Simvastatin downregulates adipogenesis in 3T3-L1 preadipocytes and orbital fibroblasts from Graves' ophthalmopathy patients.

BACKGROUND: Smoking is a strong risk factor for the development of Graves' ophthalmopathy (GO). Immediate early genes (IEGs) are overexpressed in patients with active GO compared to healthy controls. The aim of this study was to study the effects of tobacco smoking and simvastatin on preadipocytes and orbital fibroblasts (OFs) in the adipogenic process. METHODS: Cigarette smoke extract (CSE) was generated by a validated pump system. Mouse 3T3-L1 preadipocytes or OFs were exposed to 10% CSE with or without simvastatin. Gene expression was studied in preadipocytes and OFs exposed to CSE with or without simvastatin and compared to unexposed cells or cells treated with a differentiation cocktail. RESULTS: In 3T3-L1 preadipocytes, Cyr61, Ptgs2, Egr1 and Zfp36 expression levels were two-fold higher in cells exposed to CSE than in unexposed cells. Simvastatin downregulated the expression of these genes (1.6-fold, 5.5-fold, 3.3-fold, 1.4-fold, respectively). CSE alone could not stimulate preadipocytes to differentiate. Scd1, Ppar-γ and adipogenesis were downregulated in simvastatin-treated preadipocytes compared to nontreated preadipocytes 18-, 35- and 1.7-fold, respectively. In OFs, similar effects of CSE were seen on the expression of CYR61 (1.4-fold) and PTGS2 (3-fold). Simvastatin downregulated adipogenesis, PPAR-γ (2-fold) and SCD (27-fold) expression in OFs. CONCLUSION: CSE upregulated early adipogenic genes in both mouse 3T3-L1 preadipocytes and human OFs but did not by itself induce adipogenesis. Simvastatin inhibited the expression of both early and late adipogenic genes and adipogenesis in preadipocytes and human OFs. The effect of simvastatin should be investigated in a clinical trial of patients with GO.

Liposuction of Postmastectomy Arm Lymphedema Decreases the Incidence of Erysipelas.

The objective of this study was to assess erysipelas incidence before and after liposuction treatment for patients suffering from post-mastectomy lymphedema. A prospective cohort study of 130 patients at Skåne University Hospital in Malmö, Sweden with postmastectomy arm lymphedema, who had poor outcomes from prior conservative treatment and clinical signs of subcutaneous adipose tissue hypertrophy, underwent liposuction between 1993-2012. Pre- and postoperative incident data on erysipelas were available for all of them. Mean duration of lymphedema prior to liposuction was 8.8 years (range1-38, standard deviation (SD) 7.0 years). Mean age at liposuction was 63 years (range 39-89, SD 10 years). Total pre-liposuction observation years were 1147, and total post-liposuction observation years were 983. Erysipelas incidence dropped significantly (p<0.001) from 0.47 attacks/year (range 0-5.0, SD 0.8 attacks/year) to 0.06 attacks/year (range 0-3.0, SD 0.3 attacks/year) after liposuction, a reduction of 87%. Also, compared to 76 patients who experienced at least 1 erysipelas episode preoperatively, only 13 patients experienced erysipelas postoperatively. Of the 54 patients who did not have erysipelas preoperatively, 6 patients had erysipelas postoperatively. The total number of erysipelas attacks observed decreased from 534 to 60 bouts after liposuction. The excess arm volume of 1607 ml (range 570-3950, SD 707) was reduced to -43 ml (range -945 to 1390, SD 379) after 6 months and was maintained during the postoperative follow-up period of, at most, 18 years. Our data suggest that liposuction can significantly reduce incidence of erysipelas in patients with post mastectomy arm lymphedema who prior to the intervention suffered one or more attacks.

Proteomics of Orbital Tissue in Thyroid-Associated Orbitopathy.

