Concurrent or sequential adjuvant letrozole and radiotherapy after conservative surgery for early-stage breast cancer (CO-HO-RT): a phase 2 randomised trial.

BACKGROUND: Letrozole radiosensitises breast cancer cells in vitro. In clinical settings, no data exist for the combination of letrozole and radiotherapy. We assessed concurrent and sequential radiotherapy and letrozole in the adjuvant setting. METHODS: This phase 2 randomised trial was undertaken in two centres in France and one in Switzerland between Jan 12, 2005, and Feb 21, 2007. 150 postmenopausal women with early-stage breast cancer were randomly assigned after conserving surgery to either concurrent radiotherapy and letrozole (n=75) or sequential radiotherapy and letrozole (n=75). Randomisation was open label with a minimisation technique, stratified by investigational centres, chemotherapy (yes vs no), radiation boost (yes vs no), and value of radiation-induced lymphocyte apoptosis (< or = 16% vs >16%). Whole breast was irradiated to a total dose of 50 Gy in 25 fractions over 5 weeks. In the case of supraclavicular and internal mammary node irradiation, the dose was 44-50 Gy. Letrozole was administered orally once daily at a dose of 2.5 mg for 5 years (beginning 3 weeks pre-radiotherapy in the concomitant group, and 3 weeks post-radiotherapy in the sequential group). The primary endpoint was the occurrence of acute (during and within 6 weeks of radiotherapy) and late (within 2 years) radiation-induced grade 2 or worse toxic effects of the skin. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00208273. FINDINGS: All patients were analysed apart from one in the concurrent group who withdrew consent before any treatment. During radiotherapy and within the first 12 weeks after radiotherapy, 31 patients in the concurrent group and 31 in the sequential group had any grade 2 or worse skin-related toxicity. The most common skin-related adverse event was dermatitis: four patients in the concurrent group and six in the sequential group had grade 3 acute skin dermatitis during radiotherapy. At a median follow-up of 26 months (range 3-40), two patients in each group had grade 2 or worse late effects (both radiation-induced subcutaneous fibrosis). INTERPRETATION: Letrozole can be safely delivered shortly after surgery and concomitantly with radiotherapy. Long-term follow-up is needed to investigate cardiac side-effects and cancer-specific outcomes. FUNDING: Novartis Oncology France.

Concurrent or Sequential Adjuvant Letrozole and Radiotherapy after Conservative Surgery for Early-stage Breast Cancer: Long-term Results of the Cohort Phase 2 Randomized Trial

Purpose/Objective(s): Letrozole radiosensitizes breast cancer cells in vitro. In clinical settings, no data exist for the combination of letrozole and radiotherapy. We assessed concurrent and sequential radiotherapy and letrozole in the adjuvant setting.Materials/Methods: The present study is registered with ClinicalTrials.gov, number NCT00208273. This Phase 2 randomized trial was undertaken in two centers in France and one in Switzerland between January 12, 2005, and February 21, 2007. One hundred fifty postmenopausal women with early-stage breast cancer were randomly assigned after conserving surgery to either concurrent radiotherapy and letrozole (n = 75) or sequential radiotherapy and letrozole (n = 75). Randomization was open label with a minimization technique, stratified by investigational centers, chemotherapy (yes vs. no), radiation boost (yes vs. no), and value of radiation-induced lymphocyte apoptosis (#16% vs. .16%). The whole breast was irradiated to a total dose of 50 Gy in 25 fractions over 5 weeks. In the case of supraclavicular and internal mammary node irradiation, the dose was 44 - 50 Gy. Letrozole was administered orally once daily at a dose of 2 - 5 mg for 5 years (beginning 3 weeks pre-radiotherapy in the concomitant group, and 3 weeks postradiotherapy in the sequential group). The primary endpoint was the occurrence of acute (during and within 6 weeks of radiotherapy) and late (within 2 years) radiation-induced Grade 2 or worse toxic effects of the skin and lung (functional pulmonary test and lung CT-scan). Analyses were by intention-to-treat. The long-term follow-up after 2 years was only performed in Montpellier (n = 121) and evaluated skin toxicity (clinical examination every 6 months), lung fibrosis (one CT-scan yearly), cosmetic outcome.Results: All patients were analyzed apart from 1 in the concurrent group who withdrew consent before any treatment.Within the first 2 years (n = 149), no lung toxicity was identified by CT scan and no modification from baseline was noted by the lung diffusion capacity test. Two patients in each group had Grade 2 or worse late effects (both radiation-induced subcutaneous fibrosis [RISF]). After 2 years (n = 121), and with a median follow-up of 50 months (38-62), 2 patients (1 in each arm) presented a Grade 3 RISF. No lung toxicity was identified by CT scan. Cosmetic results (photographies) and quality of life was good to excellent. All patients who had Grade 3 subcutaneous fibrosis had an RILA value of 16% or less, irrespective of the sequence with letrozole.Conclusions:With long-term follow-up, letrozole can be safely delivered shortly after surgery and concomitantly with radiotherapy.

