced by RF currents of different frequencies on EDJ and DSJ and discuss possible applications of the interfacial therapy in aesthetic medicine.

Hilos de oro subcutáneos en una paciente con cervicalgia / Subcutaneous gold threads in a patient with neck pain

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Lipoatrofia semicircular: 3 casos clínicos / Semicircular lipoatrophy: three clinical cases

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[Subcutaneous calcinosis, a late and severe complication of radiotherapy: Three cases]. / La calcinose sous-cutanée, une complication rare et sévère de la radiothérapie: trois observations.

BACKGROUND: Radiation-induced subcutaneous calcinosis is a rare and special form of potentially severe subcutaneous calcinosis of late onset. Herein, we report three cases of this disease, occurring in each instance more than 10 years after use of radiotherapy as an adjuvant treatment in breast cancer. PATIENTS AND METHODS: Our report concerns 3 women aged 69-88 years consulting for pre-sternal ulcers (n=2) and/or subcutaneous nodules (n=2). These lesions developed on areas irradiated between 10 and 38 years earlier for breast cancer. In all three cases, radiological explorations showed extensive subcutaneous calcification. In one case, calcification extended into the mediastinum. In each patient, a diagnosis of radiation-induced subcutaneous calcinosis was made and symptomatic treatment was given. DISCUSSION: Radiation-induced subcutaneous calcinosis is an irreversible and rare complication of high-dose radiation that usually occurs several years after radiotherapy. Its severity is related to potential ulcerations, pain and a risk for in-depth extension up to the mediastina. This complication remains unclear and treatment has not been codified. The only option seems to be "heavy" plastic surgery.

Alopecia rectangular transitoria tras embolización endovascular: presentación de un caso y descripción de los hallazgos histopatológicos / Transitory Rectangular Alopecia After Endovascular Embolization: A Case Report and Description of the Histopathology Findings

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Relative biological effectiveness of carbon ions for tumor control, acute skin damage and late radiation-induced fibrosis in a mouse model.

BACKGROUND: The aim of the present study was to compare the biological effectiveness of carbon ions relative to x-rays between tumor control, acute skin reaction and late RIF of CDF1 mice. MATERIAL AND METHODS: CDF1 mice with a C3H mouse mammary carcinoma implanted subcutaneously on the foot of the right hind limb were irradiated with single fractions of either photons, or (12)C ions using a 30-mm spread-out Bragg peak. The endpoint of the study was local control (no tumor recurrence within 90 days). For the acute skin reaction, non-tumor bearing CDF1 mice were irradiated with a comparable radiation scheme, and monitored for acute skin damage between Day 7 and 40. Late RIF was assessed in the irradiated mice. RESULTS: The TCD50 (dose producing tumor control in 50% of mice) values with 95% confidence interval were 29.7 (25.4-34.8) Gy for C ions and 43.9 (39.2-49.2) Gy for photons, with a corresponding Relative biological effectiveness (RBE) value of 1.48 (1.28-1.72). For acute skin damage the MDD50 (dose to produce moist desquamation in 50% of mice) values with 95% confidence interval were 26.3 (23.0-30.1) Gy for C ions and 35.8 (32.9-39.0) Gy for photons, resulting in a RBE of 1.36 (1.20-1.54). For late radiation-induced fibrosis the FD50 (dose to produce severe fibrosis in 50% of mice) values with 95% confidence interval were 26.5 (23.1-30.3) Gy for carbon ions and 39.8 (37.8-41.8) Gy for photons, with a RBE of 1.50 (1.33-1.69). CONCLUSION: The observed RBE values were very similar for tumor response, acute skin damage and late RIF when irradiated with large doses of high- linear energy transfer (LET) carbon ions. This study adds information to the variation in biological effectiveness in different tumor and normal tissue models.

Thermal and elastic response of subcutaneous tissue with different fibrous septa architectures to RF heating: numerical study.

