Far Infrared Radiation Therapy for Gynecological Cancer-Related Lymphedema Is an Effective and Oncologically Safe Treatment: A Randomized-Controlled Trial.

Background: Gynecological cancer-related lymphedema (GCRL) is a devastating condition that adversely influences function, health, and quality of life. We conducted a randomized-controlled clinical study as well as in vitro experiments to investigate the efficacy and safety of far infrared radiation (FIR) to treat lymphedema in patients having previously undergone surgery for gynecological tumors. Materials and Methods: Seventy-four women with GCRL, cancer free for 5 years or more, were randomly allocated into two treatment groups: standard of care with bandage treatment and treatment with FIR plus bandage. Variations of fluid, circumference of lymphedematous limbs, serum tumor markers (cancer antigen 125 [CA125]), inguinal-pelvic lymph nodes, vagina, lungs, and adverse reactions were assessed after 1 year. In vitro experiments examined the effects on cell viability, proliferation, apoptosis, and the cell cycle of fibroblast, A2780, SKOV-3, HELA, and Ishikawa cells. Results: The FIR+bandage group showed significantly decreased tissue fluid and reduced limb circumference (p < 0.05) in comparison with the control group at 1 year. There was no increase of serum CA125 in both groups, and no recurrence of neoplasia or lymphadenopathy was detected. No adverse reactions were recorded. In addition, no changes were detected after FIR treatment for fibroblast, A2780, SKOV-3, HELA, and Ishikawa cells in cell viability, proliferation, apoptosis, and cell cycle. Conclusion: FIR can be used to treat patients with GCRL following gynecological cancer treatment. Following clinical and experimental studies, we confirm that FIR is an oncologically safe treatment for lymphedema in gynecological tumor patients.

Treatment of hypertrophic scars and keloids using an intralesional 1470 nm bare-fibre diode laser: a novel efficient minimally-invasive technique.

Hypertrophic and keloid scars result from abnormal wound healing and can have a variable response to a number of available treatment modalities. The evolution of laser treatments in recent years has shown a wide range of clinical applications including their use in the treatment of scars. We investigated the effectiveness of a 1470 nm diode laser using an intralesional optical fibre delivery device in the treatment of hypertrophic and keloid scars. We evaluated its safety and efficacy as a novel and minimally invasive treatment alternative for scar modulation and volume reduction. A prospective cohort study was performed involving 21 patients with hypertrophic scars (HS) (n = 9) and keloids (n = 12) resulting from various aetiology. Patients were treated with one to three treatment sessions. Comprehensive evaluations were performed using the Vancouver Scar Scale, Doppler ultrasound, Cutometer, Mexameter and PeriCam PSI. Scar thickness was reduced by an average of 0.308 ± 0.138 cm (p < 0.001). In particular the two subgroups showed a significant 27.7% and 28.2% reduction in scar thickness of HS and Keloids, respectively. Scar firmness showed a significant improvement of 1.2% (p < 0.05) for HS, though for keloids this was 0.4% (p = 0.26). Keloids had a significant reduction in pigmentation at 21.3%. Blood perfusion had a significant reduction of 29.6% in HS and 22.7% in Keloids. Overall VSS total score improvement of 42% in the HS and at 37.9% in the Keloid subgroup. No adverse events such as hypo/hyperpigmentation, skin infection, or recurrence were reported. This study shows that the intralesional 1470 nm bare-fibre diode laser significantly improved hypertrophic and keloid scars based on both subjective and objective analyses and supports this type of laser therapy as a safe and effective minimally-invasive treatment option.

Use of the Keystone Perforator Island Flap in the treatment of chronic lower extremity wounds complicated by osteomyelitis.