CONTEXT: A potentially altered protein expression profile in orbital tissue from patients with thyroid-associated orbitopathy (TAO) is suspected. OBJECTIVE: To detect for the first time changes in proteomic patterns of orbital connective tissue in TAO and compare these with control tissue using mass spectrometry. DESIGN: Proteomics cross-sectional, comparative study. SETTING: Two academic endocrine institutions. SAMPLES: A total of 64 orbital and peripheral adipose tissue samples were collected from 39 patients with TAO and 25 control subjects. METHODS: Samples were analyzed and identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry technology. MAIN OUTCOME MEASURES: Mean intensity values of all identified peptides per protein. RESULTS: Thirty-one proteins were identified, of which 16 differentiated between controls and patients with TAO. Different protein patterns between orbital and peripheral adipose tissue were observed. Compared to controls, 10 proteins were markedly up-regulated (≥ 2-fold) in the orbital tissue of untreated patients: beta IV spectrin (6.2-fold), GTP binding G protein 2 (5.6-fold), POTE ankyrin domain family member F (5.4-fold), xylulokinase (4.1-fold), kinesin family member 1A and lipocalin 1 (both 3.6-fold), semicarbazide-sensitive metalloproteinase amine oxidase 3 and polymerase I transcript release factor (both 3.4-fold), cell-cycle protein elongin A binding protein 1 (3.3-fold), annexin A2 and cavin (both 3-fold), protein pointing to cell proliferation histone H4 (2.8-fold), and ADAM metallopeptidase with thrombospondin type 1 motif 14 (2.7-fold). The highest protein up-regulations were noted in the orbital tissue of medically untreated patients. Steroid therapy markedly reduced up-regulation of these proteins, foremost in nonsmokers. CONCLUSIONS: Proteins involved in tissue inflammation, adipose tissue differentiation, lipid metabolism, and tissue remodeling were up-regulated in orbital tissue of untreated patients with TAO. Steroids decreased the expression of these proteins, whereas smoking attenuated such effect.

Neuropeptide levels in Dercum's disease (adiposis dolorosa).

Dercum's disease (adiposis dolorosa) is characterised by adiposity and chronic pain in the adipose tissue. It has been proposed that conditions encompassing chronic pain have altered concentrations of neuropeptides involved in pain transmission. The aim of this investigation was to examine whether patients with Dercum's disease have abnormal concentrations of different neuropeptides. In cerebrospinal fluid (CSF) and in plasma (P) from 53 patients with Dercum's disease substance P-like immunoreactivity (SP-LI), neuropeptide Y-like immunoreactivity (NPY-LI), ß-endorphin-like immunoreactivity (ß-END-LI), calcitonin gene-related peptidelike immunoreactivity (CGRP-LI), met-enkephalin-like immunoreactivity (m-ENK-LI), vasoactive intestinal polypeptide-like immunoreactivity (VIP-LI), somatostatin (SOM-LI), γ2-melanocyte-stimulating hormone-like immunoreactivity (γ2-MSH-LI), and dynorphin-like immunoreactivity (DYN-LI) were measured. Three of the substances were also measured in a control group. The CSF concentration of SP was statistically significantly lower in the Dercum group than in the control group, whereas NPY-LI and b-END-LI were borderline statistically significantly lower and higher, respectively, in Dercum patients compared to controls. Compared with reference values, CSF-MSH-LI levels were slightly elevated and CSF-NPY-LI levels were slightly lowered in the Dercum group. The other substances in both CSF and plasma were within the reference values with a high degree of statistical significance. In conclusion, altered levels of neuropeptides that have previously been seen in different pain conditions cannot clearly be demonstrated in Dercum's disease.

Clinical trials needed to evaluate compression therapy in breast cancer related lymphedema (BCRL). Proposals from an expert group.

