724 Improving the Lives of Patients with Large Amelobastomas In Ethiopia: Long-Term Outcomes of Mandibular Reconstruction for Ameloblastoma Using Non-Vascularised Rib Grafts

Background Ameloblastomas are odontogenic tumours that often require radical excision and mandibular reconstruction. This is challenging in resource-limited settings where access to microsurgery is limited. Non-vascularised rib-grafts can be used as an alternative, however robust long-term outcomes are lacking. Method Adult patients with large ameloblastomas underwent hemimandibulectomy and autologous rib graft reconstruction on short-term surgical missions to Ethiopia between 2012 and 2015. Long-term follow-up was conducted over a two-week period in rural Ethiopia in 2017. Results Follow-up was possible for seven patients (58% of those treated). Mean post-operative follow-up time was 42.9 months (SD 11.7; range 24-60 months). Early complications were four superficial surgical site infections. Late complications were two cases of wire extrusion and one of keloid scarring. There were no graft failures. Patients reported reduced social stigma (p = 0.04), excellent function and 100% satisfaction. Conclusions When situational factors preclude the use of microsurgery, bundle rib-grafts offer a reliable alternative for partial or total mandibular reconstruction for patients after ameloblastoma resection. Mild complications were experienced by most patients, but these were straightforward to manage and the bundle rib-grafts still took well, being surprisingly resistant to infection. Importantly, this technique is associated with long-term improvements in social stigma and quality of life for patients.

Calcium Electroporation for Keloids: A First-in-Man Phase I Study

<b><i>Background:</i></b> Keloid scarring is a pathologic proliferation of scar tissue that often causes pruritus, pain, and disfigurement. Keloids can be difficult to treat and have a high risk of recurrence. Recent studies have shown promising results in the treatment of cutaneous metastases with intralesional calcium combined with electroporation (calcium electroporation). As calcium electroporation has shown limited side effects it has advantages when treating benign keloid lesions, and on this indication we performed a phase I study. <b><i>Methods:</i></b> Patients with keloids were treated with at least 1 session of calcium electroporation and followed up for 2 years. Calcium was administered intralesionally (220 mM) followed by the application of eight 100-µs pulses (400 V) using linear-array electrodes and Cliniporator (IGEA, Italy). Treatment efficacy was evaluated clinically (size, shape, erythema), by patient self-assessment (pruritus, pain, other) and assessed histologically. <b><i>Results:</i></b> Six patients were included in this small proof of concept study. Treatment was well tolerated, with all patients requesting further treatment. Two out of 6 patients experienced a decrease in keloid thickness over 30%. A mean reduction of 11% was observed in volume size, and a mean flattening of 22% was observed (not statistically significant). Five out of 6 patients reported decreased pain and pruritus. No serious adverse effects or recurrences were observed over a mean follow-up period of 338 days. <b><i>Conclusion:</i></b> In this first phase I clinical study on calcium electroporation for keloids, treatment was found to be safe with minor side effects. Overall, patients experienced symptom relief, and in some patients keloid thickness was reduced.

Emerging and Novel Therapies for Keloids

Keloids are abnormal fibroproliferative scars with aggressive dermal growth expanding beyond the borders of the original injury. Different therapeutic modalities, such as corticosteroids, surgical excision, topical silicone gel sheeting, laser therapy, cryotherapy, photodynamic therapy and radiotherapy, have been used to treat keloids; however, none of these modalities has proven completely effective. Recently, researchers have devised several promising anti-keloid therapies including anti-hypertensive pharmaceuticals, calcineurin inhibitors, electrical stimulation, mesenchymal stem cell therapy, microneedle physical contact and ribonucleic acid-based therapies. The present review summarises emerging and novel treatments for keloids. PubMed® (National Library of Medicine, Bethesda, Maryland, USA), EMBASE (Elsevier, Amsterdam, Netherlands) and Web of Science (Clarivate Analytics, Philadelphia, Pennsylvania, USA) were searched for relevant literature published between January 1987 to June 2020. A total of 118 articles were included in this review. A deeper understanding of the molecular mechanisms underlying keloid scarring pathogenesis would open further avenues for developing innovative treatments. KEYWORDS Keloid; Treatment; Fibroblast; Scar; Dermatology.

