The Management of Chronic Graft-Versus-Host Disease Skin Ulcers after Hematopoietic Stem Cell Transplantation: A Case Report.

ABSTRACT: The comprehensive management of a patient with chronic graft-versus-host disease skin ulcers after hematopoietic stem cell transplantation is challenging. This report describes the case of a 53-year-old woman who presented with ulcers on her right leg 140 weeks after a bone marrow transplant. The patient received wound assessment and management based on the Triangle of Wound Assessment and Wound Bed Preparation 2021, respectively. Hydrogel and antibacterial protease dressings were applied along with systemic oral administration of moxifloxacin hydrochloride (two capsules, two times daily) and JiXueGanPian tablets (classic Chinese herbal formula; two capsules, two times daily), hospital-community-home continuous care, and patient-centered education. Finally, after 133 days of nursing, the patient's wound was completely healed without complications or other skin issues. The use of hydrogel combined with the antibacterial protease dressing was a promising technique for handling this type of wound, enhanced by multidisciplinary collaboration. Of course, providing patients with education that focuses on prevention is necessary.

Healing refractory livedoid vasculopathy-related skin ulcers by ozone therapy: a case-based review.

Chronic skin wounds represent a prominent etiological factor in the occurrence of non-traumatic foot amputations on a global scale and pose a substantial threat to the patient's well-being and mortality in the absence of effective treatment strategies. There exists a subset of patients that exhibit an insufficient response to different treatment options, comprising antibiotics, dressings, gauze bandages, debridement, rehabilitation, collagen patch, and vacuum-assisted closure. In this patient group, distinct treatment strategies emerge before surgery and amputation. Ozone therapy is one of them. Ozone exhibits a wide variety of effects such as antimicrobial, anti-inflammatory, antioxidant, and trophic. Its trophic effect is mediated by disinfection, stimulation of granulation tissue, acceleration of the angiogenesis process, and detoxification mechanisms. In this article, we presented the beneficial effect of ozone therapy in a case of chronic skin ulcer associated with livedoid vasculopathy. In this context, we aimed to discuss the role of ozone therapy in the management of chronic skin ulcers. Finally, we focused on ozone therapy as a promising method in inflammatory rheumatic diseases.

Non-surgical local treatments of digital ulcers in systemic sclerosis: a systematic literature review.

INTRODUCTION: Digital ulcers (DUs) are difficult to treat in patients with systemic sclerosis (SSc) and systemic (i.e., pharmacological) therapy is currently considered the 'standard of care'. Our aim was to examine the safety and efficacy of local, non-surgical treatment for SSc-DUs. METHODS: A systematic literature review (SLR) of original research articles up to August, 29 2022 was performed according to the PICO framework. References were independently screened by two reviewers and risk of bias was assed using validated tools. Due to study heterogeneity narrative summaries are used to present data. RESULTS: Among 899 retrieved references, 14 articles were included (2 randomised trials (RTs), and 12 observational (OBS) studies). The most frequently studied procedure (5 studies) was botulin A toxin (hand or single finger) injection with a reported healing rate (HR) of 71%-100%. Amniotic and hydrocolloid membranes were examined in one study each and associated with a good HR. Tadalafil 2% cream was studied in a single study with a reduction in the number of DUs. Vitamin E gel was associated with a reduction in ulcer healing time. Low-level light therapy, hydrodissection and corticosteroid injection, extracorporeal shock wave (ESW) and photobiomodulation were evaluated in a single study each and showed a positive trend. Dimethyl sulfoxide was associated with significant local toxicity. CONCLUSIONS: A range of non-surgical, local treatments for SSc-DUs have been explored and showed efficacy to some extent. We have identified methodological flaws that should be avoided in the design of future studies to explore locally-acting treatments for SSc-DUs.

Case report and literature review on a large MBC with ulceration.

