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Full-thickness lower eyelid defects after Mohs micrographic surgery are frequently referred out to oculoplastic surgery for reconstruction. Reconstructive options include wedge closure with or without canthotomy/cantholysis and tarsoconjunctival sliding flaps. Defects > 50% of the eyelid margin have traditionally required the two-stage Hughes flap, leaving the patient with monocular vision for 3-6 weeks until pedicle division. To demonstrate single-stage periosteal flaps performed by dermatologic surgeons can result in safe, functional, and cosmetically acceptable repairs for large full thickness eyelid defects, an institutional review board-approved retrospective study of repairs performed by two dermatologic surgeons between January 2017 and July 2021 at the University of Minnesota. Patient demographics, operative notes, and follow-up notes were reviewed. Defect and follow-up photographs were scored using a visual analogue scale to assess aesthetic results. Ten cases were included in the analysis. Six patients were male and the average age was 62 years old. 8/10 were basal cell carcinoma and 2/10 were melanoma. The mean defect was 9.5 cm 2 , with a range of 1-24 cm 2 . The median cosmetic score was 85.8 ± 10.7. There were no serious complications reported. Mohs micrographic surgeons can safely and successfully reconstruct large, full thickness eyelid defects by periosteal flap., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Compared with sun-exposed melanomas, less is known regarding the pathogenesis of sun-protected melanomas. Sun-protected melanomas share many epidemiologic factors, but their genetic heterogeneity is not well studied., Objective: We investigated the genomic profile of acral, mucosal, and vulvovaginal melanomas. We hypothesize that mucosal melanomas, recognized for their uniquely aggressive clinical behavior, have distinct genomic features., Methods: We performed whole transcriptome messenger RNA and DNA (1711 genes) sequencing, messenger RNA expression profiling, tumor mutational burden, ultraviolet signature, and copy number variants analysis on 29 volar/digital acral, 7 mucosal, and 6 vulvovaginal melanomas., Results: There was significant genetic heterogeneity, particularly in acral melanomas, with 36% having BRAF alterations, whereas other melanomas had none (P = .0159). Nonzero ultraviolet signatures were more frequent in acral melanomas, suggesting greater ultraviolet involvement. Mucosal melanomas formed a distinct group with increased expression of cell cycle and proliferation genes. Various targetable aberrations were identified, such as AURKA and ERBB2, in mucosal and acral melanomas, respectively., Limitations: The sample size was a small., Conclusion: There is significant genetic heterogeneity among sun-protected melanomas. Mucosal melanomas have upregulation in cell cycle and proliferation genes, which may explain their aggressive behavior. Ultraviolet radiation plays some role in a subset of acral but not other melanomas., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Anti-TNF biological therapies such as infliximab (INF) have revolutionised the treatment of inflammatory bowel diseases (IBD). However, serious adverse effects due to systemic administration can significantly impact patient quality of life, limiting their success. Oral nanomedicines propose an innovative solution to provide local delivery to inflamed gastrointestinal tissues, thereby limiting systemic exposure and enhancing therapeutic efficacy. This study aimed to examine the potential of INF nanomedicines for IBD treatment with a focus on nanoparticle (NP) size to modulate the targeting of INF to the epithelial barrier., Methods: Healthy and inflamed in vitro models of the intestinal epithelial barrier were established to examine the cell interaction of PLGA-PEGNPs of varying particle sizes and polydispersities. INF-loaded NPs were prepared by electrostatic interaction of INF with