Intravenous gentamicin therapy induces functional type VII collagen in patients with recessive dystrophic epidermolysis bullosa: an open-label clinical trial.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable widespread blistering skin disorder caused by mutations in the gene encoding for type VII collagen (C7), the major component of anchoring fibrils. OBJECTIVES: To evaluate the efficacy and safety of intravenous (IV) gentamicin readthrough therapy in patients with RDEB harbouring nonsense mutations. The primary outcomes were increased expression of C7 in patients' skin and safety assessments (ototoxicity, nephrotoxicity, autoimmune response); secondary outcomes included measuring wound healing in target wounds and assessment by a validated Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) scoring system. METHODS: An open-label pilot trial to assess two different IV gentamicin regimens between August 2018 and March 2020 with follow-up through to 180 days post-treatment was carried out. Three patients with RDEB with confirmed nonsense mutations in COL7A1 in either one or two alleles and decreased baseline expression of C7 at the dermal-epidermal junction (DEJ) of their skin participated in the study. Three patients received gentamicin 7.5 mg kg-1 daily for 14 days and two of the three patients further received 7.5 mg kg-1 IV gentamicin twice weekly for 12 weeks. Patients who had pre-existing auditory or renal impairment, were currently using ototoxic or nephrotoxic medications, or had allergies to aminoglycosides or sulfate compounds were excluded. RESULTS: After gentamicin treatment, skin biopsies from all three patients (age range 18-28 years) exhibited increased C7 in their DEJ. With both regimens, the new C7 persisted for at least 6 months post-treatment. At 1 and 3 months post-treatment, 100% of the monitored wounds exhibited > 85% closure. Both IV gentamicin infusion regimens decreased EBDASI total activity scores. Of the patients assessed with the EBDASI, all exhibited decreased total activity scores 3 months post-treatment. All three patients completed the study; no adverse effects or anti-C7 antibodies were detected. CONCLUSIONS: IV gentamicin induced the readthrough of nonsense mutations in patients with RDEB and restored functional C7 in their skin, enhanced wound healing and improved clinical parameters. IV gentamicin may be a safe, efficacious, low-cost and readily available treatment for this population of patients with RDEB.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare and life-threatening inherited skin disease that causes widespread skin blisters that heal with scarring. RDEB affects around 1 in every 100,000 individuals globally. The condition is caused by a mutation in the gene coding for type VII collagen (C7), resulting in a deficiency of C7. C7 is a vital component of the skin as it is responsible for holding the skin's upper two layers together. To date, there are no approved systemic treatments that can cure RDEB. This study, from the United States, aimed to evaluate the effectiveness and safety of intravenous (medicine delivered directly into a patient's vein) gentamicin (an antibiotic) for people with RDEB who have nonsense mutations in their genes (a type of mutation that prevents the production of complete proteins by introducing an inappropriate 'stop signal'). We gave gentamicin to three patients with RDEB every day for 14 days, and two of the three patients further received intravenous gentamicin twice a week for 12 weeks. After gentamicin treatment, all three patients showed increased expression of C7. With both regimens, the new C7 stayed for at least 6 months after the treatment. At 1 and 3 months after treatment, 100% of the wounds being monitored in the patients had closed by more than 85%. All three patients completed the study, and no side-effects were experienced. In conclusion, intravenous gentamicin increased the production of C7 and improved wound healing and quality of life in patients with RDEB carrying nonsense mutations. Intravenous gentamicin may offer a safe, effective, low-cost and readily available therapy in patients with RDEB.

Surgery or Not? A Systematic Review of Facial Congenital Melanocytic Nevi Treatment Patterns and Outcomes.

BACKGROUND: Treatment management for congenital melanocytic nevi (CMN) on the face (FCMN) is highly variable and requires a thorough assessment of multiple factors. To date, a systematic review of FCMN treatment is lacking. The purpose of the present study was to elucidate the frequency, variety, and outcomes of treatment modalities for FCMN with different levels of complexity. METHODS: A comprehensive review of Pubmed, Embase, and Google Scholar databases from 1950 to 2022 was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Articles reporting on FCMN treatment approaches, outcomes, and associated complications were screened and data were extracted according to inclusion criteria. Data were tabulated for thematic analysis of FCMN treatment types, anatomic locations, outcomes, and complications. RESULTS: Of the 561 studies retrieved, 34 met inclusion criteria including 19 surgical treatments, 14 nonsurgical treatments, and one combined surgical and nonsurgical treatment study, totaling 356 patients. The majority of treated FCMN were small-to-medium-sized (56%). Facial CMN treated conservatively were mostly located on the cheek (27%) and/or perinasal region (21%), whereas FCMN treated with surgery were primarily located in the periorbital region (44%) and/or the cheek (17%). Across all treatment cohorts, 22% of patients experienced at least one complication, with 12% of complications experienced by patients treated by surgery. CONCLUSIONS: There is a greater need for standardized FCMN nomenclature that encompasses nevi pattern, dimensions, anatomical coverage, and quantitative measurements of treatment outcome. Future studies should focus on identifying anatomic locations of FCMN that are more prone to complications and determine which treatment approach optimizes outcomes.