RATIONALE: Metaplastic breast cancer (MBC) is a rare tumor of the breast, and skin ulceration of breast tumors is a difficult clinical problem that reduces the patient's quality of life. PATIENT CONCERNS: There are currently no Standard Treatment Guidelines for MBC at present, and the treatment for the skin ulceration of breast tumors is limited in clinics. DIAGNOSIS: Here, we report the case of a patient with a large MBC and skin ulceration, accompanied by exudation and odor. INTERVENTION: The combined treatment of albumin paclitaxel and carrelizumab (anti-PD-1 immunotherapy) was effective in reducing the tumor, but it increased the severity of the skin ulceration. After taking traditional Chinese medicine, the skin ulceration healed completely. Then the patient underwent a mastectomy and radiotherapy. OUTCOMES: The patient has a high quality of life and was in good condition after the comprehensive treatment. LESSONS: This suggests that traditional Chinese medicine may have a good auxiliary therapeutic effect on the skin ulceration of MBC.

Efficacy of local oxygen-ozone therapy for the treatment of digital ulcer refractory to medical therapy in systemic sclerosis: A randomized controlled study.

BACKGROUND: This study aimed to investigate the efficacy of local oxygen-ozone therapy in systemic sclerosis (SSc) patients with digital ulcers (DUs) who were resistant to medical therapy and had impairment in activities of daily living. METHODS: Participants' demographic data, and clinical parameters were recorded. Twenty-five SSc patients with DUs were randomized to the ozone group (I) (n = 13) to receive medical treatment plus local oxygen-ozone therapy and the control group (II) (n = 12) to receive medical treatment only. Hand functions were assessed using the Health Assessment Questionnaire (HAQ) and the Modified Hand Mobility in Scleroderma (HAMISm) test. Clinical parameters, HAQ, and mHAMIS scores were re-evaluated in participants 4 weeks after the initiation of treatment. RESULTS: Demographic and clinical characteristics of the two groups showed no significant differences. At 4 weeks after the initial treatment, the efficacy rate was significantly higher in the ozone group than that in the control group (92% versus 42% P = 0.010). Clinical parameters, HAQ, and HAMISm scores were significantly improved in the treatment group compared to those in the control group (P < 0.05). CONCLUSION: Local oxygen-ozone therapy was effective in the treatment of SSc patients with resistant DUs and improved clinical parameters and functional disability.

Gene set enrichment analysis and ingenuity pathway analysis to identify biomarkers in Sheng-ji Hua-yu formula treated diabetic ulcers.

ETHNOPHARMACOLOGICAL RELEVANCE: Sheng-ji Hua-yu (SJHY) formula is a Chinese herbal prescription for diabetic ulcers (DUs) treatment, which can accelerate wound reconstruction and shorten the healing time. However, its mechanism role maintains unclear. AIM OF THE STUDY: To elucidate the molecular mechanisms of SJHY application on DUs. MATERIALS AND METHODS: To begin with, transcriptome sequencing was adopted to identified differentially expression mRNAs among normal ulcers, DUs, and DUs + SJHY treatment in vivo. Liquid chromatography-tandem mass spectrometry was applied for the quality control of SJHY formula. GO and KEGG enrichment analysis were used to identify the mechanisms underlying the therapeutic effect of SJHY formula, and then gene set enrichment analysis and ingenuity pathway analysis were conducted for functional analysis. Further, qPCR detection was performed in vivo for validation. RESULTS: SJHY administration could regulate the glucose metabolic process, AMPK and HIF-1 pathway to accelerate healing processes of DUs. Besides, CRHR1, SHH, and GAL were identified as the critical targets, and SLC6A3, GRP, FGF23, and CYP27B1 were considered as the upstream genes of SJHY treatment. Combined with animal experiments, the prediction results were validated in DUs mice model. CONCLUSIONS: This study used modular pharmacology analysis to identify the biomarkers of SJHY formula and provide the potential therapeutic targets for DUs treatment as well.

Locoregional Treatments for Digital Ulcers in Systemic Sclerosis: A Systematic Review.

