Reducing the incidence of problematic seroma formation and skin necrosis post-lymphadenectomy: Triple action of topical tranexamic acid, negative pressure wound therapy, and prolonged drainage.

BACKGROUND: Axillary and inguinal lymph node dissections are commonly associated with complications that often require additional interventions. METHODS: Patients who underwent axillary or inguinal lymphadenectomy via standard procedures were compared to an intervention cohort of patients who underwent axillary or inguinal lymphadenectomy with the use of topical tranexamic acid (TXA) to the wound cavity, a PICO (Smith&Nephew UK) closed-incision negative pressure dressing, and discharged early with a drain in-situ. RESULTS: Seventy-six patients in the control group (mean age 65.8 years, mean BMI 28.4 kg/m2) underwent open lymphadenectomy without topical TXA and a simple dressing. Seventy-eight patients were included in the intervention group (mean age 67.1 years, mean BMI 28.5 kg/m2). Patients in the intervention group had an inpatient stay of mean 5.6 days fewer than those in the control group (CI 3.09-5.31; p < .0001), an estimated saving to the healthcare trust of £ 3046.40 (US$3723.61) per patient in "bed days." They had longer drain duration (mean 15 days vs. 8.3 days); however, they had a statistically significant lower risk of seroma formation requiring drainage (6.4% vs. 21%; p = .009), and skin necrosis (0% vs. 6.6%; p = .027). They also had a lower risk of infection (17% vs. 29%), wound dehiscence (15% vs. 25%), and readmission (7.7% vs. 14%), although they were not statistically significant. Patients in the control group were more likely to receive antibiotics as inpatients (51% vs. 7.7%; p < .00001) and on discharge (24% vs. 5%; p < .0011) than those in the intervention group. CONCLUSIONS: Topical TXA, PICO dressing, and early discharge with a drain following lymphadenectomy results in a reduced rate of complications.

Subungual Melanoma of the Hand.

BACKGROUND: The diagnosis of subungual melanoma (SUM) can be challenging and SUMs generally have a worse prognosis than melanomas arising elsewhere. Due to their rarity, the evidence to guide management is limited. This study sought to identify clinicopathological features predictive of outcome and to provide guidelines for management. METHODS: From a large, single-institution database, 103 patients with in situ (n = 9) or invasive (n = 94) SUMs of the hand treated between 1953 and 2014 were identified and their features analyzed. RESULTS: The most common site of hand SUMs was the thumb (53%). Median tumor thickness was 3.1 mm, and SUMs were commonly of the acral subtype (57%), ulcerated (58%), amelanotic (32%), and had mitoses (73%). Twenty-one patients reported prior trauma to the tumor site. Twenty-two patients were stage III at diagnosis; 7 underwent therapeutic lymph node dissection and 22 underwent elective lymph node dissection (5 positive), while 36 had sentinel node biopsy (SNB), 28% of which were positive. Forty percent of SNB-positive patients had involved non-sentinel nodes (SNs) in their completion lymph node dissection. Five-year melanoma-specific survival (MSS) and disease-free survival (DFS) rates were 70% and 52%, respectively. On multivariate analysis, regional node metastasis and right-hand tumor location were significant predictors of shorter DFS and MSS, whereas mitoses negatively impacted DFS only and increasing Breslow thickness impacted MSS only. CONCLUSIONS: This study confirms that SUMs on the hand usually present at an advanced stage. Distal amputation appears safe for invasive SUMs, and SNB should be considered as these patients have a high risk of both SN and non-SN metastasis.

Margins of excision and prognostic factors for cutaneous eyelid melanomas.