Plastic surgery in chest wall reconstruction: relevant aspects - case series

Objective: to discuss the participation of Plastic Surgery in the reconstruction of the chest wall, highlighting relevant aspects of interdisciplinaryness. Methods: we analyzed charts from 20 patients who underwent extensive resection of the thoracic integument, between 2000 and 2014, recording the indication of resection, the extent and depth of the raw areas, types of reconstructions performed and complications. Results: among the 20 patients, averaging 55 years old, five were males and 15 females. They resections were: one squamous cell carcinoma, two basal cell carcinomas, five chondrosarcomas and 12 breast tumors. The extent of the bloody areas ranged from 4x9 cm to 25x40 cm. In 12 patients the resection included the muscular plane. In the remaining eight, the tumor removal achieved a total wall thickness. For reconstruction we used: one muscular flap associated with skin grafting, nine flaps and ten regional fasciocutaneous flaps. Two patients undergoing reconstruction with fasciocutaneous flaps had partially suffering of the flap, solved with employment of a myocutaneous flap. The other patients displayed no complications with the techniques used, requiring only one surgery. Conclusion: the proper assessment of local tissues and flaps available for reconstruction, in addition to the successful integration of Plastic Surgery with the specialties involved in the treatment, enable extensive resections of the chest wall and reconstructions that provide patient recovery.

Bariatric and Post-Bariatric Surgery: from Metabolic Surgery to Plastic Surgery Indications

Background: Controversy exists concerning indications and outcomes of major bariatric surgery procedures. Massive weight loss after bariatric surgery leads to excess skin with functional and aesthetic impairments. The aim of this study was to investigate the major bariatric surgery procedures and their outcomes in two specific subgroups of morbidly obese patients, ≥55-year-olds and the superobese. Further aims were to evaluate whether the preoperative weight loss correlates with laparoscopic gastric bypass complications. The prevalence and impact of excess skin and the desire for body contouring after bariatric surgery were also studied. Patients and Methods: Data from patients who underwent Laparoscopic Adjustable Gastric Banding (LAGB) and Laparoscopic Roux-en-Y Gastric Bypass (LRYGB) at Vaasa Central Hospital were collected and postoperative outcomes were evaluated according to the BMI, age and preoperative weight loss. Patients who had undergone bariatric surgery procedures were asked to complete a questionnaire to estimate any impairment due to redundant skin and to analyse each patient’s desire for body contouring by area. Results: No significant difference was found in operative time, hospital stay, or overall early postoperative morbidity between LAGB and LRYGB. Mean excess weight loss percents (EWL%) at 6 and 12 months after LRYGB were significantly higher. A significant difference was found in operative time favouring patients <55 years. Intraoperative complications were significantly more frequent in the group aged >55 years. No significant difference was detected in overall postoperative morbidity rates. A significant difference was found in operative time and hospital stay favouring all patients who lost weight preoperatively. Most patients reported problems with redundant skin, especially on the abdomen, upper arms and rear/buttocks, which impaired daily physical activity in half of them. Excess skin was significantly associated with female gender, weight loss and ΔBMI. Patients with a WL >20 kg, ΔBMI ≥10 kg/m2 and an EWL % > 50 showed a significantly surplus skin discomfort (p < 0.001). Most patients desired body contouring surgery, with high or very high desire for waist/abdomen (62.2%), upper arm (37.6%), chest/breast (28.3%), and rear/buttock (35.6%) contouring. Conclusions: LRYGB is effective and safe in superobese (BMI >50) and elderly (>55 years) patients. A preoperative weight loss >5% is recommended to improve the outcomes and reduce complications. A WL >20 kg, ΔBMI ≥10 kg/m2 and an EWL % > 50 are associated with a higher functional discomfort due to redundant skin and to a stronger desire for body contouring plastic surgery.