[MOCK MOLE: PRODUCING SYNTHETIC IMAGES THAT RECAPITULATE CONFOCAL PATTERNS OF MELANOCYTIC NEVI VIA DEEP-LEARNING MODELS].

INTRODUCTION: Melanocytic nevi present microscopic patterns, which differ in their associated melanoma risk, and can be non-invasively recognized under Reflectance Confocal Microscopy (RCM). AIMS: To train a Generative Adversarial Network (GAN) deep-learning model to produce synthetic images that recapitulate RCM patterns of nevi, enabling reliable classification by human readers and by a Convolutional Neural Network (CNN) computer model. METHODS: A dataset of RCM images of nevi, presenting a uniform pattern, were chosen and classified into one of three patterns - Meshwork, Ring or Clod. Images were used for training a GAN model, which in turn, produced synthetic images recapitulating RCM patterns of nevi. A random sample of synthetic images was classified by two independent human readers and by a CNN model. Human and computer-model classifications were compared. RESULTS: The training set for the GAN model included 1496 RCM images, including 977 images (65.3%) with Meshwork pattern, 261 (17.4%) with Ring and 258 (17.2%) with Clod pattern. The GAN model produced 6000 synthetic RCM-like images. Of these, 302 images were randomly chosen and classified by human readers, including 83 (27.5%) classified as Meshwork, 131 (43.4%) as Ring, and 88 (29.1%) as Clod pattern. Human inter-observer concordance in pattern classification was 91.7%, and human-to-CNN concordance was 87.7%. CONCLUSIONS: We demonstrate feasibility of producing synthetic images, which recapitulate RCM patterns of nevi and can be reproducibly recognized by human readers and by deep-learning models. Synthetic image datasets may allow teaching RCM patterns to novices, training of computer models, and data sharing between research centers.

Gastrostomy tube feeding in epidermolysis bullosa: A multi-center assessment of caregiver satisfaction.

BACKGROUND/OBJECTIVES: Gastrostomy tubes (G-tubes) are a feasible intervention for nutritional support in patients with epidermolysis bullosa (EB) who suffer from gastrointestinal involvement. However, some parents may be apprehensive about this surgical intervention. The purpose of this study is to assess caregiver satisfaction and experiences after G-tube insertion in children with EB. METHODS: Nine institutions sent an anonymous 89-item online questionnaire to caregivers of patients with EB and active G-tubes during an 8-week study period. The questionnaire consisted of eight sections and was formatted with multiple choice, Likert scales, dichotomous scales (yes/no), and free text. RESULTS: Twenty caregiver surveys were completed. All caregivers were parents (100%). The average age of G-tube placement was 2.7 years (SD: 2.1, range 0-8) and duration of the G-tube utilization was an average of 12.0 years (SD: 7.8, range 1-25). EB subtypes were dystrophic (n = 15/20, 75%), junctional (n = 3/20, 15%), and simplex (n = 2/10, 10%). Almost all caregivers (n = 18/20, 90%) reported high levels of satisfaction with G-tube management (scores > 20 on the modified SAGA-8 scale). More than half of caregivers (n = 12/20, 60%) reported that, retrospectively, they would have desired earlier adoption of the G-tube. Caregivers rated mealtimes as more enjoyable and easier both for themselves and the individual with EB post-G-tube placement. CONCLUSION: The survey demonstrates a high rate of satisfaction for G-tube use among caregivers of patients with EB across varying ages and household settings. The free-text responses provide unique insight into caregiver's individual experiences regarding G-tubes to be considered for future studies.

Sirolimus for diffuse intestinal infantile hemangioma with PHACE features: systematic review.

