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Histologic Outcomes With Vedolizumab Versus Adalimumab in Ulcerative Colitis: Results From An Efficacy and Safety Study of Vedolizumab Intravenous Compared to Adalimumab Subcutaneous in Participants With Ulcerative Colitis (VARSITY).
Peyrin-Biroulet, L, Loftus, EV, Colombel, JF, Danese, S, Rogers, R, Bornstein, JD, Chen, J, Schreiber, S, Sands, BE, Lirio, RA
Gastroenterology. 2021;(4):1156-1167.e3
Abstract
BACKGROUND AND AIMS VARSITY (An Efficacy and Safety Study of Vedolizumab Intravenous [IV] Compared to Adalimumab Subcutaneous [SC] in Participants With Ulcerative Colitis) showed superior clinical remission and endoscopic improvement in ulcerative colitis with vedolizumab vs adalimumab. This analysis compared histologic outcomes. METHODS Patients in VARSITY were randomized 1:1 to maintenance with vedolizumab IV 300 mg every 8 weeks or adalimumab SC 40 mg every 2 weeks (both following standard induction). Geboes Index and Robarts Histopathology Index (RHI) scores were used to assess prespecified histologic exploratory end points of histologic remission (Geboes <2 or RHI ≤2) and minimal histologic disease activity (Geboes ≤3.1 or RHI ≤4) at weeks 14 and 52. RESULTS In total, 769 patients received vedolizumab (n = 383) or adalimumab (n = 386). Mean baseline histologic disease activity was similar between vedolizumab and adalimumab groups. Vedolizumab induced greater histologic remission than adalimumab at week 14 (Geboes: 16.7% vs 7.3%, Δ9.4% [95% confidence interval {CI}, 4.9%-13.9%], P < .0001; RHI: 25.6% vs 16.1%, Δ9.5% [95% CI, 3.8%-15.2%], P = .0011) and week 52 (Geboes: 29.2% vs 8.3%, Δ20.9% [95% CI, 15.6%-26.2%], P < .0001; RHI: 37.6% vs 19.9%, Δ17.6% [95% CI, 11.3%-23.8%], P < .0001) overall and in both anti-tumor necrosis factor (TNF)-naïve and -failure subgroups. Results were similar for minimal histologic disease activity. Histologic outcomes were generally better in anti-TNF-naïve vs -failure patients. At week 52, rates of mucosal healing (composite end point of histologic plus endoscopic improvement) were also higher with vedolizumab than adalimumab (Geboes: 25.6% vs 6.7%; RHI: 30.5% vs 14.5%). CONCLUSIONS Higher rates of histologic remission, minimal histologic disease activity, and combined histologic plus endoscopic outcomes were observed with vedolizumab than with adalimumab in ulcerative colitis in both anti-TNF-naïve and -failure subgroups. REGISTRATION ClinicalTrials.gov NCT02497469; EudraCT 2015-000939-33.
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A bioengineered living cell construct activates metallothionein/zinc/MMP8 and inhibits TGFβ to stimulate remodeling of fibrotic venous leg ulcers.
Stone, RC, Stojadinovic, O, Sawaya, AP, Glinos, GD, Lindley, LE, Pastar, I, Badiavas, E, Tomic-Canic, M
Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society. 2020;(2):164-176
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Abstract
Venous leg ulcers (VLU) represent a major clinical unmet need, impairing quality of life for millions worldwide. The bioengineered bilayered living cell construct (BLCC) is the only FDA-approved therapy demonstrating efficacy in healing chronic VLU, yet its in vivo mechanisms of action are not well understood. Previously, we reported a BLCC-mediated acute wounding response at the ulcer edge; in this study we elucidated the BLCC-specific effects on the epidermis-free ulcer bed. We conducted a randomized controlled clinical trial (ClinicalTrials.gov NCT01327937) enrolling 30 subjects with nonhealing VLUs, and performed genotyping, genomic profiling, and functional analysis on wound bed biopsies obtained at baseline and 1 week after treatment with BLCC plus compression or compression therapy (control). The VLU bed transcriptome featured processes of chronic inflammation and was strikingly enriched for fibrotic/fibrogenic pathways and gene networks. BLCC application decreased expression of profibrotic TGFß1 gene targets and increased levels of TGFß inhibitor decorin. Surprisingly, BLCC upregulated metallothioneins and fibroblast-derived MMP8 collagenase, and promoted endogenous release of MMP-activating zinc to stimulate antifibrotic remodeling, a novel mechanism of cutaneous wound healing. By activating a remodeling program in the quiescent VLU bed, BLCC application shifts nonhealing to healing phenotype. As VLU bed fibrosis correlates with poor clinical healing, findings from this study identify the chronic VLU as a fibrotic skin disease and are first to support the development and application of antifibrotic therapies as a successful treatment approach.