The management of digital ulcers in systemic sclerosis is difficult. While the 2017 European League Against Rheumatism (EULAR) guidelines clearly defined the use of systemic therapies for digital ulcers, little is known about the efficacy of locoregional treatments. The aim of this review is to systematically assess the spectrum of published locoregional therapies for digital ulcers. A total of 58 studies were included. Among the different locoregional treatment strategies described, injections of fat-derived cells and botulinum toxin showed promising results in the reduction of pain and the number of digital ulcers. By contrast, this review found that sympathectomy yielded disappointing results, with low rates of effectiveness and frequent recurrence. For other treatments, such as hyperbaric oxygen therapy, phototherapy (ultraviolet A), low-level light therapy, intermittent compression, Waon therapy, extracorporeal shockwave, vitamin E gel, and topical dimethyl sulphoxide, the conflicting results or limited published data reflected the low level of evidence. Larger randomized clinical trials are required to confirm the validity of promising techniques.

Clinical Features, Prognostic Factors, and Treatment Interventions for Ulceration in Patients With Infantile Hemangioma.

Importance: Ulceration is a common complication of infantile hemangioma (IH), which leads to substantial morbidity. Ulceration in IH has not been systematically studied since the advent of ß-blocker therapy for IH. Objectives: To examine treatment interventions used for ulceration in IH and identify clinical prognostic indicators of healing time. Design, Setting, and Participants: A retrospective, multicenter cohort study was conducted on 436 consecutive patients with a clinical diagnosis of ulcerated IH and available clinical photographs. Patients receiving care at tertiary referral centers evaluated between 2012 and 2016 were included; statistical and data analysis were performed from February 7 to April 27, 2020. Exposures: Clinical characteristics, treatment interventions, course, complications, and resource use were analyzed. Treatment interventions for ulceration in IH included local (wound care, topical), systemic (ß-blocker, corticosteroids), and procedural (pulsed-dye laser). Main Outcomes and Measures: The primary end point was time to complete or nearly complete ulceration healing. Clinical characteristics were analyzed to determine the responses to most common interventions and prognostic factors for healing of ulceration. Results: Of the 436 patients included in the study, 327 were girls (75.0%); median age at ulceration was 13.7 weeks (interquartile range, 8.86-21.30 weeks). The median heal time was 4.79 weeks (95% CI, 3.71-5.86 weeks) with wound care alone, 5.14 weeks (95% CI, 4.57-6.00 weeks) with timolol, 6.36 weeks (95% CI, 5.57-8.00 weeks) with a systemic ß-blocker, and 7.71 weeks (95% CI, 6.71-10.14 weeks) with multimodal therapy. After adjusting for IH size, a dose of propranolol less than or equal to 1 mg/kg/d was associated with shorter healing time compared with higher propranolol doses (hazard ratio, 2.04; 95% CI, 1.11 to 3.73; P = .02). Size of the IH was identified as a significant prognostic factor for healing time in multivariable analysis. Increasing size of IH portends a proportionately longer time to heal of the ulceration. Conclusions and Relevance: Despite the use of ß-blockers, this cohort study found that a subset of patients with IH ulceration continued to experience prolonged IH healing times. Larger IH size appears to be a poor prognostic factor for time to heal. For patients requiring systemic therapy, initiation of propranolol at lower doses (≤1 mg/kg/d) should be considered.

ARTERIAL INSUFFICIENCIES: Hyperbaric Oxygen Therapy for Selected Problem Wounds.

The use of hyperbaric oxygen (HBO2) for the treatment of selected problem wounds has focused almost entirely on the diabetic foot ulcer (DFU) in recent years. The prevalence of DFUs in today's patient population and the reimbursement available for the treatment of DFUs have given it priority status in discussions about problem wounds, but there are sound fundamental reasons why additional oxygen may have benefits in the treatment of non-DFU wounds.

Melatonin loaded lecithin-chitosan nanoparticles improved the wound healing in diabetic rats.