NPs and examined for their therapeutic efficacy in the inflamed epithelial cell barrier model., Results: NP interaction was significantly enhanced in the inflamed cell barrier model, with increased transport observed for 130 - 300 nm NPs and accumulation of larger NPs (∼600 nm) at the barrier. Delivery of INF directly to the inflamed barrier by ∼600 nm NPs accelerated recovery of barrier integrity and reduced inflammatory cytokine secretion and cytotoxicity in comparison to treatment with INF alone., Conclusions: Results from this study show that NP particle size can be used to differentially target and treat the inflamed intestinal barrier. Oral INF nanomedicines of modulated size present a novel strategy for the local, targeted treatment of IBD., Competing Interests: Declaration of Competing Interest None of the authors report financial conflicts of interest nor have any conflict of interest in relation to publication of this work., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Histopathologic assessment of melanocytic neoplasms is the current gold standard of diagnosis. However, there are well recognized limitations including inter-observer diagnostic discordance. This study aimed to determine if integrating dermoscopy with histopathology of melanocytic neoplasms impacts diagnosis and improves inter-observer agreement. We conducted a prospective cohort study in a pigmented lesion clinic. Consecutive melanocytic lesions were identified for biopsy based on atypical gross or dermoscopic features. Standardized immunohistochemistry and levels were ordered on each specimen. The cases were randomized. Three dermatopathologists blinded to the clinical impression assessed each lesion. The cases were then re-randomized and re-assessed with addition of gross clinical and dermoscopic images. Inter-rater reliability (IRR) using Fleiss' kappa statistic revealed an increase from 0.447 without to 0.496 with dermoscopy amongst all dermatopathologists. The kappa increased from 0.495 before to 0.511 with dermoscopy in separating high-grade atypia or melanoma from moderate atypia or less. In 16 of 136 cases, at least 2 of 3 dermatopathologists favored a diagnosis of melanoma only after dermoscopy. In total, the consensus grade of atypia changed in 24.3% (33/ 136) of cases thereby representing changes to excisional margins and patient follow up. This study is limited by the cohort size. Dermoscopy significantly impacts diagnosis and improves identification of early melanomas in high risk populations and improves inter-observer agreement.

Oral nanomedicines are being investigated as an innovative strategy for targeted drug delivery to treat inflammatory bowel diseases. Preclinical studies have shown that nanoparticles (NPs) can preferentially penetrate inflamed intestinal tissues, allowing for targeted drug delivery. NP size is a critical factor affecting their interaction with the inflamed intestinal barrier and this remains poorly defined. In this study we aimed to assess the impact of NP particle size (PS) and polydispersity (PDI) on cell interaction and uptake in an inflamed epithelial cell model. Using 10, 55 and 100 mg/mL poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG), NPs of 131, 312 and 630 nm PS, respectively, were formulated by solvent dispersion. NP recovery was optimised by differential centrifugation to yield NPs of decreased and unimodal size distribution. NP-cell interaction was assessed in healthy and inflamed caco-2 cell monolayers. Results show that NP interaction with caco-2 cells increased with increasing PS and PDI and was significantly enhanced in inflamed cells. Trypan blue quenching revealed that a significant proportion of multimodal NPs were primarily membrane bound, while monomodal NPs were internalized within cells. These results are interesting as the PS and PDI of NPs can be optimised to allow targeting of therapeutic agents to the epithelial membrane and/or intracellular targets in the inflamed intestinal epithelium.