BACKGROUND AND OBJECTIVE: Radiofrequency currents are commonly used in dermatology to treat cutaneous and subcutaneous tissues by heating. The subcutaneous morphology of tissue consists of a fine, collagenous and fibrous septa network enveloping clusters of adipocyte cells. The architecture of this network, namely density and orientation of septa, varies among patients and, furthermore, it correlates with cellulite grading. In this work we study the effect of two clinically relevant fibrous septa architectures on the thermal and elastic response of subcutaneous tissue to the same RF treatment; in particular, we evaluate the thermal damage and thermal stress induced to an intermediate- and a high-density fibrous septa network architecture that correspond to clinical morphologies of 2.5 and 0 cellulite grading, respectively. STUDY DESIGN/MATERIALS AND METHODS: We used the finite element method to assess the electric, thermal and elastic response of a two-dimensional model of skin, subcutaneous tissue and muscle subjected to a relatively long, constant, low-power RF treatment. The subcutaneous tissue is constituted by an interconnected architecture of fibrous septa and fat lobules obtained by processing micro-MRI sagittal images of hypodermis. As comparison criteria for the RF treatment of the two septa architectures, we calculated the accumulated thermal damage that corresponds to 63% loss in cell viability. RESULTS: Electric currents preferentially circulated through the fibrous septa in the subcutaneous tissue. However, the intensity of the electric field was higher within the fat because it is a poor electric conductor. The power absorption in the fibrous septa relative to that in the fat varied with septum orientation: it was higher in septa with vertical orientation and lower in septa with horizontal orientation. Overall, maximum values of electric field intensity, power absorption and temperature were similar for both fibrous septa architectures. However, the high-density septa architecture (cellulite grade 0) had a more uniform and broader spatial distribution of power absorption, resulting in a larger cross-sectional area of thermal damage (≈1.5 times more). Volumetric strains (expansion and contraction) were small and similar for both network architectures. During the first seconds of RF exposure, the fibrous septa were subjected to thermal expansion regardless of orientation. In the long term, the fibrous septa contracted due to the thermal expansion of fat. Skin and muscle were subjected to significantly higher Von Mises stresses (measure of yield) or distortion energy than the subcutaneous tissue. CONCLUSION: The distribution of electric currents within subcutaneous tissues depends on tissue morphology. The electric field is more intense in septum oriented along the skin to muscle (top to bottom) direction, creating lines or planes of preferential heating. It follows that the more septum available for preferential heating, the larger the extent of volumetric RF-heating and thermal damage to the subcutaneous tissue. Thermal load alone, imposed by long-exposure to heating up to 50 °C, results in small volumetric expansion and contraction in the subcutaneous tissue. The subcutaneous tissue is significantly less prone to non-reversible deformation by a thermal load than the skin and muscle.

Improvement in the repair of defects in maxillofacial soft tissue in irradiated minipigs by a mixture of adipose-derived stem cells and platelet-rich fibrin.

To find out if adipose-derived stem cells (ASC) and platelet-rich fibrin (PRF), alone or combined, had any effect on the repair of maxillofacial soft tissue defects in irradiated minipigs, ASC were isolated, characterised, and expanded. Twenty female minipigs, the right parotid glands of which had been irradiated, were randomly divided into 4 groups of 5 each: those in the first group were injected with both ASC and PRF (combined group), the second group was injected with ASC alone (ASC group), the third group with PRF alone (PRF group), and the fourth group with phosphate buffer saline (PBS) (control group). Six months after the last injection, the size and depth of each defect were assessed, and subcutaneous tissues were harvested, stained with haematoxylin and eosin, and examined immunohistologically and for apoptosis. Expanded cells were successfully isolated and identified. Six months after injection the defects in the 3 treated groups were significantly smaller (p<0.001) and shallower (p<0.001) than those in the control group. Those in the combined group were the smallest and shallowest. Haematoxylin and eosin showed that the 3 treated groups contained more subcutaneous adipose tissue than the control group, and also had significantly greater vascular density (p<0.001) and fewer apoptotic cells (p<0.001). Both ASC and PRF facilitate the repair of defects in maxillofacial soft tissue in irradiated minipigs, and their combined use is more effective than their use as single agents.

microRNA alterations driving acute and late stages of radiation-induced fibrosis in a murine skin model.

PURPOSE: Although ionizing radiation is critical in treating cancer, radiation-induced fibrosis (RIF) can have a devastating impact on patients' quality of life. The molecular changes leading to radiation-induced fibrosis must be elucidated so that novel treatments can be designed. METHODS AND MATERIALS: To determine whether microRNAs (miRs) could be responsible for RIF, the fibrotic process was induced in the right hind legs of 9-week old CH3 mice by a single-fraction dose of irradiation to 35 Gy, and the left leg served as an unirradiated control. Fibrosis was quantified by measurements of leg length compared with control leg length. By 120 days after irradiation, the irradiated legs were 20% (P=.013) shorter on average than were the control legs. RESULTS: Tissue analysis was done on muscle, skin, and subcutaneous tissue from irradiated and control legs. Fibrosis was noted on both gross and histologic examination by use of a pentachrome stain. Microarrays were performed at various times after irradiation, including 7 days, 14 days, 50 days, 90 days, and 120 days after irradiation. miR-15a, miR-21, miR-30a, and miR-34a were the miRs with the most significant alteration by array with miR-34a, proving most significant on confirmation by reverse transcriptase polymerase chain reaction, c-Met, a known effector of fibrosis and downstream molecule of miR-34a, was evaluated by use of 2 cell lines: HCT116 and 1522. The cell lines were exposed to various stressors to induce miR changes, specifically ionizing radiation. Additionally, in vitro transfections with pre-miRs and anti-miRs confirmed the relationship of miR-34a and c-Met. CONCLUSIONS: Our data demonstrate an inverse relationship with miR-34a and c-Met; the upregulation of miR-34a in RIF causes inhibition of c-Met production. miRs may play a role in RIF; in particular, miR-34a should be investigated as a potential target to prevent or treat this devastating side effect of irradiation.

