Nathalie Roche

Penile reconstruction: is the radial forearm flap really the standard technique?

Background: The ideal goals in penile reconstruction are well described, but the multitude of flaps used for phalloplasty only demonstrates that none of these techniques is considered ideal. Still, the radial forearm flap is the most frequently used flap and universally considered as the standard technique. Methods: In this article, the authors describe the largest series to date of 287 radial forearm phalloplasties performed by the same surgical team. Many different outcome parameters have been described separately in previously published articles, but the main purpose of this review is to critically evaluate to what degree this supposed standard technique has been able to meet the ideal goals in penile reconstruction. Results: Outcome parameters such as number of procedures, complications, aesthetic outcome, tactile and erogenous sensation, voiding, donor-site morbidity, scrotoplasty, and sexual intercourse are assessed. Conclusions: In the absence of prospective randomized studies, it is not possible to prove whether the radial forearm flap truly is the standard technique in penile reconstruction. However, this large study demonstrates that the radial forearm phalloplasty is a very reliable technique for the creation, mostly in two stages, of a normal-appearing penis and scrotum, always allowing the patient to void while standing and in most cases also to experience sexual satisfaction. The relative disadvantages of this technique are the rather high number of initial fistulas, the residual scar on the forearm, and the potential long-term urologic complications. Despite the lack of actual data to support this statement, the authors feel strongly that a multidisciplinary approach with close cooperation between the reconstructive/plastic surgeon and the urologist is an absolute requisite for obtaining the best possible results.

Disposition of soy isoflavones in normal human breast tissue

BACKGROUND Despite decades of research on the relation between soy and breast cancer, questions regarding the absorption, metabolism, and distribution of isoflavones in breast tissue largely remain unanswered. OBJECTIVE We evaluated the potential health effects of isoflavone consumption on normal breast tissue; isoflavone concentrations, metabolites, and biodistribution were investigated and compared with 17beta-estradiol exposure. DESIGN In this dietary intervention study, healthy women were randomly allocated to a soy milk (n = 11; 16.98-mg genistein and 5.40-mg daidzein aglycone equivalents per dose), soy supplement (n = 10; 5.27-mg genistein and 17.56-mg daidzein aglycone equivalents per dose), or control (n = 10) group. After a run-in period > or = 4 d, 3 doses of soy milk or soy supplements were taken daily for 5 d before an esthetic breast reduction. Blood and breast biopsies were collected during surgery and analyzed with liquid chromatography-tandem mass spectrometry. RESULTS After soy administration, genistein and total daidzein concentrations, which were expressed as aglycone equivalents, ranged from 135.1 to 2831 nmol/L and 105.1 to 1397 nmol/L, respectively, in hydrolyzed serum and from 92.33 to 493.8 pmol/g and 22.15 to 770.8 pmol/g, respectively, in hydrolyzed breast tissue. The major metabolites identified in nonhydrolyzed samples were genistein-7-O-glucuronide and daidzein-7-O-glucuronide, with an overall glucuronidation of 98%. Total isoflavones showed a breast adipose/glandular tissue distribution of 40:60, and their mean (+/-SEM) derived 17beta-estradiol equivalents toward estrogen receptor beta were 21 +/- 4-fold and 40 +/- 10-fold higher than the 17beta-estradiol concentrations in adipose (0.283 +/- 0.089 pmol/g, P < 0.001) and glandular (0.246 +/- 0.091 pmol/g, P = 0.001) fractions, respectively. CONCLUSION After intake of soy milk and soy supplements, isoflavones reach exposure levels in breast tissue at which potential health effects may occur.

The use of pedicled perforator flaps for reconstruction of lumbosacral defects.

&NA; Large lumbosacral defects remain a difficult challenge in reconstructive surgery, especially in the nonparaplegic patient. Traditional options for closure include local rotation or transposition flaps and musculocutaneous flaps. These flaps, however, are not an optimal option in previously irradiated or operated areas, or in cases of large defects. Application of the perforator principle to the traditional musculocutaneous flap creates perforator flaps, which are an additional tool in the treatment of these defects in the nonparaplegic patient. A large amount of healthy, wellvascularized tissue can be transferred on one perforator without sacrificing important underlying muscles. The are of rotation is also larger than in traditional flaps. The authors present an anatomic overview of three types of pedicled perforator flaps: the superior gluteal artery perforator flap, the lumbar artery perforator flap, and the intercostal artery perforator flap. They also report 4 patients in whom a pedicled perforator flap was used to reconstruct a large lumbosacral defect. Roche NA, Van Landuyt K, Blondeel PN, Matton G, Monstrey SJ. The use of pedicled perforator flaps for reconstruction of lumbosacral defects. Ann Plast Surg 2000;45:7‐14