Background: Atypical network encompasses several patterns. Few studies assess the sensitivity, specificity, and positive and negative predictive values of network subtypes., Objective: We assessed the diagnostic value of atypical network subtypes and their histopathologic correlates in cutaneous melanocytic lesions., Methods: A retrospective search (2014-2018) from a high-risk melanoma clinic for cases scored for atypical network with accompanying dermoscopic photographs yielded 120 lesions (15 melanoma; 30 severely, 38 moderately, and 32 mildly atypical nevi; 4 compound nevi; and 1 junctional nevus). A dermatopathologist blinded to diagnosis assessed dermoscopic and histologic features. Network abnormality correlates with histopathology and clinical diagnoses were assessed with sensitivity, specificity, positive and negative predictive values, and odds ratios., Results: A multivariable model with shiny white streaks (odds ratio 3.02) and inverse network (OR 4.46) was most predictive of melanoma or severe atypia. Positive predictive value for melanoma or severe atypia in decreasing order was inverse network (73.9%), shiny white streaks (71.4%), loss of network (46%), branched streaks (29.4%), and thick brown lines (28.4%)., Limitations: Cases were retrospectively found from a pigmented lesion clinic and evaluated by a single dermatopathologist., Conclusion: Shiny white streaks and inverse network are most predictive of melanoma or severe atypia and warrant biopsy if found on dermoscopy., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Some melanomas closely resemble pigmented spindle cell nevi (PSCN) of Reed histologically. The distinction of these entities is important for clinical management. A recent study showed most PSCN (78%) are fusion-driven, commonly involving NTRK3 (57%). Conversely, BRAF V600E mutations are not characteristic of PSCN but are frequent in melanoma., Objective: In this study, we assessed clinical, histologic and genomic differences between PSCN of Reed and Reed-like melanomas (RLMs)., Methods: We performed BRAF V600E immunohistochemistry (IHC) for 18 PSCN and 20 RLM cases. All 23 benign PSCN cases previously underwent whole transcriptome and targeted DNA sequencing with a 1711 gene panel., Results: We previously demonstrated the majority of PSCN (18 of 23) has chimeric fusions. Among PSCN without a chimeric fusion, BRAF mutations were common. Noncanonical BRAF mutations were identified in 2 of 5 nonfusion cases, and 1 case had a canonical BRAF mutation. Alternatively, 70% of RLM demonstrated a BRAF V600E mutation. RLM also occurred more frequently in older patients., Limitations: The overall sample size was small., Conclusions: In diagnostically challenging cases, ancillary IHC studies can assist in distinguishing PSCN from RLM. Our study suggests positive staining by IHC for BRAF V600E and older age strongly favors a diagnosis of RLM.

The newest World Health Organization classification of skin tumors suggests the elimination of cases with BRAF and NRAS mutations from the categories of Spitz tumors (ST) and Spitz melanoma (SM). The objective of this study is to better characterize the genomics of Spitz neoplasms and assess whether the integration of genomic data with morphologic diagnosis improves classification and prognostication. We performed DNA and RNA sequencing on 80 STs, 26 SMs, and 22 melanomas with Spitzoid features (MSF). Next-generation sequencing data were used to reclassify tumors by moving BRAF and/or NRAS mutated cases to MSF. In total, 81% of STs harbored kinase fusions and/or truncations. Of SMs, 77% had fusions and/or truncations with eight involving MAP3K8. Previously unreported fusions identified were MYO5A-FGFR1, MYO5A-ERBB4, and PRKDC-CTNNB1. The majority of MSFs (84%) had BRAF, NRAS, or NF1 mutations, and 62% had TERT promoter mutations. Only after reclassification, the following was observed: (i) mRNA expression showed distinct clustering of MSF, (ii) six of seven cases with recurrence and all distant metastases were of MSFs, (iii) recurrence-free survival was worse in MSF than in the ST and SM groups (P = 0.0073); and (iv) classification incorporating genomic data was highly predictive of recurrence (OR 13.20, P = 0.0197). The majority of STs and SMs have kinase fusions as primary initiating genomic events. The elimination of BRAF and/or NRAS mutated neoplasms from these categories results in the improved classification