Assessing the Effect of Enzymatic Debridement on the Scar Quality in Partial-Thickness Burns to Deep Dermal Burns of the Hand: A Long-Term Evaluation.

Background and Objectives: Burn surgery on the hands is a difficult procedure due to the complex anatomy and fragility of the area. Enzymatic debridement has been shown to effectively remove burn eschar while minimizing damage to the surrounding tissue and has therefore become a standard procedure in many burn centers worldwide over the past decade. However, surprisingly, our recent literature review showed limited valid data on the long-term scarring after the enzymatic debridement of the hands. Therefore, we decided to present our study on this topic to fill this gap. Materials and Methods: This study analyzed partial-thickness to deep dermal burns on the hands that had undergone enzymatic debridement at least 12 months prior. Objective measures, like flexibility, trans-epidermal water loss, erythema, pigmentation, and microcirculation, were recorded and compared intraindividually to the uninjured skin in the same area of the other hand to assess the regenerative potential of the skin after EDNX. The subjective scar quality was evaluated using the patient and observer scar assessment scale (POSAS), the Vancouver Scar Scale (VSS), and the "Disabilities of the Arm, Shoulder, and Hand" (DASH) questionnaire and compared interindividually to a control group of 15 patients who had received traditional surgical debridement for hand burns of the same depth. Results: Between January 2014 and December 2015, 31 hand burns in 28 male and 3 female patients were treated with enzymatic debridement. After 12 months, the treated wounds showed no significant differences compared to the untreated skin in terms of flexibility, trans-epidermal water loss, pigmentation, and skin surface. However, the treated wounds still exhibited significantly increased blood circulation and erythema compared to the untreated areas. In comparison to the control group who received traditional surgical debridement, scarring was rated as significantly superior. Conclusions: In summary, it can be concluded that the objective skin quality following enzymatic debridement is comparable to that of healthy skin after 12 months and subjectively fares better than that after tangential excision. This confirms the superiority of enzymatic debridement in the treatment of deep dermal burns of the hand and solidifies its position as the gold standard.

Sexual Health Screening for Gynecologic and Breast Cancer Survivors: A Review and Critical Analysis of Validated Screening Tools.

INTRODUCTION: Studies have shown that the sexual health concerns of gynecologic and breast cancer survivors are not adequately being addressed by clinicians. AIM: To provide a comprehensive narrative review of validated sexual health screening tools and aid clinicians in choosing a screening tool that will allow them to best address their patients' sexual health concerns METHODS: A review of PubMed and Google Scholar databases was conducted, using search terms "sexual health", "screening", "tools", "cancer", and "survivors" to identify sexual health screening tools meeting the following inclusion criteria: 1) published in a peer-reviewed journal, 2) were written in English, 3) included breast and/or gynecological cancer patient population, 4) included self-reported measure of sexual health and function, and 5) underwent psychometric validation. MAIN OUTCOME MEASURE: Criteria used to evaluate identified screening tools included ability to assess desire, arousal, satisfaction, orgasm, dyspareunia, solo sexual expression, relationship with partner, body image, distress over changes in sexual function, and support systems. Pre and post- treatment comparisons, differentiation between lack of sexual desire and inability, heterosexual bias, diversity in patient population, and ease of scoring were also evaluated. RESULTS: Based upon the inclusion criteria, the following 10 sexual health screening tools were identified and reviewed: Female Sexual Function Index, European Organization for Research and Treatment of Cancer Quality of Life Questionnaires for both Cervical and Endometrial Cancer, Sexual Adjustment and Body Image Scale, Sexual Adjustment and Body Image Scale- Gynecologic Cancer, Sexual Function and Vaginal Changes Questionnaire, Gynaecologic Leiden Questionnaire, Information on Sexual Health: Your Needs after Cancer, Sexual Satisfaction Questionnaire, and Sexual Activity Questionnaire. Most tools assessed satisfaction (n=10), desire (n=9), and dyspareunia (n=8). Fewer addressed objective arousal (n=7), body image/femininity (n=7), partner relationship (n=7), orgasm (n=5), pre/post treatment considerations (n=5), distress (n=4), and solo-sexual expression (n=2). Heterosexual bias (n=3) and failure to differentiate between lack of desire and inability (n=2) were encountered. CONCLUSION: Understanding the strengths and limitations of sexual health screening tools can help clinicians more effectively address cancer survivors' sexual health concerns, which is essential in providing comprehensive care and improving quality of life. Screening tools have room for improvement, such as eliminating heterosexual bias and including cancer and treatment-specific questions. Clinicians can use this guide to select the most appropriate screening tool for their patients and begin bridging the gap in sexual healthcare. Tounkel I, Nalubola S, Schulz A, et al. Sexual Health Screening for Gynecologic and Breast Cancer Survivors: A Review and Critical Analysis of Validated Screening Tools. Sex Med 2022;10:100498.