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Efficacy and Safety of 4% Hibiscus rosa-sinensis Leaf Extract Ointment as an Adjunct Treatment to Compression Stockings on the Closure of Venous Leg Ulcers: A Pilot Study.
Maralit Bruan, MJ, Tianco, EA
Wounds : a compendium of clinical research and practice. 2019;(9):236-241
Abstract
INTRODUCTION Venous leg ulcers (VLUs), the most common leg ulceration worldwide, are caused by venous hypertension due to venous reflux, the failure of the calf muscle to pump, and venous flow obstruction. They are associated with a reduced quality of life, particularly in relation to pain and physical function. Hibiscus rosa-sinensis is commonly employed because of its many medicinal properties, and studies have shown Hibiscus contains phytochemicals that have antimicrobial, antioxidant, and anti-inflammatory properties that promote wound healing. OBJECTIVE The authors evaluate the efficacy and safety of 4% gumamela leaf extract ointment in the closure of VLUs among patients seen in a dermatology outpatient department in the Philippines. MATERIALS AND METHODS The study included male or female patients with leg ulcers confirmed by duplex scan to be venous in origin and willing to have elastic compression therapy. Patients were instructed to clean the wound with normal saline solution and to apply the extract twice daily. The study was conducted for 12 weeks or until wound closure. Wounds were evaluated and photographed at baseline and every subsequent 2 weeks. Efficacy of therapy was evaluated based on ulcer area size using planimetry method at each visit. Safety was assessed using a 4-point grading system to monitor possible adverse reactions, namely pruritus, rash, burning, and urticaria. RESULTS Twelve patients were included in the study; 5 patients had an initial ulcer area of ⟩ 10 cm2 and 7 had an initial ulcer area of ≤ 10 cm2. By the end of the study, 10 patients (83.3%) achieved complete ulcer closure in ⟨ 12 weeks, 1 patient (8.3%) had a decrease in ulcer area ⟩ 50% by week 12, and 1 patient (8.3%) had ⟨ 50% decrease in ulcer area at the end of the study. CONCLUSIONS Data showed compression stockings with 4% gumamela leaf extract ointment application could close VLUs in ⟨ 12 weeks. Applied with compression stockings, the ointment shows potential use in VLU management.
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The Use of a Sea Salt-based Spray for Diabetic Foot Ulcers: A Novel Concept.
Pougatsch, DA, Rader, A, Rogers, LC
Wounds : a compendium of clinical research and practice. 2017;(2):E5-E9
Abstract
Several patients present to wound healing specialists seeking a natural or alternative medical approach to their wounds. The purpose of this prospective, case-cohort study of 10 patients was to evaluate the use of Oceanzyme Wound Care Spray (Ocean Aid, Inc, Boynton Beach, FL) in improving healing in diabetic foot ulcers during a 12-week period. This product contains water purified by reverse osmosis, coral reef sea salt, lysozyme, and sodium benzoate. The primary endpoint was wound closure, and secondary endpoints were infection rate and wound area reduction. Overall, 2 patients healed, 2 withdrew, and the remaining 6 had an average of 73% reduction in wound area. While more study is needed, the use of this sea salt-based spray may provide a viable alternative for patients seeking a natural therapy for their wound care.
