Using an Elastomeric Skin Protectant to Manage Donor Site Wounds of Split-thickness Skin Grafts: A Case Series.

ABSTRACT: Split-thickness skin grafting (STSG) is a common surgical procedure to manage acute and chronic wounds. A plethora of dressings exists to treat STSG donor site wounds (DSWs). Recently, a new elastomeric skin protectant was adopted (Cavilon Advanced Skin Protectant; 3M) in the treatment of incontinence-associated dermatitis. In this report, the authors assess the effects of this elastomeric skin protectant as an alternative wound dressing for STSG donor sites.The authors report a single-center prospective case series that was performed to establish a treatment protocol. Nine consecutive patients with different indications for treatment with an STSG from May to September 2018 were included. Collected data included general patient information, comorbidities, complications, blood loss, pain during dressing change, and the duration of DSW healing.This case series showed promising results in terms of duration of DSW healing when applying the elastomeric skin protectant. The authors also observed less blood loss and less pain during dressing changes. No infections were seen during the trial.

Case Report of Two Patients With COVID-19 and Sacral Pressure Injuries Associated with Pyoderma Gangrenosum.

ABSTRACT: During the COVID-19 pandemic, an increasing number of patients have been admitted to the ICU with severe respiratory complications requiring prolonged supine positioning. Recently, many case reports have been published regarding dermatologic manifestations associated with COVID-19. However, there is little information about the clinical features of these manifestations. Pyoderma gangrenosum (PG) is an ulcerative noninfectious inflammatory disease of the skin. In at least 50% of the cases, the etiology is unknown. Nevertheless, PG is associated with many systemic diseases. In this article, the authors report two critically ill patients with COVID-19 who developed sacral ulcers during their recovery in the ICU. These ulcers had an atypical course and were exacerbated by surgical debridements. Accordingly, providers suspected PG, which was confirmed by the clinical evolution of the ulcers and biopsies taken from the wounds. To the best of the authors' knowledge, no previous articles have reported sacral pressure injuries associated with PG in patients with COVID-19. Providers should suspect PG in patients with COVID-19 who develop nonhealing pressure injuries.

A Rare Case of KID Syndrome: The Use of Hydrosurgery and Strategies for Antiseptic Wound Care.

A 14-year-old girl with a history of keratitis-ichthyosis-deafness (KID) syndrome, a rare autosomal dominant condition, was referred to the Department of Plastic Surgery at Brussels University Hospital in June 2016 for progressively worsening inguinoperineal ulceration exacerbated by overapplication of combination drug treclinax (tretinoin and erythromycin). On assessment, a large area of purulent papillomatous hyperkeratosis with follicular plugging, likely superimposed bacterial colonization, and deep ulceration were noted requiring thorough debridement.A first procedure was performed in June 2016 with hydrosurgical debridement (Versajet IITM; Smith & Nephew, Forth Worth, Texas). During the procedure, significant blood loss was noted, and topical adrenaline, blood transfusion, and a short ICU stay were required for monitoring during which the patient remained hemodynamically stable. The wound was primarily dressed with an antimicrobial barrier silver dressing; meropenem, ceftazidime, and fluconazole were started to treat for Gram-negative, Gram-positive, and anaerobic bacilli, as well as Pseudomonas aeruginosa and fungal infections in situ. A further three debridements were required 6, 12, and 26 days after the initial procedure. The patient was discharged 36 days after admission without any antibiotics and with an outpatient wound care plan.Not only was this case rare, but it also reflected the importance of a careful approach when tackling KID syndrome's cutaneous manifestations. Multiple debridements, thorough wound care, and appropriate antibiotic therapy may be required to achieve local healing and a satisfactory result. Hydrosurgical debridement offered a precise and well-controlled method for treating a large ulcerating hyperkeratotic urogenital lesion in this pediatric patient.

Exploring the learning needs of clinicians in Belgium and Sweden regarding prone positioning and skin damage prevention: A qualitative study.

INTRODUCTION: During the coronavirus pandemic (COVID -19), the use of prone positioning in critically ill patients with acute respiratory distress syndrome (ARDS) increased substantially. As a result, clinicians had to (re)learn how to treat the patient in the prone position while preventing adverse events such as pressure ulcers, skin tears and moisture-associated skin damage. AIM: The purpose of the study was to determine participants' learning needs related to patients in the prone position and the prevention of skin damage, such as pressure ulcers, and what they perceived as a positive or negative learning experience. DESIGN: This study used a qualitative methodological framework and employed an exploratory design. PARTICIPANTS: A purposive sample of clinicians (n = 20) with direct or indirect work experience with prone ventilated patients was recruited in Belgium and Sweden. METHODS: Individual semi-structured interviews were conducted in Belgium and Sweden between February and August 2022. Data were analysed thematically using an inductive approach. The COREQ guideline was utilised to comprehensively report on the study. FINDINGS: Two themes were identified: 'Adapting to a crisis' and 'How to learn', with the latter having two subthemes: 'balancing theory and practice' and 'co-creating knowledge'. Unexpected circumstances necessitated a personal adaption, a change in learning methods and a pragmatic adaptation of protocols, equipment and working procedures. Participants recognised a multifaceted educational approach which would contribute to a positive learning experience regarding prone positioning and skin damage prevention. The importance of poising theoretical teaching with practical hands-on training was highlighted with an emphasis on interaction, discussion, and networking between peers. CONCLUSIONS: The study findings highlight learning approaches which may help inform the development of befitting educational resources for clinicians. Prone therapy for ARDS patients is not limited to the pandemic. Therefore, educational efforts should continue to ensure patient safety in this important area.