Prospective study of local control and late radiation toxicity after intraoperative radiation therapy boost for early breast cancer.

PURPOSE: To report the local recurrence rate and late toxicity of intraoperative radiation therapy (IORT) boost to the tumor bed using the Intrabeam System followed by external-beam whole-breast irradiation (WBI) in women with early-stage breast cancer in a prospective single-institution study. METHODS AND MATERIALS: Women with breast cancer≤3 cm were recruited between February 2003 and May 2005. After breast-conserving surgery, a single dose of 5 Gy IORT boost was delivered using 50-kV x-rays to a depth of 10 mm from the applicator surface. This was followed by WBI to a total dose of 50 Gy in 25 fractions. Patients were reviewed at regular, predefined intervals. Late toxicities were recorded using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring systems. RESULTS: Fifty-five patients completed both IORT boost and external-beam WBI. Median follow-up was 3.3 years (range, 1.4-4.1 years). There was no reported locoregional recurrence or death. One patient developed distant metastases. Grade 2 and 3 subcutaneous fibrosis was detected in 29 (53%) and 8 patients (15%), respectively. CONCLUSIONS: The use of IORT as a tumor bed boost using kV x-rays in breast-conserving therapy was associated with good local control but a clinically significant rate of grade 2 and 3 subcutaneous fibrosis.

Effect of fibrous septa in radiofrequency heating of cutaneous and subcutaneous tissues: computational study.

BACKGROUND AND OBJECTIVES: Radiofrequency (RF) energy exposure is a popular non-invasive method for generating heat within cutaneous and subcutaneous tissues. Subcutaneous fat consists of fine collagen fibrous septa meshed with clusters of adipocytes having distinct structural, electrical and thermal properties that affect the distribution and deposition of RF energy. The objectives of this work are to (i) determine the electric and thermal effects of the fibrous septa in the RF heating; (ii) investigate the RF heating of individual fat lobules enclosed by fibrous septa; and, (iii) discuss the clinical implications. METHODS AND RESULTS: We used the finite element method to model the two-dimensional, time-dependent, electro-thermal response of a three-layer tissue (skin, subcutaneous fat, and muscle). We considered two different configurations of subcutaneous fat tissue: a homogenous layer of fat only and a honeycomb-like layer of fat with septa. Architecture of the fibrous septa was anatomically accurate, constructed from sagittal images from human micro-MRI. For a large electrode applied to the skin surface, results show that the absorbed electric power density is greater in some septa than in the surrounding fat lobules, favoring the flux of electric current density. Fibers aligned parallel to the electric field have higher electric flux and, consequently, absorb more power. Heat transfer from the septa occurs over time during and after RF energy delivery. There is a greater temperature rise in fat with fibrous septa. CONCLUSIONS: The presence of septa affects the local distribution of the static electric field, facilitates the flux of electric current and enhances the bulk electric power absorption of the subcutaneous fat layer. Fibrous septa aligned with the local electric field have higher absorbed power density than septa oriented perpendicular to the electric field. Individual fat lobules gain heat instantly by local power absorption and, eventually, by diffusion from the surrounding septa.

Histological reaction of the subcutaneous tissue of rats following implantation of bone morphogenetic protein (rhBMP-2) in inorganic bone scaffold and stimulation using low-power laser light / Reação histológica do tecido subcutâneo de rato após implante de proteína morfogenética óssea(rhBMP-2) em arcabouço de osso inorgânico e estimulado com luz laser de baixa potência