Normal skin and hypertrophic scar fibroblasts differentially regulate collagen and fibronectin expression as well as mitochondrial membrane potential in response to basic fibroblast growth factor

Basic fibroblast growth factor (bFGF) regulates skin wound healing; however, the underlying mechanism remains to be defined. In the present study, we determined the effects of bFGF on the regulation of cell growth as well as collagen and fibronectin expression in fibroblasts from normal human skin and from hypertrophic scars. We then explored the involvement of mitochondria in mediating bFGF-inducedeffects on the fibroblasts. We isolated and cultivated normal and hypertrophic scar fibroblasts from tissue biopsies of patients who underwent plastic surgery for repairing hypertrophic scars. The fibroblasts were then treated with different concentrations of bFGF (ranging from 0.1 to 1000 ng/mL). The growth of hypertrophic scar fibroblasts became slower with selective inhibition of type I collagen production after exposure to bFGF. However, type III collagen expression was affected in both normal and hypertrophic scar fibroblasts. Moreover, fibronectin expression in the normal fibroblasts was up-regulated after bFGF treatment. bFGF (1000 ng/mL) also induced mitochondrial depolarization in hypertrophic scar fibroblasts (P < 0.01). The cellular ATP level decreased in hypertrophic scar fibroblasts (P < 0.05), while it increased in the normal fibroblasts following treatment with bFGF (P < 0.01). These data suggest that bFGF has differential effects and mechanisms on fibroblasts of the normal skin and hypertrophic scars, indicating that bFGF may play a role in the early phase of skin wound healing and post-burn scar formation.

Understanding post-operative temperature drop in cardiac surgery: a mathematical model

A mathematical model is presented to understand heat transfer processes during the cooling and re-warming of patients during cardiac surgery. Our compartmental model is able to account for many of the qualitative features observed in the cooling of various regions of the body including the central core containing the majority of organs, the rectal region containing the intestines and the outer peripheral region of skin and muscle. In particular, we focus on the issue of afterdrop: a drop in core temperature following patient re-warming, which can lead to serious post-operative complications. Model results for a typical cooling and re-warming procedure during surgery are in qualitative agreement with experimental data in producing the afterdrop effect and the observed dynamical variation in temperature between the core, rectal and peripheral regions. The influence of heat transfer processes and the volume of each compartmental region on the afterdrop effect is discussed. We find that excess fat on the peripheral and rectal regions leads to an increase in the afterdrop effect. Our model predicts that, by allowing constant re-warming after the core temperature has been raised, the afterdrop effect will be reduced.

Outcome Analysis of Immediate and Delayed Conservative Breast Surgery Reconstruction With Mastopexy and Reduction Mammaplasty Techniques

Background: Bilateral mammaplasty or mastopexy is frequently used for oncoplastic objectives. However, little information has been available regarding outcome following immediate and delayed reconstruction. Method: Patients were divided into Group I (immediate reconstruction) and Group II (delayed reconstruction). Retrospective review was performed to compare complications, length of hospital stay, revision surgeries, and satisfaction. The associations between the complications with potential risk factors (timing, age, body mass index, smoking, and comorbid medical conditions) were analyzed. Results: There were a total of 144 patients with a mean follow-up of 47 months. Of the 106 patients in Group I, complications occurred in 24 (22.6%), skin necrosis was observed in 7.5%, fat necrosis in 5.6%, and 6.6% patients developed local recurrence. Mean period of hospitalization was 1.89 days. Of the 38 patients of the Group II, complications occurred in 12 (31.5%), skin necrosis was observed in 7 (18.4%), fat necrosis in 4 (10.5%), and 5.2% patients developed local recurrence. Mean period of hospitalization was 1.35 days. Increased length of hospital stay greater than 1 day (P < 0.001) and the number of revision surgeries (P = 0.043) were associated with the timing of the reconstruction. In univariate analysis, no difference between groups was found with respect to complication incidence (P = 0.275); however, after adjusting for other risk factors, the probability of complications tend to be higher for Group II (OR = 2.65; 95% confidence interval - 1.01-7.00; P = 0.049). Conclusions: On the basis of the results of our study, the probability of complications tends to be higher for delayed reconstructions, and it is demonstrated that obesity and smoking are risk factors for complications. Ultimately, these data may facilitate the provision of individualized risk information for shared medical decision-making.