Rapid enzymatic burn debridement: A review of the paediatric clinical trial experience.

NexoBrid (NXB) has been proven to be an effective selective enzymatic debridement agent in adults. This manuscript presents the combined clinical trial experience with NXB in children. Hundred and ten children aged 0.5 to 18 years suffering from deep thermal burns of up to 67% total body surface area were treated with NXB in three clinical trials. Seventy-seven children were treated with NXB in a phase I/II study, where 92.7% of the areas treated achieved complete eschar removal within 0.9 days from admission. Thirty-three children (17 NXB, 16 standard of care [SOC]) participated in a phase III randomized controlled trial. All wounds treated with NXB achieved complete eschar removal. Time to complete eschar removal (from informed consent) was 0.9 days for NXB vs 6.5 days for SOC (P < .001). The incidence of surgical excision was 7.9% for NXB vs 73.3% for SOC (P < .001). Seventeen of these children participated in a phase III-b follow-up study (9 NXB and 8 SOC). The average long-term modified Vancouver Scar Scale scores were 3.4 for NXB-treated wounds vs 4.4 for SOC-treated wounds (NS). There were no significant treatment-related adverse events. Additional studies are needed to strengthen these results.

Inhibition of Bromelain Activity During Enzymatic Debridement of Burn Wounds Pretreated With Frequently Used Products.

An enzyme mixture containing bromelain (NexoBrid®) was found to be suitable for enzymatic debridement of burn wounds, as determined by the criteria of patient comfort and pain, selectivity, and efficiency. Nevertheless, daily experience showed that pretreatment of burn wounds with several other clinical agents may inhibit debridement efficiency. Therefore, the current study was performed to identify those agents and evaluate their debridement inhibition capabilities. The impact of several common agents as well pH, on NexoBrid® debridement efficiency was evaluated in vitro. A collagen-based dermal substitute (MatriDerm®) was exposed to NexoBrid® in the presence of different agents of varying concentrations. Digestion was documented. The criteria used for judging digestion were independently classified by 3 investigators at least 3 times in succession. When a low concentration (1.0 mg/ml) of NexoBrid® was used, a ≥ 50% concentration of Prontosan® had an impact on enzymatic activity. Comparable results were obtained when even lower concentrations of Octenisept® (≥ 10%) were used. A 100-µmol/L concentration of copper inhibited the enzymatic activity of both a low (1.0 mg/ml) and high (10 mg/ml) concentration of NexoBrid®. Silver-sulfadiazine at concentrations of 10% and 90% inhibited the activity of 1 mg/ml NexoBrid®. No complete inhibition of NexoBrid® activity occurred at any concentration of iron. We recommend using polyhexanide-containing agents (Prontosan®) to rinse and presoak burn wounds. Pretreatment of burn wounds with agents containing silver and copper should be avoided. Experimentally, we found a partial inhibition of NexoBrid® activity at the distinct pH values of 3 and 11.