BACKGROUND: Guidelines for wide excision of cutaneous melanomas according to Breslow thickness are impractical when considering melanomas arising on eyelid skin. No consensus exists regarding appropriate excision margins for these tumours. This study sought to determine whether excision margins influenced locoregional recurrence, and to identify prognostic factors for survival in these patients. METHODS: Fifty-six cases of invasive cutaneous eyelid melanomas diagnosed between 1985 and 2011 were identified from the database of Melanoma Institute Australia. Clinical and pathological factors were assessed for their associations with recurrence and survival. RESULTS: Local recurrence occurred in 12 patients (21%), nodal metastasis in 6 (11%) and distant metastasis in 2 (4%). Pathological margins>2 mm from the in situ component of the tumour were associated with increased disease-free survival (P=0.029) compared with margins≤2 mm but there was no statistically significant benefit for a pathological margin>2 mm from the invasive component. Lower eyelid melanomas were found to have a significantly higher local recurrence rate than upper eyelid melanomas (P=0.044). CONCLUSIONS: This series of cutaneous eyelid melanomas is the largest yet reported. The results suggest that, as a minimum, an in vivo surgical margin of 3 mm (corresponding to a 2 mm pathological margin after tissue fixation) is desirable for eyelid melanomas. We recommend a surgical excision margin of 3 mm for eyelid melanomas≤1 mm in Breslow thickness. However, for melanomas>1 mm in thickness, the current practice of aiming to achieve 5 mm margins would seem reasonable. Patients with lower eyelid melanomas warrant particularly close follow-up given their higher local recurrence rate.

Scar-improving efficacy of avotermin administered into the wound margins of skin incisions as evaluated by a randomized, double-blind, placebo-controlled, phase II clinical trial.

BACKGROUND: The authors report on a prospective, randomized, placebo-controlled phase II trial to investigate avotermin (transforming growth factor beta-3) for reducing scarring resulting from acute incised skin wounds. METHODS: Seventy-one healthy male subjects (18 to 45 years) received avotermin at 50 or 200 ng/100 µl/linear centimeter of wound margin. Subjects received three standardized 1-cm incisional wounds on the inner aspect of each upper arm. Wounds were randomized to receive (into each margin): no injection (standard wound care only), one intradermal injection of avotermin or placebo (immediately before surgery), or two injections of avotermin or placebo (immediately before surgery and 24 hours later). The primary efficacy variable was a 10-cm visual analog scale score, which assessed how closely scars resembled normal skin, administered at month 12 by an independent external scar assessment panel (a panel of lay public individuals). RESULTS: Avotermin at 200 ng/100 µl/linear centimeter, administered once or twice, achieved significant improvements in scar appearance compared with controls (p<0.02 for all comparisons). The 50-ng dose, administered twice, achieved significant improvements in scar appearance versus placebo (p=0.043). Treatment was well tolerated. CONCLUSION: These results confirm that avotermin is the first of a new class of regenerative medicines that reduce scarring when administered once or twice to the approximated margins of acute skin incisions.

Prophylactic administration of avotermin for improvement of skin scarring: three double-blind, placebo-controlled, phase I/II studies.

BACKGROUND: Research into mechanisms of skin scarring identified transforming growth factor beta3 (TGFbeta3) as a potential antiscarring therapy. We assessed scar improvement with avotermin (recombinant, active, human TGFbeta3). METHODS: In three double-blind, placebo-controlled studies, intradermal avotermin (concentrations ranging from 0.25 to 500 ng/100 microL per linear cm wound margin) was administered to both margins of 1 cm, full-thickness skin incisions, before wounding and 24 h later, in healthy men and women. Treatments (avotermin and placebo or standard wound care) were randomly allocated to wound sites by a computer generated randomisation scheme, and within-participant controls compared avotermin versus placebo or standard wound care alone. Primary endpoints were visual assessment of scar formation at 6 months and 12 months after wounding in two studies, and from week 6 to month 7 after wounding in the third. Investigators, participants, and scar assessors were blinded to treatment. Efficacy analyses were intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00847925, NCT00847795, and NCT00629811. RESULTS: In two studies, avotermin 50 ng/100 microL per linear cm significantly improved median score on a 100 mm visual analogue scale (VAS) by 5 mm (range -2 to 14; p=0.001) at month 6 and 8 mm (-29 to 18; p=0.0230) at month 12. In the third, avotermin significantly improved total scar scores at all concentrations versus placebo (mean improvement: from 14.84 mm [95 % CI 5.5-24.2] at 5 ng/100 microL per linear cm to 64.25 mm [49.4-79.1] at 500 ng/100 microL per linear cm). Nine [60%] scars treated with avotermin 50 ng/100 microL per linear cm showed 25% or less abnormal orientation of collagen fibres in the reticular dermis versus five [33%] placebo scars. After only 6 weeks from wounding, avotermin 500 ng/100 microL per linear cm improved VAS score by 16.12 mm (95% CI 10.61-21.63). Adverse events at wound sites were similar for avotermin and controls. Erythema and oedema were more frequent with avotermin than with placebo, but were transient and deemed to be consistent with normal wound healing. INTERPRETATION: Avotermin has potential to provide an accelerated and permanent improvement in scarring.