Transdermal behaviour of the N-alkylamide spilanthol (affinin) from Spilanthes acmella (Compositae) extracts

AIM OF THE STUDY N-Alkylamides are a large group of bioactive molecules found in several plants from the genera Echinacea, Xanthoxylum and Spilanthes. Extracts and formulations derived from these plants are not only orally used, but also applied on the skin as well. However, there is currently no specific information available about the intrinsic local pharmacokinetics of N-alkylamides after topical application on human skin, questioning the role of this mode of administration. The present study investigates the transdermal behaviour of spilanthol, a prominent N-alkylamide. MATERIALS AND METHODS Two pharmaceutically accepted dose solutions (ethanol and propylene glycol based aqueous donor vehicles), combined with three different receptor fluids (PBS, PBS+0.5% HPbetaCD, EtOH/H(2)O (30:70, v/v)), were applied on split-thickness human skin in a Franz diffusion cell (FDC) system. Fundamental permeation characteristics of spilanthol in a solvent-independent way (100% aqueous dose solution) were also obtained using an extrapolation approach with different organic solvent/H(2)O ratios. RESULTS AND CONCLUSIONS We demonstrated for the first time that spilanthol permeates the skin. The following aqueous-extrapolated primary transdermal parameters were obtained (mean+/-SEM): K(p,aq)=3.31 (+/-0.29)x10(-3)cm/h, D(m,aq)=1.86 (+/-0.09)x10(-4)cm(2)/h and K(m,aq)=7.28 (+/-1.59)x10(-1). Partitioning (K(m)) was strongly dependent on the donor solution composition, while diffusion (D(m)) was mainly influenced by the receptor fluid composition.

Indoleamine 2,3-dioxygenase, a new prognostic marker in sentinel lymph nodes of melanoma patients

BACKGROUND Indoleamine 2,3-dioxygenase (IDO), an enzyme with immunosuppressive properties is considered as a factor that impairs the antitumour immune response in melanoma. In this study, we investigated the expression of IDO in sentinel nodes of melanoma patients to determine its prognostic relevance. PATIENTS AND METHODS One hundred and sixteen melanoma patients were enrolled in this study with a median follow-up time after diagnosis of 71 months. The expression of IDO and forkhead box P3 (Foxp3) in the sentinel lymph nodes was determined by immunohistochemistry and correlated with progression-free survival and overall survival. In 42 patients, regulatory T cells were investigated by flow cytometry. RESULTS Cox regression survival analysis showed a significant negative effect of IDO expression on progression-free survival (p = 0.015) and overall survival (p = 0.010). High IDO expression was correlated with a significant higher frequency of Foxp3-positive cells in uninvaded lymph nodes (p = 0.016). The presence of IDO expression in the sentinel nodes was not associated with an increased frequency of circulating regulatory T cells (Tregs) but was significantly correlated with an increased mean fluorescence intensity of Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) in Tregs (p = 0.019). After CD3CD28 stimulation, peripheral blood mononuclear cells of patients with high IDO expression showed a lower production of interferon-gamma (IFN-γ) (p = 0.025). CONCLUSIONS This study points to an independent predictive role of IDO on survival, especially in melanoma patients with uninvolved sentinel nodes. Investigating IDO expression in the sentinel nodes of melanoma patients may be a useful marker to pre-identify patients with a less favourable prognosis in stage I and II disease.

Shaping the Breast in Aesthetic and Reconstructive Breast Surgery: An Easy Three-Step Principle. Part II-Breast Reconstruction after Total Mastectomy

This is Part II of four parts describing the three-step principle being applied in reconstructive and aesthetic breast surgery. Part I explains how to analyze a problematic breast by understanding the main anatomical features of a breast and how they interact: the footprint, the conus of the breast, and the skin envelope. This part describes how one can optimize results with breast reconstructions after complete mastectomy. For both primary and secondary reconstructions, the authors explain how to analyze the mastectomized breast and the deformed chest wall, before giving step-by-step guidelines for rebuilding the entire breast with either autologous tissue or implants. The differences in shaping unilateral or bilateral breast reconstructions with autologous tissue are clarified. Regardless of timing or method of reconstruction, it is shown that by breaking down the surgical strategy into three easy (anatomical) steps, the reconstructive surgeon will be able to provide more aesthetically pleasing and reproducible results. Throughout these four parts, the three-step principle will be the red line on which to fall back to define the problem and to propose a solution.

