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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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Antiseptic negative pressure instillation therapy for the treatment of septic wound healing deficits in oral and maxillofacial surgery.
Eckstein, FM, Pinsel, V, Wurm, MC, Wilkerling, A, Dietrich, EM, Kreißel, S, von WIlmowsky, C, Schlittenbauer, T
Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery. 2019;(3):389-393
Abstract
INTRODUCTION Impaired wound healing, chronic wounds and extended soft tissue defects present a crucial problem in reconstructive surgery of the head and neck region, even more after radiation therapy. In such cases the standard is a prolonged open wound treatment. The negative pressure instillation therapy might present an alternative therapy option. MATERIAL AND METHODS In this study the effects of negative pressure instillation therapy on the healing of chronic wounds in 15 patients diagnosed with impaired wound healing were investigated. These based upon infected osteoradionecrosis and osteomyelitis of the jaw. The parameters investigated as markers of the therapeutic success were serum inflammatory parameters i.e. white blood cell counts, wound smear results and wound surface reduction. RESULTS The use of negative pressure instillation therapy lead to a reduction of the bacterial load and formation of a stabile granulation tissue in all but one case. The mean inpatient time of the patients was 13.33 ± 4.62 days. Between 2 and 8 dressing changes were needed to reach clinical sufficient wound healing results. Secondary intention wound healing could be obtained in 14 out of 15 cases. The crucial part for the successful application was a watertight enoral suturing as oro-cutaneous fistulae were present in most cases. CONCLUSION The negative pressure instillation therapy poses a good treatment for wound healing problems and extended size soft tissue defects, even when oro-cutaneous fistulae were present. Especially in cases that contraindicate micro-vascular reconstruction, negative pressure instillation therapy could be a good alternative.
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Improvement in wound healing, pain, and quality of life after 12 weeks of SNF472 treatment: a phase 2 open-label study of patients with calciphylaxis.
Brandenburg, VM, Sinha, S, Torregrosa, JV, Garg, R, Miller, S, Canals, AZ, Bahr, D, Joubert, PH, Salcedo, C, Carroll, KJ, et al
Journal of nephrology. 2019;(5):811-821
Abstract
BACKGROUND Calciphylaxis in end-stage renal disease is characterized by painful necrotic skin ulcers and high mortality. There are no approved therapies. SNF472, an intravenous formulation of myo-inositol hexaphosphate, inhibits the formation and growth of hydroxyapatite crystals, the final common pathway in the pathogenesis of vascular calcification. METHODS In this open-label, single-arm study, calciphylaxis patients on thrice-weekly hemodialysis and standard care, received intravenous SNF472 3 times per week for 12 weeks. The primary endpoint was wound healing assessed using the quantitative Bates-Jensen Wound Assessment Tool (BWAT). Pain visual analog scale (VAS), quality of life (wound-QoL), and qualitative wound image review were secondary endpoints. Quantitative changes from baseline were analyzed by paired t-tests using multiple imputation to account for missing observations. RESULTS Fourteen patients received SNF472. Improvements from baseline to week 12 were observed for mean BWAT score (- 8.1; P < 0.001), pain VAS (- 23.6 mm; P = 0.015) and wound-QoL global score (- 0.90; P = 0.003). Of the 9 patients with ulcerated lesions at baseline who completed treatment, wound image review showed improvement for 7. SNF472 was well tolerated with no serious treatment-related adverse events. The most common adverse events were infections which occur frequently in patients on hemodialysis. None of these were considered as treatment-related. CONCLUSIONS SNF472 was well-tolerated and improvements from baseline to week 12 in wound healing, pain, and quality of life were observed. A randomized, double-blind, placebo-controlled trial is planned to evaluate SNF472 in patients with calciphylaxis.
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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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Hypertrophic Scars: Are Vitamins and Inflammatory Biomarkers Related with the Pathophysiology of Wound Healing?