Treatment of Genital Burn Injuries: Traditional Procedures and New Techniques.

OBJECTIVE: Because genital burns are rare, only limited information on treatment guidelines is available in the literature. Vital tissue should be preserved to promote spontaneous healing because reconstruction does not always lead to satisfying results. The aim of this report is to present a general overview of current, prevailing treatment for genital burns and compare this to study authors' experiences. In addition, the article describes an entirely new approach of tissue-preserving bromelain-based enzymatic debridement of genital burn wounds. METHODS: This single-center study includes all patients who were treated for severe genital and perineal burn wounds at a burn intensive care unit between December 1995 and December 2016. A review of literature was performed in PubMed covering the years 1990 to 2016. RESULTS: A total of 149 patients were admitted with severe burns or scalding of the genitals or the perineum. As in the majority of cases reported in the current literature, most of these patients were treated conservatively. When there was demarcation of necrotic tissue, tangential excision and skin grafting were performed, and since 2015, 3 patients admitted to this facility have been treated with bromelain-based debridement followed by spontaneous healing. Certain small-scale studies in the literature describe a disproportionate number of surgical interventions. CONCLUSIONS: Based on this evidence, study authors support a conservative view of genital burn treatment. Enzymatic debridement allows earlier and more selective debridement, which can improve the aesthetic outcome.

Effect of Bromelain-Based Enzymatic Debridement on Skin Cells.

Several reports have concluded that enzymatic debridement based on Bromelain (NX) is selective and efficient. Although clinical trials showed that viable tissue is not damaged at the macroscopic level, the effect on the cellular level is largely unknown. The current study is meant to close this gap by evaluating whether NX has an effect on vital cells of the human dermis on a cellular level. In an experimental in vitro study design, the effect of NX on human keratinocytes, fibroblasts, and macrophages was analyzed. Enzymatic treatment was performed for 4 hours by using either cell culture medium or phosphate-buffered saline as diluting agent for NX. Cell viability and relative cell number in relation to untreated control cells were determined using a resazurin-based assay. In addition, the development of enzyme activity during clinical treatment was analyzed: wound fluid collected from a burn wound at different points of debridement was applied on collagen-elastin disks to prove enzymatic digestion activity. Both keratinocytes and fibroblasts were damaged by NX even at low concentrations. Both cell types showed improved survival when a medium was used for dissolving NX. Macrophages appeared to resist NX treatment more efficiently than the other cell types. In the clinical trial, NX activity in the wound fluid decreased clearly following 4 hours of enzymatic debridement. NX induces toxicity of vital skin cells in vitro. However, macrophages appear to be more resistant against NX treatment in vitro. The inflammatory responses of vital cells in the burn wound itself are likely to inhibit NX activity. The effect of this inflammatory process on NX activity will have to be investigated in future studies.

Eschar removal by bromelain based enzymatic debridement (Nexobrid®) in burns: An European consensus.

Early debridement and/or eschar removal is regarded as a significant step in the treatment of deep partial and full thickness burns. It aims to control wound bioburden and allows early wound closure by conservative treatment or skin grafting. Preservation of viable dermis accompanied by early wound closure, is regarded as a necessary step to reduce scar related complication, e.g. functional limitations and/or unaesthetic scar formation. Aside from the classical techniques of surgical excision as tangential excision for eschar removal, hydro-surgery, maggot therapy, laser, enzymatic debridement have been described as additional techniques in the burn surgeon's armamentarium. It is widely accepted that early eschar removal within 72h improves the outcome of burn wound treatment by reducing bacterial wound colonization, infection and length of hospital stay. In contrast, the right technique for eschar removal is still a matter of debate. There is increasing evidence that enzymatic debridement is a powerful tool to remove eschar in burn wounds, reducing blood loss, the need for autologous skin grafting and the number of wounds requiring surgical excision. In order to assess the role and clinical advantages of enzymatic debridement by a mixture of proteolytic enzymes enriched in Bromelain (Nexobrid®) beyond the scope of the literature and in view of users' experience, a European Consensus Meeting was scheduled. The aim was to provide statements for application, based on the mutual experience of applying enzymatic debridement in more than 500 adult and pediatric patients by the consensus panelists. Issues to be addressed were: indications, pain management and anesthesia, timing of application, technique of application, after-intervention care, skin grafting after enzymatic debridement, blood loss, training strategies and learning curve and areas of future research needs. Sixty-eight (68) consensus statements were provided for the use of enzymatic debridement. The degree of consensus was remarkably high, with a unanimous consensus in 88.2% of statements, and lowest degree of consensus of 70% in only 3 statements. This consensus document may serve as preliminary guideline for the use of enzymatic debridement with user-oriented recommendations until further evidence and systematic guidelines are available.