Wound healing in diabetic patients remains a worldwide problem that can cause amputations and even lead to death. This work aimed to produce lecithin-chitosan nanoparticles loaded with melatonin (MEL-NP) incorporated in a topical formulation to be evaluated for healing in the in vivo animal model for diabetes. To produce nanoparticles, an ethanolic solution containing soybean lecithin and melatonin was added dropwise to an aqueous solution of chitosan under sonication. The nanoparticles were physicochemical characterized and evaluated in vivo for toxicity using the Galleria mellonella model and its potential for wound healing in diabetic rats. The MEL-NPs presented a particle size of 160 nm and a zeta potential of 25 mV. The melatonin entrapment efficiency was 27%. Our results indicated that treatment with MEL-NP improved wound healing demonstrated by wound closure earlier than the other treatments evaluated. A desired therapeutic effect was achieved by MEL-NP in the induction of fibroblast and angiogenic proliferation. In addition, it was accompanied by an expressive collagen deposition. Considering the observed data, the MEL-NP developed could be used as a proof of concept to develop a promising strategy for the healing of diabetic wound.

Frontiers in translational systemic sclerosis research: A focus on the unmet 'cutaneous' clinical needs (Viewpoint).

This viewpoint considers four cutaneous unmet clinical needs of patients with systemic sclerosis (SSc), namely the rapidly progressive skin thickening (scleroderma) which occurs early on in diffuse cutaneous disease; digital (finger and toe) ulcers; calcinosis; and cutaneous telangiectases. All four problems cause pain, disability and/or disfigurement, all impact on quality of life, and for each, we require effective treatments. For each unmet need, we give a brief description of the clinical problem (including clinical burden), pathophysiology and current treatment, followed by a personal viewpoint of the key questions which research must address. For the painful, debilitating skin thickening of early diffuse cutaneous SSc, studies are required to decide whether corticosteroids are effective and safe (current opinion is divided) and whether phototherapy approaches have a role. Also, we need to develop and validate reliable outcome measures for clinical trials of promising new therapies: these could be composite indices, novel non-invasive imaging methods and patient-reported outcome measures, possibly in combination as they provide complementary information. For digital ulcers, again we require validated outcome measures for clinical trials. We also need to explore local (including topical) treatments, which are free from systemic adverse effects, and preventative strategies for high-risk patients. For calcinosis, we need to better understand pathophysiology, to validate outcome measures and to develop topical treatments. For telangiectases, we need to "use" these highly accessible lesions to help unravel the vascular pathophysiology of SSc and explore their different properties as potential biomarkers.

Effects of Moist Exposed Burn Therapy and Ointment (MEBT/MEBO) on the autophagy mTOR signalling pathway in diabetic ulcer wounds.

Context: Burn therapy (MEBT)/moist exposed burn ointment (MEBO) is an effective traditional Chinese medicine method to treat diabetic wound, but the mechanism is unclear. Autophagy has been proved to be closely related with wound healing, so MEBO/MEBT is hypothesized to promote diabetic wound healing by regulating autophagy.Objective: To explore the mechanism of moist exposed MEBT/MEBO promoting diabetic wound repair.Materials and methods: Eighty male Wistar rats were randomly assigned to control (n = 20) and diabetic group induced by intraperitoneal injection of STZ (n = 60), which were further randomly assigned to MEBO, Kangfuxin and model groups (n = 20 each). All rats underwent full-thickness skin resection in the back. Wound healing was dynamically observed and wound tissues were collected at five time points for pathological examination, autophagosome and the expression of PI3K, Akt and mTOR.Results: The healing time in the control group was the shortest, no statistically significant difference was found between the MEBO and the Kangfuxin group (p = 0.76). The morphology of autophagosomes ranged large to small, which was the most obvious in the MEBO group. The mRNA and protein expression of PI3K, Akt and mTOR in each group reached the peak on Day 5, the levels in the MEBO group were the highest (F = 18.43, 19.97, 15.36, p < 0.05). On Day 11, the expression levels in each group began to decline.Discussion and conclusions: In this study, we discussed the molecular mechanism of MEBT/MEBO promoting the repair of diabetic ulcer wounds through autophagy and PI3K-Akt-mTOR signalling pathway, which provides a new way for drug design in the future.

Beneficial Effect of Intense Pulsed Light on the Wound Healing in Diabetic Rats.