INTRODUCTION: Reconstruction of chronic lower extremity wounds can be especially challenging when these wounds are complicated by osteomyelitis. They require the joint expertise of plastic and orthopaedic surgeons. METHODS: We report our experience using the Keystone Perforator Island Flap following wound and bone debridement as a valuable surgical tool for coverage of complex wounds with bone infection. RESULTS: Twelve patients underwent similar procedures with overall good outcomes, although two patients experienced a complication, specifically partial flap necrosis and wound dehiscence subsequent to recurrent osteomyelitis. We also reviewed the underlying physiological mechanisms of employing the Keystone flap in order to demonstrate its advantages and efficacy. CONCLUSION: Our results confirm that the Keystone flap can be a safe, reliable and effective method for coverage of soft tissue defects and the preservation of bone integrity in the management of patients with chronic osteomyelitis.

The 1470 nm diode laser with an intralesional fiber device: a proposed solution for the treatment of inflamed and infected keloids.

BACKGROUND: Keloids are the result of abnormal wound healing and often are subject to infections and recurrent inflammation. We present a study conducted with a 1470 nm diode laser using an intralesional optical fiber device for the treatment of inflamed keloid scars. We evaluate its efficacy as a novel alternative method to decrease keloid infection and inflammation. METHODS: The patients who underwent 1470 nm laser treatment from February 2016 to February 2018 at the plastic and reconstructive surgery department of the Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University with keloid accompanying serious local infection and fester were included. Patients took curative effect evaluation before and 1 year after the treatment. The test items included infection frequency in each year; pain, by visual analogue scale (VAS); itch, using VAS; quality of life (QOL), using QOL scale; and blood supply, using PeriCam PSI. RESULTS: A total of 19 patients (mean age 35.21 years, range 11-66) with history of inflamed keloids with episodes of infection or abscess were enrolled. Patients underwent to a 1470 nm laser therapy for average of 1.16 times. After treatment, infection frequency and blood supply in keloids were reduced (p < 0.001). Pain, itching, and QOL were improved (p < 0.001). CONCLUSION: The present study shows that 1470 nm fiber laser treatment could improve inflamed keloids fairly well by decreasing inflammation, and a relative stabilization of collagen composition. Therefore, it is an effective minimally invasive scar therapy, but further studies are essential to confirm the present results.

Sandro Botticelli's Madonna of the Pomegranate: the hidden cardiac anatomy.

Sandro Botticelli was one of the most renowned artists of the 15th century. He was based in Florence during the flourishing of the Renaissance, a time when anatomical knowledge of ancient times was reclaimed through cadaveric dissection. This report proposes that such knowledge enabled Botticelli to enhance the iconography of his masterpieces, Madonna of the Pomegranate, by incorporating a concealed image of the heart and cardiac anatomy within it.

Reliable scar scoring system to assess photographs of burn patients.

BACKGROUND: Several scar-scoring scales exist to clinically monitor burn scar development and maturation. Although scoring scars through direct clinical examination is ideal, scars must sometimes be scored from photographs. No scar scale currently exists for the latter purpose. MATERIALS AND METHODS: We modified a previously described scar scale (Yeong et al., J Burn Care Rehabil 1997) and tested the reliability of this new scale in assessing burn scars from photographs. The new scale consisted of three parameters as follows: scar height, surface appearance, and color mismatch. Each parameter was assigned a score of 1 (best) to 4 (worst), generating a total score of 3-12. Five physicians with burns training scored 120 representative photographs using the original and modified scales. Reliability was analyzed using coefficient of agreement, Cronbach alpha, intraclass correlation coefficient, variance, and coefficient of variance. Analysis of variance was performed using the Kruskal-Wallis test. Color mismatch and scar height scores were validated by analyzing actual height and color differences. RESULTS: The intraclass correlation coefficient, the coefficient of agreement, and Cronbach alpha were higher for the modified scale than those of the original scale. The original scale produced more variance than that in the modified scale. Subanalysis demonstrated that, for all categories, the modified scale had greater correlation and reliability than the original scale. The correlation between color mismatch scores and actual color differences was 0.84 and between scar height scores and actual height was 0.81. CONCLUSIONS: The modified scar scale is a simple, reliable, and useful scale for evaluating photographs of burn patients.

Hepatic apoptosis postburn is mediated by c-Jun N-terminal kinase 2.