and prognostication of melanocytic neoplasms with Spitzoid cytomorphology., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent advances in next generation sequencing (NGS) have allowed for efficient whole transcriptome sequencing, leading to the identification of important kinase fusions as the primary driver in some melanocytic neoplasms. These fusions typically occur mutually exclusively of one another and other well-known initiating mutations such as BRAF, NRAS, NF1, KIT, and GNAQ. Fusions are found in over 50% of Spitz neoplasms, including ALK, BRAF, NTRK1, NTRK3, ROS1, MET, MAP3K8, and RET. Familiarity with the typical morphologic features of certain fusion-driven melanocytic neoplasms can help with classification, diagnosis, and identification of targeted molecular therapies in malignant cases. Spitz tumors with ALK, NTRK1, and NTRK3 fusions have characteristic morphologic features. BRAF and MAP3K8 fusions, in particular, tend to be epithelioid, high grade, and more frequent in Spitz melanoma than other fusion subtypes. Sporadic cases of pigmented epithelioid melanocytoma may have PRKCA fusions and sheets of monomorphic epithelioid melanocytes. Fusion events are also enriched among melanomas without the key mutations BRAF, NRAS, or NF1. Although NGS is the most reliable method to detect fusions, immunohistochemistry and fluorescence in situ hybridization are cost-effective alternatives in some cases. We describe recent discoveries regarding the role of kinase fusions in melanocytic neoplasms and their associated morphologies., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Paediatric melanoma is rare and challenging to diagnose. The three subtypes are Spitzoid melanoma, melanoma arising in a congenital melanocytic nevus, and conventional (also known as adult-type) melanoma. Spitzoid melanomas have characteristic histopathological and genomic aberrations. Despite frequent involvement of the sentinel lymph nodes, most cases have an uneventful clinical course. Among congenital nevi, the risk of melanoma varies by projected size in adulthood, with the greatest risk in large or giant nevi. The clinical course is generally aggressive and accounts for most melanoma-related deaths in childhood. In conventional melanoma, superficial spreading and nodular melanoma account for most cases, with risk factors and presentation largely similar to adult disease. In this Review, we discuss advances in histological diagnosis using adjunctive molecular assays, and summarise the genetic basis of paediatric melanoma., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Recent studies have described kinase fusions as the most common initiating genomic events in Spitzoid neoplasms. Each rearrangement generates a chimeric protein with constitutive activation of the tyrosine kinase domain, resulting in the development of a Spitzoid neoplasm. Identifying key initiating genomic events and drivers may assist in diagnosis, prognostication, and management. Retrospective, consecutive search of our database between 2009 and 2018 for Spitzoid neoplasms identified 86 cases. Whole transcriptome mRNA and DNA sequencing (1714 genes) detected 9% of cases (8/86) with structural rearrangements in MAPK genes other than BRAF and 47% (40/86) with kinase fusions previously described in Spitzoid neoplasms. We identified in-frame fusions of MAP3K8-DIPC2, MAP3K8-PCDH7, MAP3K8-UBL3, MAP3K8-SVIL (n=6), and ATP2A2-MAP3K3 (n=1) as well as a p.I103_K104 in-frame deletion of MAP2K1 (n=1), in the absence of well-recognized drivers of melanocytic neoplasia. Fluorescence in situ hybridization validated all cases (n=7) with available tissue. Cases occurred in younger patients (median age 18 y). Morphologically, cases were predominantly epithelioid (P=0.0032), often with some melanin pigment (P=0.0047), and high-grade nuclear atypia (P=0.012). A significant proportion were thought to be Spitzoid melanomas (3/8). Average follow-up time was 11 months. One MAP3K8-DIP2C Spitzoid melanoma involved 4/5 sentinel lymph nodes and led to a complete lymph node dissection with unremarkable follow-up at 9 months. One MAP3K8-DIPC2 atypical Spitz tumor raised concern for recurrence at 10 months and was reexcised. We present a distinct subtype of Spitzoid neoplasm characterized by structural alterations in MAPK genes, which are important to recognize given the potential for treatment with MAPK inhibitors in metastatic cases.