The NHance® Mutation-Equipped Anti-MET Antibody ARGX-111 Displays Increased Tissue Penetration and Anti-Tumor Activity in Advanced Cancer Patients.

Dysregulation of MET signaling has been implicated in tumorigenesis and metastasis. ARGX-111 combines complete blockade of this pathway with enhanced tumor cell killing and was investigated in 24 patients with MET-positive advanced cancers in a phase 1b study at four dose levels (0.3-10 mg/kg). ARGX-111 was well tolerated up to 3 mg/kg (MTD). Anti-tumor activity was observed in nearly half of the patients (46%) with a mean duration of treatment of 12 weeks. NHance® mutations in the Fc of ARGX-111 increased affinity for the neonatal Fc receptor (FcRn) at acidic pH, stimulating transcytosis across FcRn-expressing cells and radiolabeled ARGX-111 accumulated in lymphoid tissues, bone and liver, organs expressing FcRn at high levels in a biodistribution study using human FcRn transgenic mice. In line with this, we observed, in a patient with MET-amplified (>10 copies) gastric cancer, diminished metabolic activity in multiple metastatic lesions in lymphoid and bone tissues by 18F-FDG-PET/CT after two infusions with 0.3 mg/kg ARGX-111. When escalated to 1 mg/kg, a partial response was reached. Furthermore, decreased numbers of CTC (75%) possibly by the enhanced tumor cell killing witnessed the modes of action of the drug, warranting further clinical investigation of ARGX-111.

Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans.

BACKGROUND: Intravenous Ig (IVIg), plasma exchange, and immunoadsorption are frequently used in the management of severe autoimmune diseases mediated by pathogenic IgG autoantibodies. These approaches modulating IgG levels can, however, be associated with some severe adverse reactions and a substantial burden to patients. Targeting the neonatal Fc receptor (FcRn) presents an innovative and potentially more effective, safer, and more convenient alternative for clearing pathogenic IgGs. METHODS: A randomized, double-blind, placebo-controlled first-in-human study was conducted in 62 healthy volunteers to explore single and multiple ascending intravenous doses of the FcRn antagonist efgartigimod. The study objectives were to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity. The findings of this study were compared with the pharmacodynamics profile elicited by efgartigimod in cynomolgus monkeys. RESULTS: Efgartigimod treatment resulted in a rapid and specific clearance of serum IgG levels in both cynomolgus monkeys and healthy volunteers. In humans, single administration of efgartigimod reduced IgG levels up to 50%, while multiple dosing further lowered IgGs on average by 75% of baseline levels. Approximately 8 weeks following the last administration, IgG levels returned to baseline. Efgartigimod did not alter the homeostasis of albumin or Igs other than IgG, and no serious adverse events related to efgartigimod infusion were observed. CONCLUSION: Antagonizing FcRn using efgartigimod is safe and results in a specific, profound, and sustained reduction of serum IgG levels. These results warrant further evaluation of this therapeutic approach in IgG-driven autoimmune diseases. TRIAL REGISTRATION: Clinicaltrials.gov NCT03457649. FUNDING: argenx BVBA.

GDF15/MIC1 and MMP9 Cerebrospinal Fluid Levels in Parkinson's Disease and Lewy Body Dementia.

Based on animal and ex-vivo experiments, Growth/Differentiation Factor-15 (GDF15, also called Macrophage Inhibitory Cytokine-1, MIC1), a member of the transforming growth factor-beta family, and Matrix Metalloproteinase-9 (MMP9), a member of the matrix metalloprotease family may be potential markers for Lewy body disorders, i.e. Parkinson's disease with (PDD) and without dementia (PDND) and Lewy body dementia (DLB). GDF15 has a prominent role in development, cell proliferation, differentiation, and repair, whereas MMP9 degrades, as a proteolytic enzyme, components of the extracellular matrix. In this study, cerebrospinal fluid GDF15 and MMP9 levels of 59 PDND, 17 PDD and 23 DLB patients, as well as of 95 controls were determined, and associated with demographic, clinical and biochemical parameters. Our analysis confirmed the already described association of GDF15 levels with age and gender. Corrected GDF15 levels were significantly higher in PDD than in PDND patients, and intermediate in DLB patients. Within Lewy body disorders, GDF15 levels correlated positively with age at onset of Parkinsonism and dementia, Hoehn & Yahr stage and cerebrospinal fluid t-Tau and p-Tau levels, and negatively with the Mini Mental State Examination. Remarkably, it does not relevantly correlate with disease duration. MMP9 was not relevantly associated with any of these parameters. Cerebrospinal GDF15, but not MMP9, may be a potential marker of and in Lewy body disorders.