Disposition of hop prenylflavonoids in human breast tissue

Hop-derived products may contain xanthohumol (XN), isoxanthohumol (IX), and the potent phytoestrogen 8-prenylnaringenin (8-PN). To evaluate the potential health effects of these prenylflavonoids on breast tissue, their concentration, nature of metabolites, and biodistribution were assessed and compared with 17beta-estradiol (E(2)) exposure. In this dietary intervention study, women were randomly allocated to hop (n=11; 2.04 mg XN, 1.20 mg IX, and 0.1 mg 8-PN per supplement) or control (n=10). After a run-in of >or=4 days, three supplements were taken daily for 5 days preceding an aesthetic breast reduction. Blood and breast biopsies were analyzed using HPLC-ESI-MS/MS. Upon hop administration, XN and IX concentrations ranged between 0.72 and 17.65 nmol/L and 3.30 and 31.50 nmol/L, and between 0.26 and 5.14 pmol/g and 1.16 and 83.67 pmol/g in hydrolyzed serum and breast tissue, respectively. 8-PN however, was only detected in samples of moderate and strong 8-PN producers (0.43-7.06 nmol/L and 0.78-4.83 pmol/g). Phase I metabolism appeared to be minor (approximately 10%), whereas extensive glucuronidation was observed (> 90%). Total prenylflavonoids showed a breast adipose/glandular tissue distribution of 38/62 and their derived E(2)-equivalents were negligible compared with E(2) in adipose (384.6+/-118.8 fmol/g, p=0.009) and glandular (241.6+/-93.1 fmol/g, p<0.001) tissue, respectively. Consequently, low doses of prenylflavonoids are unlikely to elicit estrogenic responses in breast tissue.

A New Discriminative Criterion for the Development of Franz Diffusion Tests for Transdermal Pharmaceuticals

PURPOSE In vitro skin/membrane permeation profiling of topical pharmaceuticals is an important overall quality attribute in the evaluation of product consistency and it is also used for IVIVR (in vitro - in vivo relationship) purposes in product development and change control. Franz diffusion cell (FDC) experiments are emerging as a generally accepted methodology in this field, where the choice of operational conditions requires a data-supported justification towards the discriminating power of the test. A response function is therefore proposed to objectively quantify the discriminating power. METHODS We evaluated the usefulness of the proposed response function by studying one of the operational conditions, i.e. the influence of receptor medium composition, on the FDC in vitro penetration behaviour of the model compound testosterone formulated in four different topical preparations, using both artificial membranes and dermatomed human skin. RESULTS From the obtained cumulative amount of testosterone in the receptor fluid versus time curves, the permeability coefficient Kp of testosterone from each formulation was calculated. The evaluation of the discriminating power of the different media was performed using our new objective response function based upon an equal spread criterion of normalised Kp values. CONCLUSION We demonstrated significant differences in discriminating power between the different media used, with the overall best results obtained with hydroxypropyl-beta-cyclodextrine (HPBCD) containing media. The proposed new criterion was found to be useful for the rational design of an in vitro diffusion test for transdermal pharmaceuticals.

Flap surgery for pressure sores: should the underlying muscle be transferred or not?

BACKGROUND Musculocutaneous flaps have become the first choice in the surgical repair of pressure sores, but the indication for including muscle in the transferred flaps still remains poorly defined. This study compares outcomes after muscle and non-muscle flap coverage of pressure sores to investigate whether it is still necessary to incorporate muscle tissue as part of the surgical treatment of these ulcers. METHODS A retrospective revision of 94 consecutive patients with ischial or sacral pressure sores operated between 1996 and 2002 was performed. Depending on the inclusion of muscle into the flap, the patients were divided in two groups: musculocutaneous flap group and fasciocutaneous flap group. Charts were reviewed for patient characteristics, ulcer features and reconstructive information. Data between groups were compared with emphasis on early (haematoma or seroma, dehiscence, infections, necrosis and secondary procedures) and late (recurrence) postoperative complications. RESULTS A total of 37 wounds were covered with muscle and 57 wounds covered without muscle tissue. The groups were comparable in relation to age, gender, ulcer characteristics and timing for surgery. There were no significant differences in early complications between the study groups. The mean follow-up period was 3.10 ± 1.8 years (range: 0.5 to 6.7). There were no statistical differences in ulcer recurrence between the groups. The type of flap used was not associated with postoperative morbidity or recurrence in the univariate and multivariate analyses. CONCLUSIONS The findings of this clinical study indicate that the musculocutaneous flaps are as good as fasciocutaneous flaps in the reconstruction of pressure sores, and they question the long-standing dogma that muscle is needed in the repair of these ulcers.

Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes

Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factors DNA binding.