Daniel Marsh

Betel-derived alkaloid up-regulates keratinocyte alphavbeta6 integrin expression and promotes oral submucous fibrosis

Oral submucous fibrosis (OSF) is a premalignant, fibrosing disorder of the mouth, pharynx, and oesophagus, with a malignant transformation rate of 7–13%. OSF is strongly associated with areca (betel) nut chewing and worldwide, over 5 million people are affected. As αvβ6 integrin is capable of promoting both tissue fibrosis and carcinoma invasion, we examined its expression in fibroepithelial hyperplasia and OSF. αvβ6 was markedly up‐regulated in OSF, with high expression detected in 22 of 41 cases (p < 0.001). We investigated the functional role of αvβ6 using oral keratinocyte‐derived cells genetically modified to express high αvβ6 (VB6), and also NTERT‐immortalized oral keratinocytes, which express low αvβ6 (OKF6/TERT‐1). VB6 cells showed significant αvβ6‐dependent activation of TGF‐β1, which induced transdifferentiation of oral fibroblasts into myofibroblasts and resulted in up‐regulation of genes associated with tissue fibrosis. These experimental in vitro findings were confirmed using human clinical samples, where we showed that the stroma of OSF contained myofibroblasts and that TGF‐β1‐dependent Smad signalling was detectable both in keratinocytes and in myofibroblasts. We also found that arecoline, the major alkaloid of areca nuts, up‐regulated keratinocyte αvβ6 expression. This was modulated through the M4 muscarinic acetylcholine receptor and was suppressed by the M4 antagonist, tropicamide. Arecoline‐dependent αvβ6 up‐regulation promoted keratinocyte migration and induced invasion, raising the possibility that this mechanism may support malignant transformation. Over 80% of OSF‐related oral cancers examined had moderate/high αvβ6 expression. These data suggest that the pathogenesis of OSF may be epithelial‐driven and involve arecoline‐dependent up‐regulation of αvβ6 integrin. Copyright

The Morbidity of the Button-over-Nail Technique for Zone 1 Flexor Tendon Repairs. Should we still be using this Technique?

The button-over-nail technique is commonly used to fix the core suture to the distal phalanx for flexor digitorum profundus repairs in zone 1. We report a retrospective study of 23 consecutive patients who had a repair of the flexor digitorum profundus tendon in zone 1 using the button-over-nail technique. Fifteen patients experienced a complication, of which ten were directly related to the button-over-nail technique. Complications included nail deformities, fixed flexion deformities of the distal interphalangeal joint, infections and prolonged hypersensitivity. Two patients required amputation of the fingertip. We recommend that the button-over-nail technique should be avoided or used only with caution and with close attention to the details of the technique.

Engineering a Single Chain Fv Antibody to αvβ6 Integrin using the Specificity-Determining Loop of a Foot-and-Mouth Disease Virus

The alpha v beta 6 integrin is a promising target for cancer therapy. Its expression is up-regulated de novo on many types of carcinoma where it may activate transforming growth factor-beta1 and transforming growth factor-beta 3, interact with the specific extracellular matrix proteins and promote migration and invasion of tumor cells. The viral protein 1 (VP1) coat protein of the O(1) British field strain serotype of foot-and-mouth disease virus is a high-affinity ligand for alpha v beta 6, and we recently reported that a peptide derived from VP1 exhibited alpha v beta 6-specific binding in vitro and in vivo. We hypothesized that this peptide could confer binding specificity of an antibody to alpha v beta 6. A 17-mer peptide of VP1 was inserted into the complementarity-determining region H3 loop of MFE-23, a murine single-chain Fv (scFv) antibody reactive with carcinoembryonic antigen (CEA). The resultant scFv (B6-1) bound to alpha v beta 6 but retained residual reactivity with CEA. This was eliminated by point mutation (Y100bP) in the variable heavy-chain domain to create an scFv (B6-2) that was as structurally stable as MFE-23 and reacted specifically with alpha v beta 6 but not with alpha 5 beta 1, alpha v beta 3, alpha v beta 5, alpha v beta 8 or CEA. B6-2 was internalized into alpha v beta 6-expressing cells and inhibited alpha v beta 6-dependent migration of carcinoma cells. B6-2 was subsequently humanized. The humanized form (B6-3) was obtained as a non-covalent dimer from secretion in Pichia pastoris (115 mg/l) and was a potent inhibitor of alpha v beta 6-mediated cell adhesion. Thus, we have used a rational stepwise approach to create a humanized scFv with therapeutic potential to block alpha v beta 6-mediated cancer cell invasion or to deliver and internalize toxins specifically to alpha v beta 6-expressing tumors.