Dark Skin Representation within Mobile Applications for Dermatology Education: an Observational Analysis (Preprint)

BACKGROUND Ethnic diversity in dermatology has previously been neglected within educational curricula. This has previously been demonstrated within many established dermatology textbooks. Many urban populations find their communities becoming increasingly diverse and medical education must match these changes. The increasing use and modernisation of mobile technology in health education may represent an avenue to provide increasingly diverse knowledge related to dermatology in dark skin populations. OBJECTIVE To review the representation of dark skin photography and diseases in dermatological educational resources provided via mobile application technology. METHODS Mobile applications related to ‘dermatology’ were reviewed within the Google Play Store. Only original mobile applications made for education of medical students or health professionals were analysed. Photographic depictions of dermatological conditions were categorised according to Fitzpatrick type 1-4, Fitzpatrick type 5-6, or uncertain. Additionally, mobile applications were reviewed for information regarding four conditions more common in people with darker skin: central centrifugal cicatricial alopecia, melasma, acral lentiginous melanoma, and keloid scarring. RESULTS Of 200 mobile applications reviewed, 12 were included within the analysis. In total 3755 in-app photographs were categorised into Fitzpatrick type 1-4 (3398 photographs, 90.5%), Fitzpatrick type 5-6 (245 photographs, 6.5%), or uncertain (112 photographs, 3.0%). The degree of photographs showing Fitzpatrick 5-6 ranged from 0.7% to 17.6% between the different mobile applications. This was not significantly different from results previously gained from photographic depictions in dermatology textbooks. Furthermore, the number of mobile applications presenting overt educational information regarding the four conditions reviewed varied considerably; central centrifugal cicatricial alopecia (1 application, 8.3%), melasma (5 applications, 41.7%), acral lentiginous melanoma (4 applications, 33.3%), and keloid scarring (6 applications, 50%). No mobile applications contained information for all four conditions. CONCLUSIONS There is limited depiction of dermatological conditions in darker skin tones within mobile applications aimed at educational students and professionals in dermatology.

Identification of Differentially Methylated CpG Sites in Fibroblasts from Keloid Scars

As a part of an abnormal healing process of dermal injuries and irritation, keloid scars arise on the skin as benign fibroproliferative tumors. Although the etiology of keloid scarring remains unsettled, considerable recent evidence suggested that keloidogenesis may be driven by epigenetic changes, particularly, DNA methylation. Therefore, genome-wide scanning of methylated cytosine-phosphoguanine (CpG) sites in extracted DNA from 12 keloid scar fibroblasts (KF) and 12 control skin fibroblasts (CF) (six normal skin fibroblasts and six normotrophic fibroblasts) was conducted using the Illumina Human Methylation 450K BeadChip in two replicates for each sample. Comparing KF and CF used a Linear Models for Microarray Data (Limma) model revealed 100,000 differentially methylated (DM) CpG sites, 20,695 of which were found to be hypomethylated and 79,305 were hypermethylated. The top DM CpG sites were associated with TNKS2, FAM45B, LOC723972, GAS7, RHBDD2 and CAMKK1. Subsequently, the most functionally enriched genes with the top 100 DM CpG sites were significantly (p ≤ 0.05) associated with SH2 domain binding, regulation of transcription, DNA-templated, nucleus, positive regulation of protein targeting to mitochondrion, nucleoplasm, Swr1 complex, histone exchange, and cellular response to organic substance. In addition, NLK, CAMKK1, LPAR2, CASP1, and NHS showed to be the most common regulators in the signaling network analysis. Taken together, these findings shed light on the methylation status of keloids that could be implicated in the underlying mechanism of keloid scars formation and remission.

53 Regulation of Glycolysis and the Warburg Effect in Keloids

Introduction Hypertrophic and keloid scarring are considered as major determinants for long-term outcomes and quality of life for burn survivors. Keloid development is predicated on prolonged local inflammation and altered glucose metabolism. Owing to its tumor-like dependence on glucose, we hypothesized that keloids would display the bioenergetics of cancer cells; namely, increased glucose uptake via Glut1 and upregulation of key glycolytic enzymes. Furthermore, burn patients who develop keloids potentially demonstrate early evidence of the aforementioned features compared to non-keloid patients. Therefore, elevated Glut1 expression could serve as a marker for keloid development in burn patients. Methods We enrolled 27 control burn patients with 39% ± 4% total body surface area (TBSA) burns. The keloid burn group included 9 burn patients with 47% ± 9% TBSA burns. Skin was obtained for histology, gene and protein expression at 0–17 days post-burn. Results Keloids have higher Glut1 expression compared to normal and burn skin (7.72 vs. 0.15, p&lt; 0.001; 7.72 vs. 2.35, p&lt; 0.05). Keloids also exhibit enhanced expression of critical glycolytic enzymes compared to burn skin at 7–10 days post-burn (HK2: 4.14 vs. 2.36, p&lt; 0.001; PFK1: 6.51 vs. 3.83, p&lt; 0.001; PFK2: 5.35 vs. 1.27, p&lt; 0.001; PDK1: 5.50 vs. 4.31, p&lt; 0.05; PKM2: 7.58 vs. 2.98, p&lt; 0.001). A Glut1 time-course analysis in burn skin from non-keloid patients indicated a significant elevation at 7–10 days post-burn compared to normal skin (3.22 vs. 0.20, p&lt; 0.01). Skin from keloid burn patients prior to development of keloids demonstrate higher Glut1 expression compared to skin from non-keloid controls when matched by days post-burn (40.5 vs. 0.58 at 0–2 days, p&lt; 0.05). Conclusions Patients who develop post-burn keloids exhibit early risk factors prior to the development of keloids (e.g. elevated skin Glut1). Keloids have an augmented reliance on glycolysis compared to burn skin. Therefore, early identification and targeting glycolysis in susceptible patients is key. Applicability of Research to Practice Upregulation of glycolytic enzymes and transporters such as Glut1 may serve as keloid predictive markers. Identification of at-risk patients allows for a tailored treatment regimen that targets dysregulated glycolysis in these patients. Pharmaceutical agents like shikonin suppress multiple glycolytic steps, serving as an effective means to interfere with the proliferative capacity of keloids. Potentially, local shikonin administration could serve as a therapy in select patients exhibiting keloid risk factors.