The aim of this study was to assess the histological reaction of the subcutaneous tissue of rats after the implantation of natural inorganic mineral scaffold from a calf femur containing recombinant human bone morphogenetic protein (rhBMP-2) and irradiated with low-power laser light. Material and methods: Sixteen Wistar rats were incised in the torso in a medial-longitudinal orientation, and the subcutaneous tissue of the left and right sides of the incision was pulled apart for implantation of the inorganic bone scaffold containing rhBMP-2. Diode laser light was applied to the right side implant at a dose of 8 J/cm2 for 3 minutes, forming two groups: G1 (control) and G2 (irradiated with laser). Implants and surrounding tissuewere removed from four animals on days 7, 21, 40 and 112 for microscopic study. The histological resultswere assessed by means of grading (0 = absence, 1 = slight presence, 2 = representative and 3 = very representative),considering the following events: formation of osteoid structure, acute inflammation, chronicinflammation, fibrin deposition, neovascularization, foreign body granuloma and fibrosis. Results: The resultsshowed no statistically significant differences in each of the four periods when the two groups werecompared (p>0.05 – Mann-Whitney’s test). Conclusion: The natural inorganic scaffold from a calf femurwith rhBMP-2 was a biocompatible combination. Under these conditions, the inductive capacity of rhBMP-2for cell differentiation was inhibited. A slight hastening of tissue healing was shown in the group that wasirradiated with low-power laser light...

O objetivo deste estudo foi avaliar a reação histológica do tecido subcutâneo de rato após o implante de matriz de osso inorgânico mineral natural de fêmur de vitelo com proteína morfogenética do osso recombinante humana (rhBMP-2) e irradiado com luz laser de baixa potência. Material e métodos: Dezesseis ratos (Wistar) foram incisados no dorso no sentido medio-longitudinal. O tecido subcutâneo do lado direito e esquerdo da incisão foram divulsionados para o implante da matriz de osso inorgânico com rhBMP-2. Na direção do implante do lado direito foi aplicada luz laser, diodo em dose única de 8 J/cm2, por 3 minutos, formando dois grupos: G1 (controle) e G2 (irradiado com laser). Foram removidos implantes com o tecido circundante de quatro animais nos períodos de 7, 21, 40 e 112 dias para estudo microscópico. Os resultados histológicos foram avaliados através de postos (0 = ausência, 1 = discreta presença, 2 = representativo e 3 = muito representativo),considerando os seguintes eventos: formação de estrutura osteoide, inflamação aguda, inflamação crônica, depósito de fibrina, neovascularização, granuloma de corpo estranho e fibrose. Resultados: Os resultados não mostraram diferenças estatísticas significativas nos eventos em cada um dos períodos quando comparados os dois grupos (p>0,05 – teste Mann-Whitney). Conclusão: A matriz de osso inorgânico natural de fêmur de vitelo com rhBMP-2 é um conjunto biocompatível. Nestas condições, a capacidade indutora de diferenciação celular da rhBMP-2 foi inibida. Ficou evidenciado discreto aceleramento na cicatrização tecidual no grupo que foi irradiado com luz laser de baixa potência...

Postirradiation pseudosclerodermatous panniculitis: three new cases with additional histopathologic features supporting the radiotherapy etiology.

Postirradiation pseudosclerodermatous panniculitis is a rare panniculitic disorder induced by radiotherapy. Clinically, it consists of an indurate plaque localized on the irradiated area that may appear months or even years after radiotherapy was administered. Histopathologically, postirradiation pseudosclerodermatous panniculitis is characterized by a mostly lobular panniculitis without vasculitis, with lipophagic granuloma involving the fat lobules, a variable inflammatory infiltrate of lymphocytes and plasma cells and sclerotic thickening of the connective tissue septa of the subcutis. We report 3 additional cases of this rare variant of panniculitis, in which besides the panniculitis findings, dermal vessels showed sclerotic vessel walls and atypical bizarre fibroblasts with large pleomorphic and hyperchromatic nuclei were interstitially arranged between collagen bundles of the dermis. These dermal findings represent additional histopathologic features supporting the pathogenic role of the radiotherapy in the development of this rare variant of panniculitis.

Complication probability model for subcutaneous fibrosis based on published data of partial and whole breast irradiation.