The trauma of a severe burn injury induces a hypermetabolic response that increases morbidity and mortality. Previously, our group showed that insulin resistance after burn injury is associated with endoplasmic reticulum (ER) stress. Evidence suggests that c-Jun N-terminal kinase (JNK) 2 may be involved in ER stress-induced apoptosis. Here, we hypothesized that JNK2 contributes to the apoptotic response after burn injury downstream of ER stress. To test this, we compared JNK2 knockout mice (-/-) with wild-type mice after inducing a 30% total body surface area thermal injury. Animals were killed after 1, 3, and 5 days. Inflammatory cytokines in the blood were measured by multiplex analysis. Hepatic ER stress and insulin signaling were assessed by Western blotting, and insulin resistance was measured by a peritoneal glucose tolerance test. Apoptosis in the liver was quantified by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. Liver function was quantified by aspartate aminotransferase and alanine aminotransferase activity assays. Endoplasmic reticulum stress increased after burn in both JNK2 and wild-type mice, indicating that JNK2 activation is downstream of ER stress. Knockout of JNK2 did not affect serum inflammatory cytokines; however, the increase in interleukin 6 mRNA expression was prevented in the knockouts. Serum insulin did not significantly increase in the JNK2 group. On the other hand, insulin signaling (PI3K/Akt pathway) and glucose tolerance tests did not improve in JNK2. As expected, apoptosis in the liver increased after burn injury in wild-type mice but not in JNK2. Aspartate aminotransferase/alanine aminotransferase activity revealed that liver function recovered more quickly in JNK2. This study indicates that JNK2 is a central mediator of hepatic apoptosis after a severe burn.

Effects of propranolol and exercise training in children with severe burns.

OBJECTIVES: To investigate whether propranolol administration blocks the benefits induced by exercise training in severely burned children. STUDY DESIGN: Children aged 7-18 years (n = 58) with burns covering ≥30% of the total body surface area were enrolled in this randomized trial during their acute hospital admission. Twenty-seven patients were randomized to receive propranolol, whereas 31 served as untreated controls. Both groups participated in 12 weeks of in-hospital resistance and aerobic exercise training. Muscle strength, lean body mass, and peak oxygen consumption (VO2 peak) were measured before and after exercise training. Paired and unpaired Student t tests were used for within and between group comparisons, and χ(2) tests for nominal data. RESULTS: Age, length of hospitalization, and total body surface area burned were similar between groups. In both groups, muscle strength, lean body mass, and VO2 peak were significantly greater after exercise training than at baseline. The percent change in VO2 peak was significantly greater in the propranolol group than in the control group (P < .05). CONCLUSIONS: Exercise-induced enhancements in muscle mass, strength, and VO2 peak are not impaired by propranolol. Moreover, propranolol improves the aerobic response to exercise in massively burned children.

The effect of ketoconazole on post-burn inflammation, hypermetabolism and clinical outcomes.

BACKGROUND: Hypercortisolemia has been suggested as a primary hormonal mediator of whole-body catabolism following severe burn injury. Ketoconazole, an anti-fungal agent, inhibits cortisol synthesis. We, therefore, studied the effect of ketoconazole on post-burn cortisol levels and the hyper-catabolic response in a prospective randomized trial (block randomization 2:1). METHODOLOGY/PRINCIPAL FINDINGS: Fifty-five severely burned pediatric patients with >30% total body surface area (TBSA) burns were enrolled in this trial. Patients were randomized to receive standard care plus either placebo (controls, n = 38) or ketoconazole (n = 23). Demographics, clinical data, serum hormone levels, serum cytokine expression profiles, organ function, hypermetabolism measures, muscle protein synthesis, incidence of wound infection sepsis, and body composition were obtained throughout the acute hospital course. Statistical analysis was performed using Fisher's exact test, Student's t-test, and parametric and non-parametric two-way repeated measures analysis of variance where applicable. Patients were similar in demographics, age, and TBSA burned. Ketoconazole effectively blocked cortisol production, as indicated by normalization of the 8-fold elevation in urine cortisol levels [F(1, 376) = 85.34, p<.001] with the initiation of treatment. However, there were no significant differences in the inflammatory response, acute-phase proteins, body composition, muscle protein breakdown or synthesis, or organ function between groups. CONCLUSIONS: Both groups were markedly hypermetabolic and catabolic throughout the acute hospital stay. Normalization of hypercortisolemia with ketoconazole therapy had no effect on whole-body catabolism or the post-burn inflammatory or hypermetabolic response, suggesting that hypercortisolemia does not play a central role in the post-burn hypermetabolic catabolic response. TRIAL REGISTRATION: ClinicalTrials.gov NCT00675714; and NCT00673309.