Correia-Sá, I, Serrão, P, Marques, M, Vieira-Coelho, MA
Obesity surgery. 2017;(12):3170-3178
Abstract
BACKGROUND Hypertrophic scars are a consequence of wound healing. OBJECTIVE The objective of the present study is to evaluate vitamin D and inflammatory biomarker plasma levels during wound healing. METHODS A prospective study was performed in patients (n = 63) submitted to body contouring surgery. Blood samples were collected before (t 0) and 5 days after surgery (t 5). Blood cell count, protein inflammatory biomarkers, and circulating plasma levels of 25(OH)D, vitamin A and vitamin E were quantified. Six months after surgery, scars were evaluated and classified as normal or hypertrophic. RESULTS At the end of the study, 73% of the patients developed a normal scar (control group, n = 46) and 27% of the patients presented hypertrophic scars (HT group, n = 17). The patients in the HT group presented higher eosinophil (0.145 × 109 /L vs. 0.104 × 109 /L, p = 0.028) and basophil count (0.031 × 109 /L vs. 0.22 × 109 /L, p = 0.049) and C-reactive protein levels (6.12 mg/L vs. 2.30 mg/L, p = 0.015) in t 0 than the patients in the control group. At t 5, the patients in the HT group showed a decrease in neutrophil (3.144 × 109/L vs. 4.03 × 109/L, p = 0.031) and an increase in basophil (0.024 × 109/L vs. 0.015 × 109/L, p = 0.005) and lymphocyte count (1.836 × 109 /L vs. 1.557 × 109/L; p = 0.028). Before surgery, vitamin D plasma levels were found to be decreased by almost 50% (23.52 ng/mL vs. 15.46 ng/mL, p = 0.031) in the patients who developed hypertrophic scars. Thirty-one percent of the patients submitted to bariatric surgery had more hypertrophic scars, versus 24% of the patients with no previous bariatric surgery. CONCLUSION There is a different systemic inflammatory profile response in the patients during the formation of hypertrophic scars. Vitamin D plasma levels are marked reduced in these patients. Considering the powerful anti-inflammatory effect of vitamin D, these findings could be related.
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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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Does intrawound application of vancomycin influence bone healing in spinal surgery?
Eder, C, Schenk, S, Trifinopoulos, J, Külekci, B, Kienzl, M, Schildböck, S, Ogon, M
European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society. 2016;(4):1021-8
Abstract
PURPOSE Surgical site infections represent a major complication of spinal surgery. The application of lyophilised vancomycin into the wound is reported to significantly decrease infection rates. As concentrations applied locally can exceed the minimal bacterial inhibitory concentration for more than a 1000-fold, toxic side effects on local tissue may be possible. METHODS Primary osteoblast cell cultures were generated from bone tissue samples of 10 patients. Samples were incubated in absence or presence of either 3, 6 or 12 mg/cm(2) vancomycin according to a planned phase I clinical trial protocol. Changes in pH, osteoblast migration, proliferation and viability were analysed. Alkaline phosphatase as well as mineralisation patterns was studied. RESULTS The application of more than 3 mg/cm(2) vancomycin induced a decline of pH. The migration potential of osteoblasts was decreased from 100% (control samples) to zero (12 mg/cm(2) vancomycin) in a dose-dependant manner. Cell proliferation was significantly inhibited at dosages above 3 mg/cm(2). Significant cell death was observed if the dosage applied exceeded 6 mg/cm(2). The synthesis of alkaline phosphatase was markedly reduced in all dosages applied and calcium deposition was significantly decreased in dosages above 3 mg/cm(2). CONCLUSION As bone remodelling requires the immigration, proliferation and differentiation of osteoblasts at the fusion site, high dosages of intrawound vancomycin might interfere with regenerative processes and increase the risk of non-union. To allow an appropriate balance of infection risk and the risk of non-union, the minimal local concentration required should be determined by controlled in vivo studies.
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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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Clinical outcomes of WF10 adjunct to standard treatment of diabetic foot ulcers.
Yingsakmongkol, N
Journal of wound care. 2013;(3):130-2, 134-6
Abstract
OBJECTIVE To study clinical outcomes and safety of WF I 0 as an adjunct to standard treatment for diabetic foot ulcers (DFU) and to determine the optimal number of WF I 0 cycles that should be administered. METHOD A prospective, open-label study of WF I 0 adjunct to standard treatment for severe DFU but salvageable foot was carried out between July 2009 and June 20 I 0. Patients were classified into three groups, according to common clinical presentations: neuropathic ulcer, ischaemic ulcer and severely infected ulcer. Ulcer assessments were monitored using the wound severity score (WSS; range 0-16).The clinical outcomes at 24 weeks were defined as 'good' (ulcer achieved endpoint [WSS=0-1 ]), 'fair'(improved from baseline [WSS=2-4]) and 'poor' (not improved or worsened [WSS > 4]). RESULTS From a total of 129 patients, 21 ( 16%) presented with neuropathic ulcers, 49 (38%) with ischaemic ulcers and 59 (46%) with severely infected ulcers.AII neuropathic ulcers achieved either a good or fair outcome, with 81% achieving a good outcome, as did 49% and 81% of ischaemic and severely infected ulcers, respectively. Minor amputations were necessary for 14 patients (I I%), but no major amputation was required. Twenty seven patients (21 %) had transient reduction of haematocrit after WF I 0 therapy. One hundred and one patients (78 %) received only I cycle of WF I 0. CONCLUSION WF I 0 as an adjunct to standard DFU treatment showed good clinical outcomes in the neuropathic ulcer group and the severely infected ulcer group. A side effect of WF I 0, transient reduction of haematocrit, was observed in 21% of patients. Most patients required only one cycle of WF I 0.