Enzymatic Versus Traditional Surgical Debridement of Severely Burned Hands: A Comparison of Selectivity, Efficacy, Healing Time, and Three-Month Scar Quality.

Severe burns of the hands are extremely challenging, given their anatomic complexity and vulnerability. Although excisional debridement with autografting remains the standard of care (SOC), previous studies have shown that use of enzymatic debridement with bromelain (NexoBrid, EDNX) enables rapid, selective enzymatic debridement, preserving viable tissue. To date, only two studies accruing data on EDNX in this setting have been published. The current study was conducted to compare EDNX with traditional surgical debridement (TSD) of deep dermal and full-thickness hand burns. This single-center, controlled clinical trial included 40 patients, aged 18 to 76 years, with deep dermal burns of the hand. The first 20 patients were debrided surgically, and the other 20 patients were using EDNX for debridement. Therapeutic selectivity, time to complete debridement and healing, complications, and 3-month functional/esthetic outcomes were compared by group. EDNX (vs TSD) significantly reduced time to complete debridement after admission (0.95 day vs 7.750 days; P < .001) and treatments needed for complete debridement (1.05 vs 1.45; P < .001), improving burn depth evaluation (initially overestimated in 55% of EDNX-treated patients). The number of wounds requiring autografting was certainly reduced (15% vs 95%; P = .034), as was time to complete healing after first debridement (23.30 vs 32.00 days; P < .001), and early scar quality after 3 months was nearly equivalent, with only heightened local redness in the EDNX group (P < .001). Compared with TSD, EDNX was superior in burn depth evaluation, tissue preservation, completeness of debridement, and wound closure. Scar quality after 3 months did not differ substantially.

Enzymatic debridement of deeply burned faces: Healing and early scarring based on tissue preservation compared to traditional surgical debridement.

INTRODUCTION: Facial burns occur frequently and depending on the injured skin layers often heal with scars which may cause permanent functional and cosmetic sequelae. Preservation of the sensitive facial skin layers, especially of the dermis is essential for scarless epithelialisation. Enzymatic debridement of deep thermal burns has already been shown to assist with preserving viable dermis. However, up to date, there are no published reports on wound healing and in the long term aesthetic outcome after enzymatic debridement of facial burns. METHODS: Therefore we performed a-single centre clinical trial that included 26 subjects aged 18-78 years with facial burns clinically evaluated as deep dermal or deeper. Burns were treated either with enzymatic debridement or excisional surgical debridement. Then we compared both groups regarding debridement selectivity, wound closure and scar quality after more than 12 months. RESULTS: Enzymatic debridement significantly reduced time to complete wound closure after admission (19.85 days versus 42.23 days, p=0.002), and after enzymatic eschar removal (18.92 days versus 35.62 days, p=0.042). The number of procedures to complete debridement were significantly lower in the enzymatic debridement group (1.00 versus 1.77, p=0.003). 77% of facial burns that had been debrided enzymatically were found to be more superficially burned than initially estimated. Wounds undergoing autografting of any size were significantly reduced by enzymatic debridement (15% versus 77%, p=0.002). Scar quality after enzymatic debridement was superior compared to surgical debridement after 12 months regarding pigmentation (p=0.016), thickness (p=0.16), relief (p=0.10), pliability (p=0.01), surface area (p=0.004), stiffness (p=0.023), thickness (0.011) and scar irregularity (p=0.011). Regarding erythema and melanin, viscoelasticity and pliability, trans-epidermal water loss or laser tissue oxygen saturation, haemoglobin level and microcirculation we found no significant differences for treated and untreated skin in the EDNX group. CONCLUSION: In our current study we found Bromelain based enzymatic debridement better in some aspects of tissue preservation in deep dermal facial burn.