BACKGROUND: We report a 3-month-old female with cardiovascular anomalies and diffuse intestinal infantile hemangioma (IIH) of the small bowel suggesting possible diagnosis of PHACE syndrome (posterior fossa anomalies, hemangioma, arterial lesions, cardiac abnormalities/coarctation of the aorta, eye anomalies). The GI symptoms persisted under treatment with propranolol, whereas the addition of sirolimus led to regression of the IIH. METHODS: A systematic review was conducted using PubMed, EMBASE, and Ovid MEDLINE databases between 1982 and 2021. RESULTS: A total of 4933 articles were identified; 24 articles met inclusion criteria with 46 IIH cases. The most common GI presentations were unspecified GI bleed (40%) and anemia (38%). The most common treatments were corticosteroids (63%), surgical resection (32.6%), and propranolol (28%). Available outcomes were primarily bleeding arrest (84%). Nine cases (19.5%) were diagnosed with definite PHACE, 5 (11%) with possible PHACE, and 32 (69.5%) no PHACE. Our case presented with symptoms most consistent with those of possible PHACE and definite PHACE. No cases in this review underwent treatment with sirolimus. CONCLUSIONS: This is the first reported case of successful treatment of IIH with sirolimus. Our case, along with other patients who present with IIH and PHACE features, suggests consideration of IIH as a diagnostic criterion for PHACE syndrome. IMPACT: This is the first reported case in which sirolimus showed regression of an intestinal infantile hemangioma. This study serves to demonstrate the presentation, treatment, outcomes of intestinal infantile hemangioma, and correlation with PHACE. The potential correlation between intestinal infantile hemangioma and PHACE deserves more study in consideration of intestinal infantile hemangioma as a diagnostic criterion of PHACE.

What's New in Topicals for Atopic Dermatitis?

Atopic dermatitis (AD) is a chronic inflammatory skin condition that can have tremendous impact on quality of life for affected children and adults. First-line therapy for acute management of AD includes topical therapies such as corticosteroids, calcineurin inhibitors, and, more recently, the phosphodiesterase inhibitor crisaborole. Topical agents have remained the mainstay therapy for decades; however, there has been a longstanding need for topical therapies with high efficacy and low risk of adverse effects with long-term use. Given the ongoing advances in understanding the pathogenesis of AD, there are novel targets for pharmacological intervention. We are now in an unprecedented time with more than 40 topical treatments in the pipeline for AD in addition to many developments and treatments on the horizon. This review summarizes selected therapeutic topical agents in later phases of development that target various aspects in the pathogenesis of AD such as Janus kinase inhibition (ruxolitinib and delgocitinib), phosphodiesterase-4 inhibition (roflumilast and difamilast), aryl hydrocarbon modulation (tapinarof), and modulation of the microbiome. We also review novel targeted therapies that are in early phase clinical trials, including AMTX-100, BEN-2293, and PRN473. Preliminary findings on efficacy and tolerability of most of these agents are promising, but further studies are warranted to evaluate the long-term safety and efficacy of these novel agents against the current standard of care.

Atopic dermatitisReview of comorbidities and therapeutics.

Atopic dermatitis (AD) is a very common skin disease associated with substantial burdens on patient health and quality of life. Knowledge regarding the pathogenesis of AD has expanded within recent years, leading to novel and efficacious therapeutic agents. Similarly, our knowledge of the impact of AD on patient's mental and physical health has also expanded. This review summarizes updates on the evolution, comorbidities, and therapeutic options of AD. AD is associated with increased cardiovascular risk, allergic diseases, and adverse mental health outcomes. Topical and systemic therapeutics have drastically altered the landscape of AD therapy in recent years.

Morphological features of benign pigmented ear lesions: a cross-sectional study.

BACKGROUND: The morphology of benign pigmented lesions on the ears has been scarcely studied. METHODS: We prospectively screened all patients presenting to a pigmented lesion clinic at a tertiary academic hospital, between November 2015 and August 2016, for the presence of benign pigmented ear lesions. Clinical and dermoscopic images were obtained for all lesions. Additionally, we performed a retrospective analysis of reflectance confocal microscopy (RCM) of benign pigmented ear lesions and a retrospective analysis of clinical and dermoscopic findings of biopsy-confirmed ear melanomas. RESULTS: In total, 165 patients (median age 48, 53% female) contributed 708 benign pigmented ear lesions to the study. Participants with multiple body nevi and those with an atypical nevus phenotype (multiple body nevi and ≥ one atypical nevus) had a higher mean number of ear lesions than those without multiple body nevi (4.5 and 5.4 vs. 3.9, P < 0.05). The most common diagnoses were nevus (35%) and solar lentigo (34%), followed by pigmented lentiginous macules (PLM) (27%). Dermoscopically scattered pigmented small globules/dots were observed in 30% of nevi and 17% of PLMs. RCM analysis of 24 ear lesions showed a comparable frequency of RCM-clods between nevi and PLMs. Analysis of 29 ear melanomas revealed larger lesions with more complex dermoscopic patterns. CONCLUSION: Multiple body nevi, and particularly an atypical nevus phenotype, were associated with having more pigmented ear lesions. Based on RCM analysis, PLMs of the ear likely represent small nevi. Ear melanomas tend to be larger and dermoscopically complex compared to ear nevi.