Pigmented epithelioid melanocytoma (PEM) is considered an intermediate grade melanocytic lesion that is histologically indistinguishable from epithelioid blue nevi associated with Carney complex. PEM are characterized by an intradermal population of heavily pigmented epithelioid-shaped melanocytes along with some spindled and dendritic melanocytes with frequent melanophages. These melanocytic tumors occasionally involve regional lymph nodes but only rarely result in distant metastases. Recent studies have demonstrated a variable but limited number of specific genomic aberrations including protein kinase A regulatory subunit alpha (PRKAR1A), BRAF, GNAQ, and MAP2K1 mutations as well as protein kinase C alpha isoform (PRKCA) fusions. We performed an 8-year retrospective review of our database and identified 16 cases of PEM. Using targeted DNA sequencing and RNA-seq to assess 1714 cancer-related genes, we detected gene fusions involving PRKCA in 31% of cases (5/16) with 5' partners SCARB1(12q24) in 2 cases, CD63 (12q13) in 1 case, ATP2B4 (1q32) in 1 case, and MAP3K3 (17q23) in 1 case. Additional fusions were identified in TPR-NTRK1 (1/16), ALK (1/16), and MYO5A-NTRK3 (1/16). PRKCA fusion lesions tended to occur in younger-aged patients and histologic examination demonstrated sheets of monomorphic epithelioid-shaped melanocytes, moderate to high-grade nuclear atypia, and higher mitotic activity (P=0.037). Our gene panel also identified previously described mutations in PRKAR1A, GNAQ, MAP2K1, BRAF, NF1. To our knowledge, this is the largest and most comprehensive study of PEM integrating molecular data with histologic features that can be utilized in future studies for improved subclassification and prognostication of heavily pigmented melanocytic neoplasms.

Background: Repigmentation at previous biopsy sites pose a significant diagnostic dilemma given clinical and histologic similarities between recurrent nevi and locally recurrent melanoma. Though common in melanoma, the role of TERT promoter mutations (TPMs) in recurrent nevi is unknown., Objective: We investigated the role of TPMs in recurrent nevi and whether the presence of hotspot TPM distinguishes recurrent nevi from locally recurrent melanoma. We also characterized clinical and histologic features differentiating these lesions., Methods: We analyzed 11 locally recurrent melanomas, 17 recurrent nevi, and melanoma and nevus controls to determine TPM status. We also assessed clinical and histologic features of the recurrent groups., Results: Hotspot TPMs were more common in recurrent melanomas than recurrent nevi (P = .008). Recurrent melanomas were more likely to have solar elastosis (P = .0047), multilayering of melanocytes in the epidermis (P = .0221), adnexal involvement (P = .0069), and epidermal consumption (P = .0204). Recurrent nevi had intra-epidermal atypia limited to the area above the scar (P < .0001) and occurred earlier after the original biopsy (P < .0008). Solar elastosis, months to recurrence, and hotspot TPMs were independently associated with recurrent melanoma in multivariate analysis., Limitations: This was a retrospective study., Conclusion: Hotspot TPMs are significantly more frequent in recurrent melanomas and could serve as a diagnostic clue in histologically ambiguous cases., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

There have been major advancements in the treatment of inflammatory bowel disease (IBD) over the past three decades. However despite significant progress, the best available treatments continue to demonstrate variable efficacy in patients and are associated with adverse effects. Therefore there remains an unmet clinical need for ongoing therapeutic advances for IBD. In recent years nanomedicines have emerged as promising diagnostic and therapeutic tools. Nanoparticles in particular show promise to facilitate targeted oral drug delivery in IBD. Here we discuss the pitfalls of current therapies and explore the potential for nanoparticles to improve the treatment of IBD. This review examines the range of conventional and novel therapies which have benefited from nanoparticle-mediated delivery and highlights the proven therapeutic efficacy of this approach in preclinical models. These strategies under development represent a novel and innovative treatment for IBD.

Adolf Wallenberg became the "anatomical conscience" to at least one famed neurologist, and was known worldwide by top neurologists. His comprehensive clinical-pathological descriptions of what became known as Wallenberg Syndrome had a large impact on neurology and launched his career. He did not let a skull base injury from an accident, or his service in the German army in World War I, impede his progress. Despite his accomplishments, because he was Jewish he was stripped of his research laboratory and forced to stop working when the Nazis took over his native Danzig. He barely escaped just before World War II began and immigrated to England, then to the United States. Because of his impact on neurology and his unusual strife, his story is one that neuroscientists should not forget.