Assessing the Augmented Breast: A Blinded Study Comparing Round and Anatomical Form-Stable Implants

BACKGROUND Controversy persists as to whether round or anatomical form-stable breast implants provide the most aesthetically pleasing results, and there is a paucity of evidence comparing cosmetic outcomes of these two implants. A blinded study comparing aesthetic outcomes was conducted in an attempt to address this issue. OBJECTIVES The authors compare aesthetic outcomes between round and anatomical form-stable breast implants. METHODS Pre- and postoperative photographs of 60 consecutive patients undergoing breast augmentation (33 round, 27 anatomical) by a single surgeon were reviewed by 22 plastic surgeons. Photographs were graded on a modified Likert scale (1, poor; 4, excellent) for overall aesthetic result, upper pole contour, and natural appearance. The panel was asked to determine implant shape. RESULTS Anatomical implants scored higher for upper pole contour: anatomical 2.80 (±0.44 - standard deviation) vs round 2.60 (±0.38). With regard to natural appearance and overall aesthetic results, anatomical implants scored higher: 2.89 (±0.42) vs 2.56 (±0.36) and 2.86 (±0.41) vs 2.72 (±0.37), respectively. None of these differences achieved statistical significance, and 62.7% of round and 49% of anatomical implants were correctly identified. There was no significant difference in the body mass index (BMI) between the 2 groups (P = .21). CONCLUSIONS No significant difference (P > .05) in the general and specific cosmetic points between round and anatomical implants was demonstrated; many on the panel were unable to identify implant shape correctly. Both techniques seem to yield good cosmetic results. Clearly the decision on which implant to use must be made on an individual patient basis because many factors influence overall aesthetic outcome. Anatomical implants should not be assumed to produce a more natural result. LEVEL OF EVIDENCE 4 Therapeutic.

Reconstruction of very large defects: a novel application of the double skin paddle anterolateral thigh flap design provides for primary donor-site closure

BACKGROUND The anterolateral thigh flap is becoming the flap of choice for reconstruction of soft tissue defects. By applying the chimaeric principle, we describe a technique to achieve primary donor-site closure in the use of the anterolateral thigh for the reconstruction of very large defects. METHODS A long anterolateral thigh flap is marked out using standard points of reference. At least two separate cutaneous perforator vessels are identified on hand-held Doppler and dissected in a retrograde fashion back to the descending branch of the lateral circumflex femoral artery. The skin paddle is then divided between the two cutaneous perforators to give two separate paddles with a common vascular supply. The skin paddles can now be stacked side by side on a flap inset, effectively doubling the width of the flap, whilst still allowing for primary donor-site closure. RESULTS We have used this flap to reconstruct chest-wall and extremity defects on six patients (mean age: 28.6 years; range: 24-35 years). The largest defect was 30x18cm and the smallest 11x12cm in diameter. In each case, the width of the defect was too great to allow for direct closure of the donor site had a conventional anterolateral flap design been used. There were no cases of flap failure or re-exploration, and in all cases the donor site was closed primarily. CONCLUSIONS The split-skin paddle anterolateral thigh flap provides bespoke cover for large soft tissue defects with improved morbidity and cosmesis of the donor site.

Bioabsorbable Fixation for Mitchell's Bunionectomy Osteotomy

UNLABELLED Although bioabsorbable pins have been used to successfully stabilize a wide range of osteotomies, to date there have been not published studies describing the results of their use for fixation of first metatarsal osteotomies in Mitchells bunionectomy. The purpose of this retrospective investigation of 78 first metatarsal osteotomies was to evaluate the effectiveness of polydioxanone bioabsorbable pin fixation of the first metatarsal osteotomy in Mitchells bunionectomy. The mean length of the first metatarsal preoperatively was 6.65 +/- 0.42 cm, and postoperatively it was 6.31 +/- 0.57 cm (P < .0001). The mean first IMA preoperatively was 17.59 degrees +/- 3.51 degrees , and postoperatively it was 9.91 degrees +/- 2.58 degrees (P < .0001). The mean HVA preoperatively was 29.74 degrees +/- 4.70 degrees , and postoperatively it was 12.89 degrees +/- 4.26 degrees (P < .0001). The average time to bony union was 6.01 +/- 0.61 weeks. There were 5 (6.41%) superficial wound infections that resolved with oral antibiotics, 1 (1.28%) deep-seated infection requiring surgical debridement, and 2 (2.56%) patients complained of transfer metatarsalgia. Five (6.41%) patients displayed persistent localized translucency at some portion of the osteotomy site on postoperative radiographs, and there were no cases of progressive osteolysis. In this series there were no complications related to pin fracture or failure of osteotomy fixation. Based on the results observed in this study, it appears that the use of polydioxanone bioabsorbable pins provides satisfactory stabilization of the first metatarsal osteotomy in Mitchells bunionectomy, and was not associated with any serious complications. LEVEL OF CLINICAL EVIDENCE 2.