Burn size and survival probability in paediatric patients in modern burn care: a prospective observational cohort study.

BACKGROUND: Patient survival after severe burn injury is largely determined by burn size. Modern developments in burn care have greatly improved survival and outcomes. However, no large analysis of outcomes in paediatric burn patients with present treatment regimens exists. This study was designed to identify the burn size associated with significant increases in morbidity and mortality in paediatric patients. METHODS: We undertook a single-centre prospective observational cohort study using clinical data for paediatric patients with burns of at least 30% of their total body surface area (TBSA). Patients were stratified by burn size in 10% increments, ranging from 30% to 100% TBSA, with a secondary assignment made according to the outcome of a receiver operating characteristic (ROC) analysis. Statistical analysis was done with Student's t test, χ(2) test, logistic regression, and ROC analysis, as appropriate, with significance set at p<0·05. FINDINGS: 952 severely burned paediatric patients were admitted to the centre between 1998 and 2008. All groups were comparable in age (mean 7·3 [SD 5·3] years, ranging from 6·1 [5·1] years in the 30-39% TBSA group to 9·6 [5·4] years in the 90-100% TBSA group) and sex distribution (628 [66%] boys, ranging from 59% [73/123] in the 60-69% TBSA group to 82% [42/51] in the 90-100% TBSA group). 123 (13%) patients died (increasing from 3% [five of 180] in the 30-39% TBSA group to 55% [28/51] in the 90-100% TBSA group; p<0·0001), 154 (16%) developed multiorgan failure (increasing from 6% [ten] in the 30-39% TBSA group to 45% [23] in the 90-100% TBSA group; p<0·0001), and 89 (9%) had sepsis (increasing from 2% [three] in the 30-39% TBSA group to 26% [13] in the 90-100% TBSA group; p<0·0001). Burn size of 62% TBSA was a crucial threshold for mortality (odds ratio 10·07, 95% CI 5·56-18·22, p<0·0001). INTERPRETATION: We established that, in a modern paediatric burn care setting, a burn size of roughly 60% TBSA is a crucial threshold for postburn morbidity and mortality. On the basis of these findings, we recommend that paediatric patients with greater than 60% TBSA burns be immediately transferred to a specialised burn centre. Furthermore, at the burn centre, patients should be treated with increased vigilance and improved therapies, in view of the increased risk of poor outcome associated with this burn size. FUNDING: Shriners Hospitals for Children, US National Institutes of Health, US National Institute on Disability and Rehabilitation Research, Institute for Translational Sciences, CFI Leaders Opportunity Fund, Physicians' Services Incorporated Foundation.

The use of exenatide in severely burned pediatric patients.

INTRODUCTION: Intensive insulin treatment (IIT) has been shown to improve outcomes post-burn in severely burnt patients. However, it increases the incidence of hypoglycemia and is associated with risks and complications. We hypothesized that exenatide would decrease plasma glucose levels post-burn to levels similar to those achieved with IIT, and reduce the amount of exogenous insulin administered. METHODS: This open-label study included 24 severely burned pediatric patients. Six were randomized to receive exenatide, and 18 received IIT during acute hospitalization (block randomization). Exenatide and insulin were administered to maintain glucose levels between 80 and 140 mg/dl. We determined 6 AM, daily average, maximum and minimum glucose levels. Variability was determined using mean amplitude of glucose excursions (MAGE) and percentage of coefficient of variability. The amount of administered insulin was compared in both groups. RESULTS: Glucose values and variability were similar in both groups: Daily average was 130 ± 28 mg/dl in the intervention group and 138 ± 25 mg/dl in the control group (P = 0.31), MAGE 41 ± 6 vs. 45 ± 12 (respectively). However, administered insulin was significantly lower in the exenatide group than in the IIT group: 22 ± 14 IU patients/day in the intervention group and 76 ± 11 IU patients/day in the control group (P = 0.01). The incidence rate of hypoglycemia was similar in both groups (0.38 events/patient-month). CONCLUSIONS: Patients receiving exenatide received significantly lower amounts of exogenous insulin to control plasma glucose levels. Exenatide was well tolerated and potentially represents a novel agent to attenuate hyperglycemia in the critical care setting. TRIAL REGISTRATION: NCT00673309.