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Rapid healing of cutaneous leishmaniasis by high-frequency electrocauterization and hydrogel wound care with or without DAC N-055: a randomized controlled phase IIa trial in Kabul.
Jebran, AF, Schleicher, U, Steiner, R, Wentker, P, Mahfuz, F, Stahl, HC, Amin, FM, Bogdan, C, Stahl, KW
PLoS neglected tropical diseases. 2014;(2):e2694
Abstract
BACKGROUND Anthroponotic cutaneous leishmaniasis (CL) due to Leishmania (L.) tropica infection is a chronic, frequently disfiguring skin disease with limited therapeutic options. In endemic countries healing of ulcerative lesions is often delayed by bacterial and/or fungal infections. Here, we studied a novel therapeutic concept to prevent superinfections, accelerate wound closure, and improve the cosmetic outcome of ACL. METHODOLOGY/PRINCIPAL FINDINGS From 2004 to 2008 we performed a two-armed, randomized, double-blinded, phase IIa trial in Kabul, Afghanistan, with patients suffering from L. tropica CL. The skin lesions were treated with bipolar high-frequency electrocauterization (EC) followed by daily moist-wound-treatment (MWT) with polyacrylate hydrogel with (group I) or without (group II) pharmaceutical sodium chlorite (DAC N-055). Patients below age 5, with facial lesions, pregnancy, or serious comorbidities were excluded. The primary, photodocumented outcome was the time needed for complete lesion epithelialization. Biopsies for parasitological and (immuno)histopathological analyses were taken prior to EC (1(st)), after wound closure (2(nd)) and after 6 months (3(rd)). The mean duration for complete wound closure was short and indifferent in group I (59 patients, 43.1 d) and II (54 patients, 42 d; p = 0.83). In patients with Leishmania-positive 2(nd) biopsies DAC N-055 caused a more rapid wound epithelialization (37.2 d vs. 58.3 d; p = 0.08). Superinfections occurred in both groups at the same rate (8.8%). Except for one patient, reulcerations (10.2% in group I, 18.5% in group II; p = 0.158) were confined to cases with persistent high parasite loads after healing. In vitro, DAC N-055 showed a leishmanicidal effect on pro- and amastigotes. CONCLUSIONS/SIGNIFICANCE Compared to previous results with intralesional antimony injections, the EC plus MWT protocol led to more rapid wound closure. The tentatively lower rate of relapses and the acceleration of wound closure in a subgroup of patients with parasite persistence warrant future studies on the activity of DAC N-055. TRIAL REGISTRATION ClinicalTrials.gov NCT00947362.
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StrataGraft skin substitute is well-tolerated and is not acutely immunogenic in patients with traumatic wounds: results from a prospective, randomized, controlled dose escalation trial.