AIM: A mainstay of lymphedema management involves the use of compression therapy. Compression therapy application is variable at different levels of disease severity. Evidence is scant to direct clinicians in best practice regarding compression therapy use. Further, compression clinical trials are fragmented and poorly extrapolable to the greater population. An ideal construct for conducting clinical trials in regards to compression therapy will promote parallel global initiatives based on a standard research agenda. The purpose of this article is to review current evidence in practice regarding compression therapy for BCRL management and based on this evidence, offer an expert consensus recommendation for a research agenda and prescriptive trials. Recommendations herein focus solely on compression interventions. METHODS: This document represents the proceedings of a session organized by the International Compression Club (ICC) in June 2009 in Ponzano (Veneto, Italy). The purpose of the meeting was to enable a group of experts to discuss the existing evidence for compression treatment in breast cancer related lymphedema (BCRL) concentrating on areas where randomized controlled trials (RCTs) are lacking. RESULTS: The current body of research suggests efficacy of compression interventions in the treatment and management of lymphedema. However, studies to date have failed to adequately address various forms of compression therapy and their optimal application in BCRL. We offer recommendations for standardized compression research trials for prophylaxis of arm lymphedema and for the management of chronic BCRL. Suggestions are also made regarding; inclusion and exclusion criteria, measurement methodology and additional variables of interest for researchers to capture. CONCLUSION: This document should inform future research trials in compression therapy and serve as a guide to clinical researchers, industry researchers and lymphologists regarding the strengths, weaknesses and shortcomings of the current literature. By providing this construct for research trials, the authors aim to support evidence-based therapy interventions, promote a cohesive, standardized and informative body of literature to enhance clinical outcomes, improve the quality of future research trials, inform industry innovation and guide policy related to BCRL.

From lymph to fat: complete reduction of lymphoedema.

Liposuction for late-stage lymphoedema remains a controversial technique. While it is clear that conservative therapies such as combined decongestive therapy (CDT) and controlled compression therapy (CCT) should be tried in the first instance, options for the treatment of late-stage lymphoedema that is not responding to treatment is not so clear. Liposuction has been used for many years to treat lipodystrophy. Some results have been far from optimal; however, improvements in technique, patient preparation and patient follow-up have led to a greater and a wider acceptance of liposuction as a treatment for lymphoedema. This paper outlines the benefits of using liposuction and presents the evidence to support its use.

Circumferential suction-assisted lipectomy for lymphoedema after surgery for breast cancer.

BACKGROUND: The incidence of arm lymphoedema after treatment for breast cancer ranges from 1 to 49 per cent. Although most women can be treated by non-operative means with satisfying results, end-stage lymphoedema is often non-responsive to compression, where hypertrophy of adipose tissue limits the outcome value of compression or massage. METHODS: This was a prospective study of 37 women with unilateral non-pitting lymphoedema. After initial conservative treatment for 2-4 days, circumferential suction-assisted lipectomy was used to remove excess volume. Limb compression was resumed after surgery with short-stretch bandages, followed by flat-knit compression garments. RESULTS: The mean preoperative excess arm volume was 1399 ml. The total aspirate volume was 2124 ml with 93 per cent aspirate adipose tissue content. After 12 months, the mean reduction in excess volume was 118 per cent. The percentage reduction in excess volume after 12 months was linearly related to the preoperative excess volume but showed no linear relationship with the duration of lymphoedema or surgeon experience. CONCLUSION: Circumferential lipectomy combined with lifelong compression hose is an effective technique in end-stage lymphoedema after treatment for breast cancer.

Controlled compression and liposuction treatment for lower extremity lymphedema.

In 1987 we noticed excess adipose tissue in a patient with arm lymphedema and later, objective studies confirmed this clinical finding in patients with non-pitting arm lymphedema following breast cancer. A prospective study was begun in 1993, and its long-term results (15 years) shows overall complete reduction of the excess volume in patients with non-pitting arm lymphedema and that adipose tissue dominates the excess volume. Encouraged by these results we operated on a patient with primary and secondary elephantiasis of the leg. The edema was first transferred from a pitting to a non-pitting state by controlled compression therapy. Then liposuction was performed to remove the remaining excess adipose tissue, and complete reduction was finally achieved. The patient wears compression garments continuously and during the 11 years of followup, no recurrence has occurred. This paper explains our philosophical approach: a pitting lymphedema first should be treated conservatively to remove excess fluid, then liposuction can be performed to remove remaining excess volume bothersome to the patient.