Maturation of the human scar: an observational study.

BACKGROUND: The natural history of scar maturation in humans has never been formally described from either a clinical or a histologic standpoint. METHODS: The maturation of incisional scars was observed in 58 healthy male volunteers who each had 2 x 1-cm incisional wounds created on the inner aspect of both upper arms. The resulting scars were photographed digitally at monthly intervals for 12 months and excised for histologic analysis at specific time points. All histologic specimens were stained using Masson's trichrome and reviewed together with the corresponding digital clinical scar images to produce macroscopic and microscopic descriptions of the maturation process. RESULTS: Three distinct groups, each displaying a different rate of longitudinal progression of scar maturation, were identified from within the study group. The majority of volunteers belonged to a "representative" subset but distinct "poor" and "excellent" subsets were also identified. The poor subset invariably contained volunteers younger than 30 years of age, whereas the majority of the excellent subset comprised subjects older than 55 years of age. CONCLUSIONS: Scar maturation occurs as a series of defined macroscopic and microscopic stages over the course of 1 year. The rate of scar maturation varied within the study group, with older subjects (>55 years) displaying accelerated maturation, whereas a prolonged high turnover state and a retarded rate of maturation were observed in younger subjects (<30 years).

Scar redness in humans: how long does it persist after incisional and excisional wounding?

BACKGROUND: The natural history of scar redness in humans has never been formally described, and the point at which normal scar redness fades is unknown. METHODS: As part of a randomized, placebo-controlled, clinical trial investigating the effects of various doses of transforming growth factor-beta3 on scar quality, the authors observed the process of scar redness and maturation in non-drug-treated incisional and excisional wounds made on the upper inner arms of 103 volunteers. Scar photographic images were assessed by a review panel to ascertain the month during which redness faded for a particular scar. Scar histology documented the level of inflammation and angiogenesis. RESULTS: Scar redness faded at an average of 7 months. Scar redness for incisions faded significantly faster than excisions (p = 0.0001, Kruskal-Wallis test), and significant differences were also seen between anteriorly and posteriorly placed scars for incisions (p = 0.0008) and excisions (p = 0.0035), respectively. Month 12 histologic examination revealed the absence of any ongoing inflammatory processes in all scars. CONCLUSIONS: Scar redness fades on average at 7 months. This is influenced by the wound type and position. The authors advocate the use of the term "rubor perseverans" to describe the physiologic redness of a normal scar as it matures beyond the first month, a process that does not involve inflammation.

Visual analogue scale scoring and ranking: a suitable and sensitive method for assessing scar quality?

BACKGROUND: The field of scar assessment lacks a standard methodology. Previous methods have focused on a wide range of scar types, resulting in poorer sensitivity and diminishing their discriminatory effectiveness. METHODS: As part of a clinical trial investigating the scar-improving efficacy of transforming growth factor-beta3, the authors investigated the use of a visual analogue scale and scar ranking as scar assessment tools. Scar photographic images were assessed using a newly developed computerized scar assessment system by an external lay panel. RESULTS: A total of 4296 scar images were collected for visual analogue scale assessment and 2148 scar pairs were collected for scar ranking. Intrarater consistency was 100 percent for the ranking data, with differences very close to zero for the visual analogue scale consistency data. Reducing the number of assessors in the external panel significantly improved intraclass correlation coefficients. From month 1 to month 12, the correlation coefficients for the difference in visual analogue scale score showed that the assessors reliably noted the changes in the maturing scars. Combining logistic regression with an area under the curve of 0.72 in a receiver operating characteristic curve analysis, the visual analogue scale score was shown to be a highly statistically significant predictor of a good scar. CONCLUSIONS: The authors have shown the visual analogue scale scar scoring and scar ranking methods to be consistent, reliable, valid, and feasible. These methods for scar assessment are highly sensitive and capable of reliably measuring differences in scar quality, making them valuable techniques, reaching an unmet clinical need, and enabling investigation of changes in scar quality (e.g., with time or after therapeutic intervention).

