A Multicenter Cohort Study

[Posted 31/Jan/2023]

AUDIENCE: Dermatology, Oncology

KEY FINDINGS: SLN⁺ is low in patients with T1a melanomas, but younger age, lymphovascular invasion, mitogenicity, and head/neck primary site appear to confer a higher risk of SLN⁺.

BACKGROUND: Sentinel lymph node biopsy is not routinely recommended for T1a cutaneous melanoma due to the overall low risk of positivity. Prognostic factors for positive sentinel lymph node (SLN⁺) in this population are poorly characterized. Aim of this study was to determine factors associated with SLN+ in patients with T1a melanoma

DETAILS: Patients with pathologic T1a (<0.80 mm, nonulcerated) cutaneous melanoma from 5 high-volume melanoma centers from 2001 to 2020 who underwent wide local excision with sentinel lymph node biopsy were included in the study. Patient and tumor characteristics associated with SLN⁺ were analyzed by univariate and multivariable logistic regression analyses. Age was dichotomized into <=42 (25% quartile cutoff) and >42 years. Of the 965 patients identified, the overall SLN⁺ was 4.4% (N = 43). Factors associated with SLN⁺ were age <=42 years (7.5% vs 3.7%; odds ratio [OR], 2.14; P = .03), head/neck primary tumor location (9.2% vs 4%; OR, 2.75; P = .04), lymphovascular invasion (21.4% vs 4.2%; OR, 5.64; P = .01), and >=2 mitoses/mm² (8.2% vs 3.4%; OR, 2.31; P = .03). Patients <42 years with >=2 mitoses/mm² (N = 38) had a SLN⁺ rate of 18.4%.

Copyright © Elsevier Ltd. All rights reserved.

Source: Shannon, A. B., Sharon, C. E., Straker III, R. J., et al. (2023). Sentinel Lymph Node Biopsy In Patients With T1A Cutaneous Malignant Melanoma: A Multicenter Cohort Study. JAAD. 2023; 88(1): 52-59. Published: January, 2023. DOI: 10.1016/j.jaad.2022.09.040.

[Posted 25/Mar/2024]

AUDIENCE: Dermatology, Family Medicine

KEY FINDINGS: Melanoma therapeutics continues to advance with combination adjuvant approaches now investigating anti-PD1 with lymphocyte activation gene 3 (LAG3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and individualized neoantigen therapies. How this progress will be integrated into the management of a unique patient to reduce recurrence, limit toxicity, and avoid over-treatment will dominate clinical research and patient care over the next decade.

BACKGROUND: With the development of effective BRAF-targeted and immune-checkpoint immunotherapies for metastatic melanoma, clinical trials are moving these treatments into earlier adjuvant and perioperative settings. BRAF-targeted therapy is a standard of care in resected stage III-IV melanoma, while anti-programmed death-1 (PD1) immunotherapy is now a standard of care option in resected stage IIB through IV disease.

DETAILS: With both modalities, recurrence-free survival and distant-metastasis-free survival are improved by a relative 35-50%, yet no improvement in overall survival has been demonstrated. Neoadjuvant anti-PD1 therapy improves event-free survival by approximately an absolute 23%, although improvements in overall survival have yet to be demonstrated. Understanding which patients are most likely to recur and which are most likely to benefit from treatment is now the highest priority question in the field. Biomarker analyses, such as gene expression profiling of the primary lesion and circulating DNA, are preliminarily exciting as potential biomarkers, though each has drawbacks. As in the setting of metastatic disease, markers that inform positive outcomes include interferon-γ gene expression, PD-L1, and high tumor mutational burden, while negative predictors of outcome include circulating factors such as lactate dehydrogenase, interleukin-8, and C-reactive protein. Integrating and validating these markers into clinically relevant models is thus a high priority.

Copyright © Springer Nature. All rights reserved.

Source: Augustin, R. C. and Luke, J. J. (2024). Rapidly Evolving Pre- and Post-surgical Systemic Treatment of Melanoma. American Journal of Clinical Dermatology. Published: March, 2024. DOI: 10.1007/s40257-024-00852-5.

Principles, Misconceptions, and Key Research Frontiers

[Posted 6/Mar/2024]

AUDIENCE: Dermatology, Family Medicine

KEY FINDINGS: The temporary reversibility of graying is highlighted by several drugs and hormones that induce repigmentation, indicating potential target pathways. Authors advise caution in directly applying mouse model concepts, define major open questions, and discuss future human antigraying strategies.

BACKGROUND: Hair graying holds psychosocial importance and serves as an excellent model for studying human pigmentation and aging in an accessible miniorgan.

DETAILS: Current evidence suggests that graying results from an interindividually varying mixture of cumulative oxidative and DNA damage, excessive mTORC1 activity, melanocyte senescence, and inadequate production of pigmentation-promoting factors in the hair matrix. Various regulators modulate this process, including genetic factors (DNA repair defects and IRF4 sequence variation, peripheral clock genes, P-cadherin signaling, neuromediators, HGF, KIT ligand secretion, and autophagic flux. This leads to reduced MITF- and tyrosinase-controlled melanogenesis, defective melanosome transfer to precortical matrix keratinocytes, and eventual depletion of hair follicle (HF) pigmentary unit (HFPU) melanocytes and their local progenitors. Graying becomes irreversible only when bulge melanocyte stem cells are also depleted, occurring later in this process. Distinct pigmentary microenvironments are created as the HF cycles: early anagen is the most conducive phase for melanocytic reintegration and activation, and only during anagen can the phenotype of hair graying and repigmentation manifest, whereas the HFPU disassembles during catagen.