Quality of life following liposuction and conservative treatment of arm lymphedema.

Arm lymphedema can produce an additional burden from a psychosocial point of view. Although edema reduction through treatment can be an advantage in terms of reduced weight of the arm and simplified clothing needs, the purpose of the present study was to register changes in psychosocial parameters during one year after treatment. Thirty-five patients underwent liposuction combined with postoperative CCT (Controlled Compression Therapy), while 14 received CCT alone. Edema volume and range of motion in the shoulder joint were measured and effects on quality of life were assessed with various questionnaires. Liposuction+CCT removed the arm lymphedema completely, whereas CCT alone reduced it by half. The treatments improved range of motion in the shoulder joint and patients' quality of life in relationship to the volume reduction. Liposuction+CCT improves patients' quality of life, particularly qualities related to the volume reduction and hence qualities associated with everyday activities. CCT is beneficial too, but the effect is less obvious than when combined with surgery, probably because the edema reduction is less. The consequences of arm lymphedema for more psychologically oriented qualities and social life in general seem to be less serious and we found few notable effects of treatment in these domains.

[Liposuction of arm lymphoedema]. / Fettabsaugung des Lymphödems am Arm.

Breast cancer is the most common disease in women, and up to 38 % develop lymphoedema of the arm following mastectomy, standard axillary node dissection and postoperative irradiation. Limb reductions have been reported utilising various conservative therapies such as manual lymph drainage and pressure therapy. Some patients with long-standing pronounced lymphoedema do not respond to these conservative treatments because slow or absent lymph flow causes the formation of excess subcutaneous adipose tissue. Previous surgical regimes utilising bridging procedures, total excision with skin grafting or reduction plasty seldom achieved acceptable cosmetic and functional results. Microsurgical reconstruction involving lympho-venous shunts or transplantation of lymph vessels has also been investigated. Although attractive in concept, the common failure of microsurgery to provide complete reduction is due to the persistence of newly formed subcutaneous adipose tissue which is not removed in patients with chronic non-pitting lymphoedema. Liposuction removes the hypertrophied adipose tissue and is a prerequisite to achieve complete reduction. The new equilibrium is maintained through constant (24-hour) use of compression garments postoperatively. Long-term follow-up (seven years) does not show any recurrence of the oedema.

Liposuction in arm lymphedema treatment.

Breast cancer is the most common disease in women, and up to 38% develop lymphedema of the arm following mastectomy, standard axillary node dissection and postoperative irradiation. Limb reductions have been reported utilizing various conservative therapies such as manual lymph and pressure therapy. Some patients with long-standing pronounced lymphedema do not respond to these conservative treatments because slow or absent lymph flow causes the formation of excess subcutaneous adipose tissue. Previous surgical regimes utilizing bridging procedures, total excision with skin grafting or reduction plasty seldom achieved acceptable cosmetic and functional results. Microsurgical reconstruction involving lympho-venous shunts or transplantation of lymph vessels has also been investigated. Although attractive in concept, the common failure of microsurgery to provide complete reduction is due to the persistence of newly formed subcutaneous adipose tissue, which is not removed in patients with chronic non-pitting lymphedema. Liposuction removes the hypertrophied adipose tissue and is a prerequisite to achieve complete reduction. The new equilibrium is maintained through constant (24-hour) use of compression garments postoperatively. Long-term follow up (7 years) does not show any recurrence of the edema.

Liposuction gives complete reduction of chronic large arm lymphedema after breast cancer.