Immediate reconstruction following breast-conserving surgery: Management of the positive surgical margins and influence on secondary reconstruction

The efficacy of breast-conserving Surgery for the local control of early breast cancer has been repeatedly evidenced. Although immediate reconstruction following breast-conserving Surgery has been described, little information is available regarding surgical management in reoperative settings due to positive margins. We studied the influence of intraoperatively assessed and postoperatively controlled Surgical margin status on the type of breast-conserving Surgery and report our results regarding complications in a reoperative breast reconstruction scenario. All patients were seen by a multidisciplinary team who recommended breast-conserving surgery. According to the breast volume, ptosis and tumor size/location, the patients were also evaluated by a plastic Surgeon, who recommended reconstruction with the appropriate technique. Intraoperative assessment Of Surgical margins was determined by histological examination of frozen sections. The mean follow-up time was 48 months. Two hundred and eighteen patients (88.5%) underwent breast-conserving Surgery and immediate reconstruction. Twelve (5.5%) patients had a positive tumor margin after review of the permanent section. All patients underwent re-exploration. In 1.3%, a second reconstructive technique was indicated and in 2.2% a skin-sparing mastectomy with total reconstruction was performed. Our findings support the important role of the intraoperative assessment of surgical margins and its interference in the selection of reconstruction techniques and negative margins: however, it will not guarantee complete excision of the tumor. Success depends on coordinated planning with the oncologic Surgeon and careful intraoperative management, (C) 2008 Elsevier Ltd. All rights reserved.

Effect of a calcium-channel blocker (verapamil) on the morphology, cytoskeleton and collagenase activity of human skin fibroblasts

The effects of verapamil modulating collagen biosynthesis have prompted us to study the role of this drug in cultured fibroblasts. In this article, we describe the effects of verapamil on fibroblast behaviour, with special emphasis to phenotypic modifications, reorganisation of actin filaments and secretion of MMP1. Human dermal fibroblasts treated with 50-mu M verapamil changed their normal spindle-shaped morphology to stellate. Treated cells showed discrete reorganisation of actin filaments, as revealed by fluorescein isothiocyanate (FITC)-phalloidin staining and confocal microscopy. We hypothesised that these effects would be associated to lower levels of cytosolic Ca(2+). Indeed, short time loading with calcium green confirmed that verapamil-treated fibroblasts exhibited lower intracellular calcium levels compared to controls. We also observed that verapamil increases the secretion of MMP1 in cultured fibroblasts, as demonstrated by zymography, specific substrate assays and immunoblot. The morphological alterations induced by verapamil are neither cytotoxic nor associated with other dramatic cytoskeleton alterations. Thus we may conclude that this drug enhances collagenase secretion and does not disrupt the major tracks necessary to deliver these enzymes in the extracellular space. The present results suggested that verapamil could be used at physiological levels to enhance collagen I breakdown, and maybe considered a potential candidate for intralesional therapy of wound healing and fibrocontractive diseases. (C) 2010 Elsevier Ltd and ISBI. All rights reserved.

Preoperative warming combined with intraoperative skin-surface warming does not avoid hypothermia caused by spinal anesthesia in patients with midazolam premedication