Assemblies of Alzheimer's peptides A beta 25-35 and A beta 31-35: reverse-turn conformation and side-chain interactions revealed by X-ray diffraction.

Alzheimer's beta amyloid protein (A beta) is a 39 to 43 amino acid peptide that is a major component in the neuritic plaques of Alzheimer's disease (AD). The assemblies constituted from residues 25-35 (A beta 25-35), which is a sequence homologous to the tachykinin or neurokinin class of neuropeptides, are neurotoxic. We used X-ray diffraction and electron microscopy to investigate the structure of the assemblies formed by A beta 25-35 peptides and of various length sequences therein, and of tachykinin-like analogues. Most solubilized peptides after subsequent drying produced diffraction patterns characteristic of beta-sheet structure. Moreover, the peptides A beta 31-35 (Ile-Ile-Gly-Leu-Met) and tachykinin analogue A beta(Phe(31))31-35 (Phe-Ile-Gly-Leu-Met) gave powder diffraction patterns to 2.8A Bragg spacing. The observed reflections were indexed by an orthogonal unit cell having dimensions of a=9.36 A, b=15.83 A, and c=20.10 A for the native A beta 31-35 peptide, and a=9.46 A, b=16.22 A, and c=11.06 A for the peptide having the Ile31Phe substitution. The initial model was a beta strand where the hydrogen bonding, chain, and intersheet directions were placed along the a, b, and c axes. An atomic model was fit to the electron density distribution, and subsequent refinement resulted in R factors of 0.27 and 0.26, respectively. Both peptides showed a reverse turn at Gly33 which results in intramolecular hydrogen bonding between the antiparallel chains. Based on previous reports that antagonists for the tachykinin substance P require a reverse turn, and that A beta is cytotoxic when it is oligomeric or fibrillar, we propose that the tachykinin-like A beta 31-35 domain is a turn exposed at the A beta oligomer surface where it could interact with the ligand-binding site of the tachykinin G-protein-coupled receptor.

Molecular organization of amyloid protofilament-like assembly of betabellin 15D: helical array of beta-sandwiches.

Betabellin is a 32-residue peptide engineered to fold into a four-stranded antiparallel beta-sheet protein. Upon air oxidation, the betabellin peptides can fold and assemble into a disulfide-bridged homodimer, or beta-sandwich, of 64 residues. Recent biophysical and ultrastructural studies indicate that betabellin 15D (B15D) (a homodimer of HSLTAKIpkLTFSIAphTYTCAVpkYTAKVSH, where p = DPro, k = DLys, and h = DHis) forms unbranched, 35-A wide assemblies that resemble the protofilaments of amyloid fibers. In the present study, we have analyzed in detail the X-ray diffraction patterns of B15D prepared from acetonitrile. The fiber diffraction analysis indicated that the B15D fibril was composed of a double helix defined by the selection rule l = n + 7m (where l is even, and n and m are any integers), and having a 199-A period and pitch, 28-A rise per unit, and 10-A radius. This helical model is equivalent to a reverse-handed, single helix with half the period and defined by the selection rule l = -3n + 7m (where l is any integer). The asymmetric unit is the single B15D beta-sandwich molecule. These results suggest that the betabellin assembly that models the protofilaments of amyloid fibers is made up of discrete subunits on a helical array. Multiple intersheet hydrogen bonds in the axial direction and intersandwich polar interactions in the lateral direction stabilize the array.