About one-third of all women treated for breast cancer develop arm lymphedema. In addition to the worry of the cancer itself, the swollen and heavy arm is both a physical and a psychosocial handicap for the patients. Previous surgical and conservative treatments have not always given satisfactory and permanent results, conceivably because lymphedema causes hypertrophy of the subcutaneous adipose tissue. From this point of view, liposuction (LS) combined with Controlled Compression Therapy (CCT) is an interesting approach, as the hypertrophied adipose tissue is effectively removed and the outcome sustained by wearing a compression garment. Pre- and postoperative arm edema volumes were measured using the water displacement technique. Skin blood flow was recorded using Laser Doppler imaging. Lymph transport in the arm was assessed by indirect lymphoscintigraphy. LS + CCT reduced the arm edema volume completely, compared with a 50% decrease following CCT alone. The use of a compression garment after liposuction is necessary in order to maintain the normalized arm volume. LS + CCT did not affect the already impaired lymph transport; it merely increased skin microcirculation. A reduced incidence of cellulitis was noted.

Liposuction combined with controlled compression therapy reduces arm lymphedema more effectively than controlled compression therapy alone.

Arm lymphedema after breast cancer therapy has been treated with various forms of conservative and surgical treatment during recent years. The clinical results usually have been modest or, in some instances, even disappointing. In a previous series of patients treated with the new liposuction technique combined with controlled compression therapy, we found, however, an overall edema reduction of 106 percent after 1 year. The purpose of this study was both to investigate how much the surgical procedure contributes to the outcome and to clarify the importance of controlled compression therapy. Twenty-eight patients were, therefore, prospectively matched into two groups. One group received liposuction combined with controlled compression therapy, and one group received the therapy alone. Additionally, the therapy group was compared with our complete group of patients treated thus far with liposuction combined with therapy (n = 30). The prospective study using matched pairs (n = 14) showed that liposuction combined with controlled compression therapy is significantly more effective than the therapy alone (p < 0.0001), with a mean difference of about 1000 ml during the entire 1-year observation period. The beneficial effect of liposuction was confirmed by the comparison between the controlled compression therapy group and our complete group of patients treated with liposuction combined with the therapy, as the edema reduction figures after 1 year were 47 percent and 104 percent, respectively (p < 0.0001). In six patients who had surgery and a complete reduction of the edema, the compression garments were removed for 1 week, 1 year postoperatively. A marked increase in the arm volume was observed, which was immediately remedied by reapplying the garments. We conclude that liposuction combined with controlled compression therapy reduces arm lymphedema more efficiently than the therapy alone. Continued use of compression garments is, however, important to maintain the primary surgical outcome.

Liposuction in Dercum's disease: impact on haemostatic factors associated with cardiovascular disease and insulin sensitivity.

OBJECTIVE: To study the impact of adipose tissue removal by liposuction on factors associated with increased risk of cardiovascular atherosclerotic disease within the coagulation and fibrinolytic system and glucose metabolism. DESIGN, SETTING AND SUBJECTS: Liposuction was performed in 53 patients with Dercum's disease. The levels of fibrinogen, von Willebrand factor antigen (VWF:Ag) and plasminogen activator inhibitor type 1 activity (PAI-1) were measured preoperatively, and 2 weeks, 4 weeks and 3 months postoperatively. In a subsample of 10 patients, insulin sensitivity was determined before and 2-4 weeks after surgery using the 2-h euglycaemic hyperinsulinaemic clamp technique. The study was performed as a single-centre study. MAIN OUTCOME MEASURE: Fibrinogen, PAI-1 and VWF:Ag levels, and glucose uptake before and after removal of adipose tissue. RESULTS: Weight reduction was sustained throughout the follow-up period with a mean decrease from 90.7 to 86.6 kg (P < 0.0001). There was a slight increase in levels of coagulation factors 2 and 4 weeks postoperatively, probably in reaction to the surgical trauma. After 3 months the values had returned to preoperative levels except for PAI-1, which still showed a slight increase (P < 0.05). In the subsample of 10 patients, glucose uptake was improved (P < 0.05) from a short-term perspective after surgery. CONCLUSION: Surgical removal of adipose tissue, without change in lifestyle, does not seem to improve the levels of coagulation and fibrinolytic factors associated with cardiovascular atherosclerotic disease, whereas glucose takeup may be facilitated and insulin sensitivity increases from a short-term perspective.