BACKGROUND AND OBJECTIVE: Wound healing in diabetes mellitus (DM) patients is one of the major health concerns globally. Intense pulsed light (IPL) has been widely used in cosmetic dermatology via mechanisms involving fibroblast stimulation, collagen synthesis, and dermal remodeling, which are events that also occur during the process of wound healing. This present study was aimed to evaluate the possible beneficial effect of IPL on the wound healing in diabetic rats. MATERIALS AND METHODS: Diabetes was induced in Sprague-Dawley rats using streptozotocin. The rats were randomly divided into four groups: normal group, DM only group, DM rats with IPL treatment 2 weeks before wounding (DM + IPL-Pre group), and DM rats with concurrent IPL exposure and wounding (DM + IPL-Con group). The wounds were created on the dorsal skin of rats. Wound closure rate, collagen deposition, and angiogenesis were assessed. RESULTS: There were no significant differences in the wound closure rate and mean time to wound closure between IPL-treated diabetic rats and normal rats. By contrast, delayed wound closure and prolonged mean time to wound closure were both noticed in DM only group. Enhanced collagen deposition and angiogenesis were observed in IPL-Pre, but not IPL-Con diabetic rats, as compared with untreated DM rats. CONCLUSION: Results of this study may provide novel insight into future preventive strategies using IPL for the management of wounds in diabetic patients. Lasers Surg Med. © 2019 Wiley Periodicals, Inc.

Use of Neem oil and Hypericum perforatum for treatment of calcinosis-related skin ulcers in systemic sclerosis.

OBJECTIVE: This study evaluated Neem oil and Hypericum perforatum (Holoil®) for treatment of scleroderma skin ulcers related to calcinosis (SU-calc).Procedure: We retrospectively analyzed 21 consecutive systemic sclerosis (SSc) patients with a total of 33 SU-calcs treated daily with Holoil® cream compared with a control group of 20 patients with 26 SU-calcs. Holoil® was directly applied to skin lesions, while the control group received only standard medication. RESULTS: Application of Holoil® either resulted in crushing and complete resolution of calcium deposits or facilitated sharp excision of calcinosis during wound care sessions in 27/33 cases (81.8%). Complete healing of SU-calc occurred in 15/33 (45%) of cases within a time period of 40.1 ± 16.3 (mean ± SD) days, while 18/33 (55%) of lesions improved in terms of size, erythema, fibrin and calcium deposits. Patients reported a reduction of pain (mean numeric rating scale 7.3 ± 1.9 at baseline versus 2.9 ± 1.4 at follow-up) The control group had longer healing times and a higher percentage of infections. CONCLUSIONS: The efficacy of local treatment with neem oil and Hypericum perforatum suggest that Holoil® could be a promising tool in the management of SSc SU-calc.

Electrical Stimulation in the Treatment of Lymphedema and Associated Skin Ulcers.

Background: Lymphedema is a disorder in which lymph accumulates in the interstitial spaces due to poor lymphatic flow resulting from hypoplasia or aplasia of the lymphatic vessels, or to morpho-functional alterations that impair lymphatic flow. Lymphedema is a debilitating condition associated initially with inflammation that then degenerates into hardening of affected tissues and the formation of ulcers on the skin of affected limbs. No definitive treatment is available. The only therapy for lymphedema consists of physiotherapy, surgery, and compression to reduce impairment, which only treats the symptoms, not the causes. A possible new therapy that could reinforce the treatment of lymphedema progression and complications is electrical stimulation (ES). Many studies underline the effects of electric currents on the different cell mechanisms associated with disease. Methods and Results: In this review, we summarize the effects of ES on the molecular and cellular processes involved in the pathophysiology of lymphedema, highlighting their therapeutic potential for edema reduction, ulcer repair, and restoration of lymphatic flow in vitro and in vivo. Conclusions: ES exerts its effect on the main stages that characterize lymphedema, from its onset to ulcer formation. There are few evidences on lymphatic models and more molecular studies are needed to understand the mechanism of action of this application in the treatment of lymphedema.