Overexpression of YY1 increases the protein production in mammalian cells.

The production of therapeutic antibodies using mammalian cells remains a high-priority in the biopharmaceutical manufacturing industry. Bioengineers have targeted different cellular processes, including transcription, translation, secretion and post-translational modifications, to overcome the metabolic bottlenecks limiting production capacity and create high-producing mammalian cell lines. The polycomb group (PcG) proteins belong to a family of chromatin regulators with important roles in multicellular development. By overexpressing and screening genes from the PcG family, we have identified an epigenetic key player for biopharmaceutical manufacturing enhancement: the transcription factor Yin Yang 1 (YY1). The overexpression of YY1 led to an increase in the production of several product genes (SEAP, VEGF165, IgG including Rituximab), provided that human YY1 (hYY1) was expressed in human cells (HeLa, HT-1080, HEK-293T, FreeStyle™ 293-F) and Chinese hamster ovary cell-derived YY1 (cYY1) was expressed in CHO cells (CHO-K1, CHO-easyC, FreeStyle™ CHO-S, CHO-B13-24, CHO-IgG1). Ectopic expression of cYY1 in the stable CHO-derived IgG producer cell lines CHO-B13-24 and CHO-IgG1 increased the antibody titer up to 6-fold, suggesting that epigenetic engineering of mammalian production cell lines could become a new strategy to improve the manufacturing of complex protein pharmaceuticals.

Novel X-linked inhibitor of apoptosis inhibiting compound as sensitizer for TRAIL-mediated apoptosis in chronic lymphocytic leukaemia with poor prognosis.

Given that aggressive DNA damaging chemotherapy shows suboptimal efficacy in chronic lymphocytic leukaemia (CLL), alternative therapeutic approaches are needed. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is able to induce tumour-specific apoptosis. However, apoptosis might be inhibited by elevated levels of X-linked inhibitor of apoptosis (XIAP). Use of XIAP-inhibiting compounds might sensitize primary CLL cells towards TRAIL-mediated apoptosis. A novel small molecule, compound A (CA), an inhibitor of XIAP, was used in combination with TRAIL to induce apoptosis in primary CLL cells (n = 48). XIAP was significantly more highly expressed in primary CLL cells (n = 28) compared to healthy B cells (n = 16) (P = 0·02). Our data obtained by specific knock-down of XIAP by siRNA identified XIAP as the key factor conferring resistance to TRAIL in CLL. Combined treatment with CA/TRAIL significantly increased apoptosis compared to untreated (P = 8·5 × 10⁻¹°), solely CA (P = 4·1 × 10⁻¹²) or TRAIL treated (P = 4·8 × 10⁻¹°) CLL cells. CA rendered 40 of 48 (83·3%) primary CLL samples susceptible to TRAIL-mediated apoptosis. In particular, cells derived from patients with poor prognosis CLL (ZAP-70(+) , IGHV unmutated, 17p-) were highly responsive to this drug combination. Our highly-effective XIAP inhibitor CA, in concert with TRAIL, shows potential for the treatment of CLL cases with poor prognosis and therefore warrants further clinical investigation.