Dual anti-idiotypic purification of a novel, native-format biparatopic anti-MET antibody with improved in vitro and in vivo efficacy.

Bispecific antibodies are of great interest due to their ability to simultaneously bind and engage different antigens or epitopes. Nevertheless, it remains a challenge to assemble, produce and/or purify them. Here we present an innovative dual anti-idiotypic purification process, which provides pure bispecific antibodies with native immunoglobulin format. Using this approach, a biparatopic IgG1 antibody targeting two distinct, HGF-competing, non-overlapping epitopes on the extracellular region of the MET receptor, was purified with camelid single-domain antibody fragments that bind specifically to the correct heavy chain/light chain pairings of each arm. The purity and functionality of the anti-MET biparatopic antibody was then confirmed by mass spectrometry and binding experiments, demonstrating its ability to simultaneously target the two epitopes recognized by the parental monoclonal antibodies. The improved MET-inhibitory activity of the biparatopic antibody compared to the parental monoclonal antibodies, was finally corroborated in cell-based assays and more importantly in a tumor xenograft mouse model. In conclusion, this approach is fast and specific, broadly applicable and results in the isolation of a pure, novel and native-format anti-MET biparatopic antibody that shows superior biological activity over the parental monospecific antibodies both in vitro and in vivo.

Depleting MET-Expressing Tumor Cells by ADCC Provides a Therapeutic Advantage over Inhibiting HGF/MET Signaling.

Hepatocyte growth factor (HGF) and its receptor MET represent validated targets for cancer therapy. However, HGF/MET inhibitors being explored as cancer therapeutics exhibit cytostatic activity rather than cytotoxic activity, which would be more desired. In this study, we engineered an antagonistic anti-MET antibody that, in addition to blocking HGF/MET signaling, also kills MET-overexpressing cancer cells by antibody-dependent cellular cytotoxicity (ADCC). As a control reagent, we engineered the same antibody in an ADCC-inactive form that is similarly capable of blocking HGF/MET activity, but in the absence of any effector function. In comparing these two antibodies in multiple mouse models of cancer, including HGF-dependent and -independent tumor xenografts, we determined that the ADCC-enhanced antibody was more efficacious than the ADCC-inactive antibody. In orthotopic mammary carcinoma models, ADCC enhancement was crucial to deplete circulating tumor cells and to suppress metastases. Prompted by these results, we optimized the ADCC-enhanced molecule for clinical development, generating an antibody (ARGX-111) with improved pharmacologic properties. ARGX-111 competed with HGF for MET binding, inhibiting ligand-dependent MET activity, downregulated cell surface expression of MET, curbing HGF-independent MET activity, and engaged natural killer cells to kill MET-expressing cancer cells, displaying MET-specific cytotoxic activity. ADCC assays confirmed the cytotoxic effects of ARGX-111 in multiple human cancer cell lines and patient-derived primary tumor specimens, including MET-expressing cancer stem-like cells. Together, our results show how ADCC provides a therapeutic advantage over conventional HGF/MET signaling blockade and generates proof-of-concept for ARGX-111 clinical testing in MET-positive oncologic malignancies.

Four individually druggable MET hotspots mediate HGF-driven tumor progression.

Activation of MET by HGF plays a key role in tumor progression. Using a recently developed llama platform that generates human-like immunoglobulins, we selected 68 different antibodies that compete with HGF for binding to MET. HGF-competing antibodies recognized 4 distinct hotspots localized in different MET domains. We identified 1 hotspot that coincides with the known HGF ß chain binding site on blades 2-3 of the SEMA domain ß-propeller. We determined that a second and a third hotspot lie within blade 5 of the SEMA domain and IPT domains 2-3, both of which are thought to bind to HGF α chain. Characterization of the fourth hotspot revealed a region across the PSI-IPT 1 domains not previously associated with HGF binding. Individual or combined targeting of these hotspots effectively interrupted HGF/MET signaling in multiple cell-based biochemical and biological assays. Selected antibodies directed against SEMA blades 2-3 and the PSI-IPT 1 region inhibited brain invasion and prolonged survival in a glioblastoma multiforme model, prevented metastatic disease following neoadjuvant therapy in a triple-negative mammary carcinoma model, and suppressed cancer cell dissemination to the liver in a KRAS-mutant metastatic colorectal cancer model. These results identify multiple regions of MET responsible for HGF-mediated tumor progression, unraveling the complexity of HGF-MET interaction, and provide selective molecular tools for targeting MET activity in cancer.