Skin ulcers infected with conditional pathogenic strains treated with local hydrogen water packing in two pemphigus vulgaris patients: Case reports with follow-up for 2 months.

We are the first to report on a new, safe, and effective treatment of infections induced by conditional pathogenic strains with local wet packing with hydrogen water. The new treatment method may also shed light on the therapy of chronic, inflammatory skin ulcers.

A feasibility study of a novel low-level light therapy for digital ulcers in systemic sclerosis.

BACKGROUND: Locally acting, well-tolerated treatments for systemic sclerosis (SSc) digital ulcers (DUs) are needed. OBJECTIVES: Our primary aim was to investigate the safety, feasibility, and tolerability of a novel low-level light therapy (LTTT). A secondary aim was to tentatively assess efficacy. METHODS: A custom-built device comprising infrared (850 nm), red (660 nm), and violet (405 nm) LEDs was utilized. DUs were irradiated with 10 J/cm2 twice weekly for 3 weeks, with follow-up at weeks 4 and 8. Any safety concerns were documented. Patient opinion on time to deliver, feasibility, and pain visual analogue score (VAS; 0-100, 100 most severe) was collected. Patient and clinician DU global assessment VAS were documented. DUs were evaluated by laser Doppler perfusion imaging pre- and post-irradiation. RESULTS: In all, 14 DUs in eight patients received a total of 46 light exposures, with no safety concerns. All patients considered LTTT 'took just the right amount of time' and was 'feasible', with a low associated mean pain VAS of 1.6 (SD: 5.2). Patient and clinician global DC VAS improved during the study (mean change: -7.1 and -5.2, respectively, both p < .001). DU perfusion significantly increased post-irradiation. CONCLUSIONS: LTTT for DUs is safe, feasible, and well tolerated. There was an early tentative suggestion of treatment efficacy.

Non-invasive Oxygen-Ozone therapy in treating digital ulcers of patients with systemic sclerosis.

BACKGROUND: Digital ulcers (DUs) in Systemic sclerosis (SSc) result from recurrent Raynaud's phenomenon (RP) and microtrauma with high impact on quality of life. Medical use of ozone (triatomic oxygen) was initiated in the 19th century. Ozone has multiple therapeutic effects in wound healing due to the property of releasing nascent oxygen, which has been shown to stimulate antioxidant enzymes. We aimed to assess the effects of ozone therapy on the healing of scleroderma DUs and determine levels of expression of vascular endothelial growth factor (VEGF), and endothelin-1 type A receptor (ETAR) autoantibodies in the wounds after treatment. SUBJECTS AND METHODS: Fifty SSc female patients with DUs, were randomized into ozone group (I) (n=25) treated by calcium channel blockers plus oxygen-ozone treatment and control group (II) (n=25) treated by calcium channel blockers only. Ozone group received noninvasive oxygen-ozone treatments for 30 minutes per day for 20 days using the ozone generator device. Therapeutic effects were graded into 4 levels according to Zhang and other researchers. The wounds sizes were measured at baseline and day 20, respectively. Expressions of VEGF and ETAR autoantibodies proteins were determined by immune-histochemical examination. RESULTS: Demographics and clinical characteristics of the 2 groups showed no significant differences. At day 20, the effective healing rate was significantly higher in group (I) than in group (II), where it represented 96% (24/25) in ozone group versus 44% (11/25) in control group, and (𝑃 = 0.007). After treatment, the wound sizes in both groups were significantly smaller than before treatment. In group (I), the wound size reduction was significantly more than in group (II) (0.75 ± 0.30 versus 2.44 ± 0.80 mm), (𝑃 = 0.00). At day 20, VEGF was significantly higher in ozone group (I), than in control group (II), (83.96±9.68) versus (67.92±6.55), (𝑃 = 0.00) while, ETAR was significantly lower in ozone group (I), than in control group (II), (3.14±1.12 versus 4.59±1.24), (𝑃 = 0.00). CONCLUSION: Ozone therapy may be beneficial tool in the treatment of DUs in SSc patients, where it promotes the wound healing through a potential induction of VEGF and down-regulation of ETAR at sites of the ulcers.