Centanni, JM, Straseski, JA, Wicks, A, Hank, JA, Rasmussen, CA, Lokuta, MA, Schurr, MJ, Foster, KN, Faucher, LD, Caruso, DM, et al
Annals of surgery. 2011;(4):672-83
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Abstract
OBJECTIVE The goal of this study was to assess the immunogenicity and antigenicity of StrataGraft skin tissue in a randomized phase I/II clinical trial for the temporary management of full-thickness skin loss. BACKGROUND StrataGraft skin tissue consists of a dermal equivalent containing human dermal fibroblasts and a fully stratified, biologically active epidermis derived from Near-diploid Immortalized Keratinocyte S (NIKS) cells, a pathogen-free, long-lived, consistent, human keratinocyte progenitor. METHODS Traumatic skin wounds often require temporary allograft coverage to stabilize the wound bed until autografting is possible. StrataGraft and cadaveric allograft were placed side by side on 15 patients with full-thickness skin defects for 1 week before autografting. Allografts were removed from the wound bed and examined for allogeneic immune responses. Immunohistochemistry and indirect immunofluorescence were used to assess tissue structure and cellular composition of allografts. In vitro lymphocyte proliferation assays, chromium-release assays, and development of antibodies were used to examine allogeneic responses. RESULTS One week after patient exposure to allografts, there were no differences in the numbers of T or B lymphocytes or Langerhans cells present in StrataGraft skin substitute compared to cadaver allograft, the standard of care. Importantly, exposure to StrataGraft skin substitute did not induce the proliferation of patient peripheral blood mononuclear cells to NIKS keratinocytes or enhance cell-mediated lysis of NIKS keratinocytes in vitro. Similarly, no evidence of antibody generation targeted to the NIKS keratinocytes was seen. CONCLUSIONS These findings indicate that StrataGraft tissue is well-tolerated and not acutely immunogenic in patients with traumatic skin wounds. Notably, exposure to StrataGraft did not increase patient sensitivity toward or elicit immune responses against the NIKS keratinocytes. We envision that this novel skin tissue technology will be widely used to facilitate the healing of traumatic cutaneous wounds.This study was registered at www.clinicaltrials.gov (NCT00618839).
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Uncontrolled, open-label, pilot study of tea tree (Melaleuca alternifolia) oil solution in the decolonisation of methicillin-resistant Staphylococcus aureus positive wounds and its influence on wound healing.
Edmondson, M, Newall, N, Carville, K, Smith, J, Riley, TV, Carson, CF
International wound journal. 2011;(4):375-84
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Abstract
Many complementary and alternative products are used to treat wounds. The essential oil of Melaleuca alternifolia, tea tree oil, has proven antimicrobial and anti-inflammatory properties, may be useful in methicillin-resistant Staphylococcus aureus (MRSA) decolonisation regimens and is reputed to have 'wound-healing' properties, but more data are required to support these indications. The primary aim of this uncontrolled case series was to assess whether a tea tree oil solution used in a wound cleansing procedure could decolonise MRSA from acute and chronic wounds of mixed aetiology. The secondary aim was to determine if the tea tree oil solution influenced wound healing outcomes. Nineteen participants with wounds suspected of being colonised with MRSA were enrolled in a pilot study. Seven were subsequently shown not to have MRSA and were withdrawn from the study. As many as 11 of the remaining 12 participants were treated with a water-miscible tea tree oil (3·3%) solution applied as part of the wound cleansing regimen at each dressing change. Dressing changes were three times per week or daily as deemed necessary by the study nurse following assessment. One participant withdrew from the study before treatment. No participants were MRSA negative after treatment. After treatment had been implemented, 8 of the 11 treated wounds had begun to heal and reduced in size as measured by computer planimetry. Although this formulation and mode of delivery did not achieve the primary aim of the study, tea tree oil did not appear to inhibit healing and the majority of wounds reduced in size after treatment.
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Two percent topical phenytoin sodium solution in treating pyoderma gangrenosum: a cohort study.
Fonseka, HF, Ekanayake, SM, Dissanayake, M
International wound journal. 2010;(6):519-23
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Abstract
Oral phenytoin is an extensively used medicine for the treatment of convulsive disorders. Topical phenytoin has also been used for various types of ulcers. To determine the effectiveness of 2% topical phenytoin sodium solution in treating recalcitrant pyoderma gangrenosum. Six patients with treatment-resistant pyoderma gangrenosum who attended to Dermatology Unit/Ward were taken to the study and applied topical 2% phenytoin sodium solution to the wounds alone with other systemic therapy. Response to the treatment was assessed weekly. Three patients had idiopathic PG and other three had secondary diseases. At the end of the 4th week four patients showed complete resolution of the ulcers whereas other two patients showed the partial resolution. No adverse effects were noted. Phenytoin sodium 2% solution is beneficial for pyoderma gangrenosum (PG) with various etiologies. It enhanced the healing of the ulcer especially when the patient has treatment resistant disease.