PURPOSE: To extend the application of current radiation therapy (RT) based normal tissue complication probability (NTCP) models of radiation-induced fibrosis (RIF) of the breast to include the effects of fractionation, inhomogeneous dose, incomplete recovery, and time after the end of radiotherapy in partial breast irradiation (PBI). MATERIALS AND METHODS: An NTCP Lyman model with biologically effective uniform dose (BEUD) with and without a correction for the effect of incomplete repair was used. The time to occurrence of RIF was also taken into account. The radiobiological parameters were determined by fitting incidences of moderate/severe RIF in published randomized studies on RT of the breast. The NTCP model was used to calculate the risk of toxicity in 35 patients treated with intensity modulated, non-accelerated PBI and the result was compared with observed incidence of RIF. RESULTS: With α/ß fixed at 3Gy the parameters of the model without correction for incomplete repair extracted from fitting were: 50% complication probability biologically effective dose BEUD(50) = 107.2 Gy (95%CI = 95.9-118.6 Gy), volume parameter n = 0.06 (95%CI = 0-0.23), and slope of dose response m = 0.22, (95%CI = 0.20-0.23). After including the correction for incomplete repair with repair halftime for subcutaneous tissue of τ = 4.4 h we obtained BEUD(50) = 105.8 Gy (95%CI = 96.9-114.6Gy), n = 0.15 (95%CI = 0-0.33), m = 0.22 (95%CI = 0.20-0.23). Average NTCP predicted by these models, 4.3% and 2.0% respectively, offered a good agreement with RIF incidence in our patients, 5.7%, after an average follow-up of 12 months. CONCLUSION: The NTCP models of RIF, incorporating the effects of fractionation, volume effect, and latency of toxicity look promising to model PBI. Clinical validation from a prospective PBI treatment study is under development and will help test this preliminary result.

Common variants of GSTP1, GSTA1, and TGFß1 are associated with the risk of radiation-induced fibrosis in breast cancer patients.

PURPOSE: To provide new insights into the genetic basis of normal tissue radiosensitivity, we evaluated the association between eight polymorphic variants located in six genes related to DNA repair mechanisms, oxidative stress, and fibroblast proliferation (XRCC1 Arg399Gln, XRCC1 Arg194Trp, TP53 Arg72Pro, GSTP1 Ile105Val, GSTA1 C-69T, eNOS G894T, TGFß1 C-509T, and TGFß1 T869C) and the risk of subcutaneous fibrosis in a retrospective series of patients who received radiotherapy after breast-conserving surgery. METHODS AND MATERIALS: Subcutaneous fibrosis was scored according to the Late Effects of Normal Tissue--Subjective Objective Management Analytical scale in 257 breast cancer patients who underwent surgery plus adjuvant radiotherapy. Genotyping was conducted by polymerase chain reaction--restriction fragment length polymorphism analysis on genomic DNA extracted from peripheral blood. The association between genetic variants and the risk of moderate to severe fibrosis was evaluated by binary logistic regression analysis. RESULTS: Two hundred thirty-seven patients were available for the analysis. Among them, 41 patients (17.3%) developed moderate to severe fibrosis (Grade 2-3), and 196 (82.7%) patients displayed no or minimal fibrotic reactions (Grade 0-1). After adjustment of confounding factors, GSTP1 Ile105Val (odds ratio [OR] 2.756; 95% CI, 1.188-6.393; p = 0.018), GSTA1 C-69T (OR 3.223; 95% CI, 1.176-8.826; p = 0.022), and TGFß1 T869C (OR 0.295; 95% CI, 0.090-0.964; p = 0.043) polymorphisms were found to be significantly associated with the risk of Grade 2-3 radiation-induced fibrosis. In the combined analysis, carriers of three risk genotypes were found to be at higher odds for the development of Grade 2-3 fibrosis than were patients with two risk genotypes (OR 4.415; 95% CI, 1.553-12.551, p = 0.005) or with no or one risk genotype (OR 8.563; 95% CI, 2.671-27.447; p = 0.0003). CONCLUSIONS: These results suggest that functional variations in genes involved in oxidative stress response and fibroblast proliferation may modulate the development of radiation-induced fibrosis in breast cancer patients. The results of the combined analysis support the notion that approaches based on the combination of different genetic markers have the potential to predict normal tissue responses.

Clinical experience with a TriPollar radiofrequency system for facial and body aesthetic treatments.

Non-invasive aesthetic treatments aiming at circumference reduction and facial wrinkle improvement are becoming increasingly popular. TriPollar treatments for the purpose of body contouring and skin tightening procedures have recently gained interest. Our aim was to evaluate the safety and efficacy of the Apollo device for non invasive treatment of localized excess fat and facial tightening. 37 female patients were treated for wrinkles, laxity and circumference reduction on different facial and body areas. Facial results were objectively analyzed with the Primos 3D imaging system. Body results were evaluated using photographs and circumferential measurements. Five volunteer patients underwent blood tests to assess changes in liver function and lipid profile following treatment. Significant reductions in body circumferences were measured. The average circumference reduction in main body areas (abdomen, buttocks, thighs), was 3.6 +/- 2.4 cm with a maximum reduction of up to 10.5 cm in the abdomen. An improvement of perioral and periorbital wrinkles was achieved and analyzed. No significant changes were found in any of the liver function and lipid profile indicators. Findings confirm safety and efficacy of the new treatment modality for localized fat reduction and for body and face contouring.