Impact of anesthesia, analgesia, and euthanasia technique on the inflammatory cytokine profile in a rodent model of severe burn injury.

Anesthetics used in burn and trauma animal models may be influencing results by modulating inflammatory and acute-phase responses. Accordingly, we determined the effects of various anesthetics, analgesia, and euthanasia techniques in a rodent burn model. Isoflurane (ISO), ketamine-xylazine (KX), or pentobarbital (PEN) with or without buprenorphine were administered before scald-burn in 72 rats that were euthanized without anesthesia by decapitation after 24 h and compared with unburned shams. In a second experiment, 120 rats underwent the same scald-burn injury using KX, and 24 h later were euthanized under anesthesia or carbon dioxide (CO2). In addition, we compared euthanasia by exsanguination with that of decapitation. Serum cytokine levels were determined by an enzyme-linked immunosorbent assay. In the first experiment, ISO was associated with elevation of cytokine-induced neutrophil chemoattractant 2 (CINC-2) and monocyte chemotactic protein 1 (MCP-1), and KX and PEN was associated with elevation of CINC-1,CINC-2, IL-6, and MCP-1. Pentobarbital also decreased IL-1". IL-6 increased significantly when ISO or PEN were combined with buprenorphine. In the second experiment, euthanasia performed by exsanguination under ISO was associated with reduced levels of IL-1", CINC-1, CINC-2, and MCP-1, whereas KX reduced CINC-2 and increased IL-6 levels. Meanwhile, PEN reduced levels of IL-1" and MCP-1, and CO2 reduced CINC-2 and MCP-1. In addition,decapitation after KX, PEN, or CO2 decreased IL-1" and MCP-1, although we found no significant difference between ISO and controls. Euthanasia by exsanguination compared with decapitation using the same agent also led to modulation of several cytokines. Differential expression of inflammatory markers with the use of anesthetics and analgesics should be considered when designing animal studies and interpreting results because these seem to have a significant modulating impact. Our findings indicate that brief anesthesia with ISO immediately before euthanasia by decapitation exerted the least dampening effect on the cytokines measured. Conversely, KX with buprenorphine may offer a better balance during longer procedures to avoid significant modulation. Standardization across all experiments that are compared and awareness of these findings are essential for those investigating the pathophysiology of inflammation in animal models.

Effects of exercise training on resting energy expenditure and lean mass during pediatric burn rehabilitation.

Severe burns cause profound hormonal and metabolic disturbances resulting in hypermetabolism, reflected in extreme elevation of resting energy expenditure (REE) and extensive skeletal muscle catabolism. Aerobic and resistive exercise programs during rehabilitation have shown substantial benefits, although whether such training potentially exacerbates basal metabolism is unknown. Therefore, the effects of exercise training on REE during the rehabilitation of severely burned pediatric patients were examined. Children with 40% total body surface area burns and greater were enrolled at admission to the burn intensive care unit to participate in a 12-week, hospital-based exercise program (EX) or a home-based standard of care program (SOC), commencing 6 months after injury. Twenty-one patients (aged 7-17 years) were enrolled and randomized to SOC (n = 10) or EX (n = 11). Age, sex, and total body surface area burned were similar. Mean change (+/-standard deviation) in REE, normalized to individual lean body mass, was almost negligible between SOC and EX group patients (SOC, 0.03 +/- 17.40% vs EX, 0.01 +/- 26.38%). A significant increase in lean body mass was found for EX patients (SOC, 2.06 +/- 3.17% vs EX, 8.75 +/- 5.65%; P = .004), which persisted when normalized to height (SOC, 0.70 +/- 2.39% vs EX, 6.14 +/- 6.46%; P = .02). Peak torque also improved significantly more in EX patients (SOC, 12.29 +/- 16.49% vs EX, 54.31 +/- 44.25%; P = .02), reflecting improved strength. Exercise training significantly enhanced lean mass and strength, without observed exacerbation of postburn hypermetabolism. Therefore, the use of exercise conditioning as a safe and effective component of pediatric burn rehabilitation is advocated.