Toe syndactyly revisited

INTRODUCTION Toe syndactyly affects around 1/2000 people and is associated with significant psychological morbidity. There are multiple techniques of toe syndactyly repair described in the literature which is indicative that as yet, no one method has proved superior to others. Here we describe the technique we employ and present results of surgery including a review of patient satisfaction. METHODS We use a modification of the technique originally described by Mondolfi using interdigitating triangular skin flaps to recreate the web space and a split thickness skin graft harvested from the instep to address the skin shortage. Patient satisfaction data were collected using a multiple response 10 point modified Likert scale questionnaire. RESULTS 15 patients and 19 conjoined toes were operated on by a single surgeon with an average follow up time of 16.3 months (range 3-30 months). Overall satisfaction with the procedure was high with a significant increase in satisfaction from 1.3/10 preoperatively to 9.3/10 post operatively. Furthermore, patients were found to have a significant reduction in concern about their condition from a preoperative score of 8.67 to score of 0.67 following surgery (p < 0.05). Of the 19 toes divided, we had 1 skin graft failure, 1 case of mild web creep and all donor sites healed well. CONCLUSIONS This is a simple technique that avoids unsightly dorsal scars and the glabrous skin graft provides excellent colour match with minimal morbidity. Complication rates seen with this technique are comparable or superior to those seen with other techniques already described in the literature. Toe syndactyly can be a relatively under treated condition and we have shown that offering these patients surgery can result in a highly satisfied patient group.

Three routine free flaps per day in a single operating theatre: principles of a process mapping approach to improving surgical efficiency

BACKGROUND Breast reconstruction is a multi-stage process, involving many individual procedures and many healthcare professionals which take the patient through from diagnosis of breast cancer to the completion of cancer treatment and ultimate breast reconstruction. With an experience of over 3,000 autologous breast reconstructions, we have refined both our surgical technique and overall approach to breast reconstruction to improve the efficiency in free flap based breast reconstruction surgery. METHODS Through a process mapping approach similar to that employed by large-scale industry, we have broken down free flap based breast reconstruction into multiple smaller processes. By looking at various steps as a simple component of the whole, we have improved our theatre efficiency to maximize patient throughput and improve our outcomes for breast reconstruction patients. RESULTS Since beginning free flap breast reconstruction surgery, we have improved overall efficiency by applying a process mapping approach. In our early experience, we undertook a single patient undergoing breast reconstruction with a free flap per theatre list, moving to two patients having breast reconstruction, and now carry out three free flap based reconstructions in a single theatre per day as a routine. Specific times are demonstrated, with no increased complication rate. CONCLUSIONS Through clearly defined processes, operative efficiency in autologous breast reconstruction can achieve three free flaps per day in a single theatre.

Cryptotia correction – the post-auricular transposition flap

BACKGROUND Cryptotia is a congenital ear deformity in which the upper pole appears buried beneath mastoid skin. Here we describe our method of cryptotia correction which we have used to good effect with minimal complications. PATIENTS AND METHODS 20 patients and 24 ears were operated on. All surgery was performed by the senior authors WS and DG. Patient age range was 4-19 years and mean follow up was 2.1 years. We use a superiorly based V-shaped flap raised from the post-auricular skin. Following ear release, the flap is rotated into the defect and donor site closed directly. Our technique ensures all scars are hidden behind the ear, there are no skin grafts required. RESULTS All patients had a satisfactory release of cryptotia, there were no cases of partial or total flap failure, none of wound dehiscence and no patients required revisional surgery. CONCLUSIONS The post-auricular flap is a simple technique, retaining the depth of the auriculotemporal sulcus, providing a good skin colour match without the need for skin grafting and without distorting the hair line. Our results are comparable or superior to those seen with other techniques previously described.

Integrin αvβ6 promotes TGF-β1-dependent myofibroblastic transdifferentiation in oral submucous fibrosis

Introduction Oral submucous fibrosis (OSF) is a chronic progressive fibrosing disorder of the oral cavity. Commonly in fibrosis, TGF-β1 promotes the transdifferentiation of fibroblasts into α-smooth muscle actin (SMA)-secreting myofibroblasts. Integrin αvβ6 is not detectable on normal oral keratinocytes but is upregulated during tissue remodelling. αvβ6 is a key activator of TGF-β1 through its interaction with its latency associated peptide.