CONTEXTO E OBJETIVO: Hipotermia inadvertida no perioperatório é freqüente durante anestesia subaracnóidea e após a administração de midazolam. O objetivo foi avaliar os efeitos do aquecimento da pele no intra-operatório, associado ou não ao aquecimento da pele durante o período de 45 minutos no pré-operatório, na prevenção de hipotermia intra- e pós-operatória determinada pela anestesia subaracnóidea em pacientes com medicação pré-anestésica com midazolam. TIPO DE ETUDO E LOCAL: Estudo prospectivo e aleatório, realizado no Hospital das Clínicas, Universidade Estadual Paulista (Unesp), Botucatu, SP. MÉTODOS: O estudo foi realizado em 30 pacientes com estado físico ASA (da Sociedade Norte-americana de Anestesiologistas) I e II submetidos à cirurgia eletiva do abdômen. Como medicação pré-anestésica, utilizou-se o midazolam, 7,5 mg via intramuscular (IM) e anestesia subaracnóidea padrão. em 10 pacientes (Gcontrole) utilizou-se isolamento térmico passivo; 10 pacientes (Gpré+intra) foram submetidos a aquecimento ativo no pré- e intra-operatório; e 10 pacientes (Gintra) foram aquecidos ativamente somente no intra-operatório. RESULTADOS: Após 45 minutos de aquecimento no pré-operatório, os pacientes do Gpré+intra apresentaram temperatura central mais elevada em relação aos dos grupos não aquecidos antes da anestesia (p < 0,05) mas não no início da cirurgia (p > 0,05). Os pacientes que receberam aquecimento no intra-operatório apresentaram temperatura central mais elevada no final da cirurgia em relação aos de Gcontrole (p < 0,05). Todos os pacientes estavam hipotérmicos na admissão da sala de recuperação pós-anestésica (temperatura central < 36º C). CONCLUSÕES: 45 minutos de aquecimento no pré-operatório combinado com aquecimento no intra- operatório não evita, mas minimiza a ocorrência de hipotermia determinada pela anestesia subaracnóidea em pacientes que receberam midazolam como medicação pré-anestésica.

Low-level laser therapy (670 nm) on viability of random skin flap in rats

This study investigated the effects of 670 nm laser, at different fluences, on the viability of skin flap in rats. One hundred male animals were used. The animals were divided into control group; group treated with 3 J/cm(2); group treated with 6 J/cm(2); group treated with 12 J/cm(2) and group treated with 24 J/cm(2). The skin flap was made on the backs of all animals studied, with a plastic sheet interposed between the flap and the donor site. Laser irradiation was done immediately after the surgery and on days 1, 2, 3 and 4 after surgery. The percentage of necrosis of the flap was calculated at the 7th postoperative day. Additionally, a sample of each flap was collected to enable us to count the blood vessels. Treated animals showed a statistically significant smaller area of necrosis than did the control group. The necrosis in the treated groups was 41.82% (group 2), 36.51% (group 3), 29.45% (group 4) and 20.37% (group 5). We also demonstrated that laser irradiation at 670 nm, at all doses used, had a stimulatory effect on angiogenesis. Our study showed that the 670 nm laser was efficient to increase the viability of the skin flap, at all fluences used, with a tendency of reaching better results at higher doses.

Clinical comparison between conventional suture and vaporization with carbon dioxide laser in rat's skin

Objective: This study compares wound healing efficiency on a rat's skin when the incision was closed with a conventional suture versus vaporized with a CO2 laser. Materials and Methods: In this study, 24 rats were used, and two longitudinal incisions were made with a conventional scalpel in the dorsum of each rat. The left incision was sutured with nylon thread, and the right incision was closed by vaporization with a defocused CO2 laser in continuous mode with an 8-watt power density. Clinical photographs were taken immediately after the procedure, 24 h later, and after 3, 7, 14, and 21 days, documenting the healing of the incision. Results: the results showed that there was an initial delay in wound repair in the vaporized incision as compared to the scalpel incision, but after 21 days, both incisions showed the same clinical characteristics. However, the vaporized incision showed no trauma of the tissue, as opposed to the sutured incision, and no hemorrhagic complications. Conclusion: These results suggest that the CO2 laser can eventually replace the use of sutures.

Magnesium sulphate given topically by iontophoresis for viability of random skin flaps in rats

Our aim was to assess the effects of magnesium sulphate given by iontophoresis on the viability of random skin flaps in rats. Endovenous magnesium sulphate is used to treat pre-eclampsia and diseases of blood vessels. Iontophoresis is an electrotherapeutic method which has shown satisfactory results in controlling ischaemia within the boundaries of the area in which it was given. Forty-five adult male Wistar rats, weighing 300 to 440 g were randomly divided into three groups of 15 animals each: random skin flap (control); random skin flap treated with magnesium sulphate without electrical stimulation; and random skin flap treated with magnesium sulphate with electrical stimulation of 4 mA for 20 minutes. The treatments were applied immediately after the operation and repeated on the following two days. The percentage of necrotic area was measured on the seventh postoperative day using a paper template. For each group, the mean percentage of flap necrosis was as follows: control, 46%; magnesium sulphate without electrical stimulation, 34%; and magnesium sulphate with electrical stimulation, 42%. There was no significant difference among the groups (p=0.18). Magnesium sulphate given by iontophoresis does not increase the viability of random skin flaps in rats.