Liposuction reduces arm lymphedema without significantly altering the already impaired lymph transport.

In a prospective study, 20 patients with arm lymphedema after breast cancer treatment underwent liposuction combined with Controlled Compression Therapy (CCT) or CCT alone. Indirect lymphoscintigraphy (ILS) was used to study lymph kinetics before and after intervention. Lymphoscintigrams from the contralateral, non-edematous arm were characterized by prompt transit of the radiotracer (99mTc-albumin nanocolloid) to the axillary nodes, whereas tracer accumulation as dermal backflow characterized tracer transport in the lymphedematous arm. Neither liposuction with CCT nor CCT alone, changed this ILS profile. Liposuction combined with CCT reduced arm edema volume by (median) 115% (range 92-179%), whereas CCT alone decreased arm edema volume by only 54% (range 7-81%) (p = 0.008). Because liposuction in conjunction with CCT was not associated with further impairment to an already restricted lymph transport, we recommend this therapy (liposuction with external compression) for chronic arm lymphedema, as it reduces edema volume safely, rapidly, and more efficiently than external compression alone. Moreover, it does not worsen an already impaired lymph transport in the lymphedematous upper extremity.

Complete reduction of lymphoedema of the arm by liposuction after breast cancer.

The incidence of lymphoedema of the arm after mastectomy ranges between 8% and 38%, and it is an appreciable problem from both functional and social aspects. Conservative and previous surgical regimens have not been completely successful. In the light of these experiences, liposuction clearly constitutes an interesting new surgical approach, which is potentially capable of effecting predictable and reliable improvements in patients with lymphoedema. Twenty eight women with lymphoedema of the arm after breast cancer were consecutively treated by liposuction. Limb compression with a compression garment was instituted immediately after operation. All patients had been given radiotherapy after the operation for breast cancer. Mean preoperative volume of oedema was 1845 ml (range 570-3915), and mean volume of aspirate was 2250 ml (range 1000-3850); volume of aspirate correlated linearly with the volume of preoperative oedema. There were no major surgical complications, but blood transfusion was necessary in eight patients whose volume of aspirate exceeded 2000 ml. After 12 months (n = 24), an average reduction in volume of oedema of 106% was found. Such a normalisation can be expected in patients with oedema that amounts to about 2500 ml. Although the oedema cannot be completely removed in more severe cases, substantial reduction is beneficial from both functional and cosmetic aspects. We conclude that liposuction is safe and effective for reducing lymphoedema of the arm after operations for breast cancer. In a one-stage procedure, oedematous and hypertrophic fat tissue can be removed with an excellent clinical outcome.

Skin blood flow of the lymphedematous arm before and after liposuction.

Twelve women with arm lymphedema after breast cancer treatment underwent liposuction followed by external compression with a garment-sleeve. Arm volumes were measured using water displacement technique, and skin blood flow was recorded with laser Doppler imaging (LDI). Data was collected before and after (3 and 12 months) liposuction. Episodes of cellulitis were also recorded. Whereas previous investigations have indicated increased total blood flow in the lymphedematous arm, we found reduced superficial skin blood flow preoperatively. Liposuction produced a median edema reduction of 87% and 97% after 3 and 12 months respectively. Both in the forearm and in the upper arm, skin blood flow increased significantly after liposuction and values were similar to those of the non-edematous (control) arm. Along with increased skin blood flow, the frequency of cellulitis also decreased. Liposuction effectively reduces arm lymphedema after breast cancer treatment, and also lowers the incidence of arm cellulitis. Improved local skin blood flow may be an important contributing factor to the reduced episodes of arm infection.