Pirfenidone inhibits epithelial–mesenchymal transition in keloid keratinocytes

Background Keloids are benign fibroproliferative skin lesions that are difficult to treat and become a lifetime predicament for patients. Several treatment modalities have been put forth, but as yet no satisfactory approach to the prevention or treatment of keloids has been identified. The process of epithelial-to-mesenchymal transition (EMT) has been implicated in keloid scarring, as keloid keratinocytes display an EMT-like phenotype. This study investigated the potential of pirfenidone, an antifibrotic agent, to counteract EMT-like alterations in keloid keratinocytes, including gene expression, cell migratory and proliferative functions. Methods Normal and keloid keratinocytes were isolated from discarded normal skin tissues and from resected keloid tissues, respectively. Cells were quiesced for 24 h without epidermal growth factor DS-Qi1MCDigital and were exposed to transforming growth factor-beta1 (TGF-β1; 10 ng/mL), with or without pirfenidone (400 μg/mL), for an additional 24 h. The effects of pirfenidone on cytotoxicity, cell migration, cell proliferation, and on expression of genes and proteins involved in EMT were assayed. Statistical significance was determined by two-way ANOVA using Sigma Plot. Results We found that pirfenidone did not elicit any cytotoxic effect at concentrations up to 1000 μg/mL. A statistically significant dose-dependent decrease in basal cell proliferation rate was noted in both normal and keloid keratinocytes when exposed to pirfenidone at concentrations ranging from 200 to 1000 μg/mL. Pirfenidone significantly decreased basal cell migration in both normal and keloid keratinocytes, but a significant decrease in TGF-β1-induced cell migration was seen only in keloid keratinocytes. Significant inhibition of the expression of TGF-β1-induced core EMT genes, namely hyaluronan synthase 2, vimentin, cadherin-11, and wingless-type MMTV integration site family, member 5A along with fibronectin-1, was observed in both normal and keloid keratinocytes treated with pirfenidone. In addition, the protein levels of vimentin and fibronectin were significantly reduced by pirfenidone (400 μg/mL) in both normal and keloid keratinocytes. Conclusions For the first time, this study shows the efficacy of pirfenidone in inhibiting the EMT-like phenotype in keratinocytes derived from keloids, suggesting that pirfenidone may counteract a critical contributor of keloid progression and recurrence.

Genetics of Keloid Scarring

Keloid disease is a benign fibro-proliferative reticular dermal tumor that develops in response to dysregulated cutaneous wound-healing process. The key alterations result in keloid formation have not been fully understood yet.Extensive literature review suggests that there is a strong genetic predisposition for keloid formation as keloid cases have appeared in twins, families, Asian and African descendant ethnic groups predominantly. Thus, there have been several attempts to investigate the genetic variations that may act as contributing factors in keloid pathogenesis, but no single genetic cause has been identified so far. Gene expression studies have shown highly variable results in linkage analysis of keloid families and in keloid fibroblasts. These findings provide clues that keloids arise from heterogeneous genetic events in coordination with immune-related components for example, the Major Histocompatibility Complex genes, consequently that may contributing towards dermal fibrosis. In addition, it is likely that multiple genetic and epigenetic factors are responsible for the development of the disease pathology. In summary, keloid disease is a disorder in which the exact genetic contribution to pathogenesis is yet to be elucidated. Understanding the genetic basis of keloid disease would help to identify targeted therapies as well as accurately assess individual genetic susceptibility to keloids, in order to provide a more personalized approach to their management.