The role of hyperglycemia in burned patients: evidence-based studies.

Severely burned patients typically experience a systemic response expressed as increased metabolism, inflammation, alteration of cardiac and immune function, and associated hyperglycemia. Hyperglycemia has been associated with an increased risk of morbidity and mortality in critically ill patients. Until recently and for many years, hyperglycemia has been expectantly managed and considered a normal and desired response of an organism to stress. However, findings reported from recent studies now suggest beneficial effects of intensive insulin treatment of critically ill patients. The literature on the management of hyperglycemia in severely burned patients is sparse, with most of the available studies involving only small numbers of burned patients. The purpose of this article is to describe the pathophysiology of hyperglycemia after severe burns and to review the available literature on the outcome of intensive insulin treatment and other anti-hyperglycemic modalities in burned patients in an evidence-based medical approach.

Emerging infections in burns.

BACKGROUND: Patients who suffer severe burns are at higher risk for local and systemic infections. In recent years, emerging resistant pathogens have forced burn care providers world wide to search for alternative forms of treatment. Multidrug-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter spp., and various fungal strains have been the major contributors to the increase in morbidity and mortality rates. Multi-drug-resistant S. aureus remains the major cause of gram-positive burn wound infections world wide. Treatment strategies include rigorous isolation protocols and new types of antibiotics where necessary. METHODS: We reviewed 398 severely burned patients (burns >40% total body surface area [TBSA]) admitted to our hospital between 2000 and 2006. Patients who did not contract multi-drug-resistant gram-negative organisms during their hospital course and received our standard antibiotic regimen-vancomycin and piperacillin/tazobactam-served as controls (piperacillin/tazobactam; n = 280). The treatment group consisted of patients who, during their acute hospital stay, developed infections with multi-drug-resistant gram-negative pathogens and were treated with vancomycin and colistin for at least three days (colistin; n = 118). RESULTS: Gram-negative organisms continue to cause the most severe infections in burn patients. Colistin has re-emerged as a highly effective antibiotic against multiresistant Pseudomonas and Acinetobacter infections of burns. Patients who required colistin therapy had a significantly larger average total and full-thickness burn than patients treated with piperacillin/tazobactam and vancomycin, and the mortality rate was significantly higher in the colistin group (p < 0.05). However, there was no significant difference between the colistin and piperacillin/tazobactam groups in the incidence of neurotoxicity, hepatic toxicity, or nephrotoxicity. The main fungal pathogens in burn patients are Candida spp., Aspergillus spp., and Fusarium spp. A definitive diagnosis is more difficult to obtain than in bacterial infections. Amphotericin B and voriconazole remain the two most important anti-fungal substances in our practice. CONCLUSIONS: Innovations in fluid management, ventilatory support, surgical care, and antimicrobial therapy have contributed to a significant reduction in morbidity and mortality rates in burn patients. Vancomycin and clindamycin are the two most important reserve antibiotics for methicillin-resistant Staphylococcus aureus infection. Oxazolidinones and streptogramins have showed high effectiveness against gram-positive infections. Colistin has re-emerged as a highly effective antibiotic against multiresistant Pseudomonas and Acinetobacter infections. Current challenges include Candida, Aspergillus, and molds. The development of new agents, prudent and appropriate use of antibiotics, and better infection control protocols are paramount in the ongoing battle against multi-resistant organisms.