Copyright © The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. All rights reserved.

Source: Paus, R., Sevilla, A., and Grichnik, J. M. (2024). Human Hair Graying Revisited: Principles, Misconceptions, and Key Research Frontiers. Journal of Investigative Dermatology. 2024; 144(3): 474-491. Published: March, 2024. DOI: 10.1016/j.jid.2023.09.276.

[Posted 28/Feb/2024]

AUDIENCE: Dermatology, Family Medicine

KEY FINDINGS:

BACKGROUND: Plectin, a highly versatile and multifunctional cytolinker, has been implicated in several multisystemic disorders. Most sequence variations in the human plectin gene (PLEC) cause epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), an autosomal recessive skin-blistering disorder associated with progressive muscle weakness.

DETAILS: In this study, authors performed a comprehensive cell biological analysis of dermal fibroblasts from three different patients with EBS-MD, where PLEC expression analyses revealed preserved mRNA levels in all cases, whereas full-length plectin protein content was significantly reduced or completely absent. Downstream effects of pathogenic PLEC sequence alterations included massive bundling of vimentin intermediate filament networks, including the occurrence of ring-like nuclei-encasing filament bundles, elongated mitochondrial networks, and abnormal nuclear morphologies. We found that essential fibroblast functions such as wound healing, migration, or orientation upon cyclic stretch were significantly impaired in the cells of patients with EBS-MD. Finally, EBS-MD fibroblasts displayed reduced adhesion capacities, which could be attributed to smaller focal adhesion contacts. Our study not only emphasizes plectin's functional role in human skin fibroblasts, it also provides further insights into the understanding of EBS-MD–associated disease mechanisms.

Copyright © The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. All rights reserved.

Source: Zrelski, M. M., Hosele, S., Kustermann, M., et al. (2024). Plectin Deficiency in Fibroblasts Deranges Intermediate Filament and Organelle Morphology, Migration, and Adhesion. Journal of Investigative Dermatology. 2024; 144(3): 547-562.e9. Published: March, 2024. DOI: 10.1016/j.jid.2023.08.020.

[Posted 19/Feb/2024]

AUDIENCE: Dermatology, Oncology

KEY FINDINGS: Delay of PORT was associated with increased LRR, usually beyond the radiation field. This is consistent with the tendency of MCC to spread quickly via lymphatics. Initiation of PORT within 8 weeks was associated with improved locoregional control and MCC-specific survival.

BACKGROUND: Merkel cell carcinoma (MCC) is often treated with surgery and postoperative radiation therapy (PORT). The optimal time to initiate PORT (Time-to-PORT [ttPORT]) is unknown. Purpose of this study was to assess if delays in ttPORT were associated with inferior outcomes.

DETAILS: Competing risk regression was used to evaluate associations between ttPORT and locoregional recurrence (LRR) for patients with stage I/II MCC in a prospective registry and adjust for covariates. Distant metastasis and death were competing risks. The cohort included 124 patients with median ttPORT of 41 days (range: 8-125 days). Median follow-up was 55 months. 17 (14%) patients experienced a LRR, 14 (82%) of which arose outside the radiation field. LRR at 5 years was increased for ttPORT >8 weeks vs less than or equal to 8 weeks, 28.0% vs 9.2%, P = .006. There was an increase in the cumulative incidence of MCC-specific death with increasing ttPORT (HR = 1.14 per 1-week increase, P = .016).

Copyright © Elsevier Ltd. All rights reserved.

Source: Alexander, N. A., Schaub, S. K., Goff, P. H., et al. (2024). Increased Risk of Recurrence and Disease-Specific Death Following Delayed Postoperative Radiation for Merkel Cell Carcinoma. Journal of the American Academy of Dermatology. 2024; 90(2): 261-2678. Published: February, 2024. DOI: 10.1016/j.jaad.2023.07.1047.

[Posted 29/Jan/2024]

AUDIENCE: Dermatology, Family Medicine

KEY FINDINGS: Authors observed potent iron storage capacity by keratinocytes in vitro and in vivo and the effects of iron on epidermal differentiation and gene expression associated with inflammation and barrier function. In mice, systemic iron was observed to be coupled to epidermal iron content. Furthermore, topical inflammation, as opposed to systemic inflammation, resulted in a primary iron-deficiency phenotype associated with low liver hepcidin. These studies suggest a role for keratinocytes and epidermal iron storage as regulators of iron homeostasis with direct contribution by the cutaneous inflammatory state.

BACKGROUND: Absorption of dietary iron is largely regulated by the liver hormone hepcidin, which is released under conditions of iron overload and inflammation.

DETAILS: Although hepcidin-dependent regulation of iron uptake and circulation is well-characterized, recent studies have suggested that the skin may play an important role in iron homeostasis, including transferrin receptor–mediated epidermal iron uptake and direct hepcidin production by keratinocytes. In this study, Authors characterized direct keratinocyte responses to conditions of high and low iron.

Copyright © The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. All rights reserved.

Source: Khalil, S., Cavagnero, K. J., Williams, M. R., et al. (2024). Regulation of Epidermal Ferritin Expression Influences Systemic Iron Homeostasis. Journal of Investigative Dermatology. 2024; 144(1): 84-95.E3. Published: January, 2024. DOI: 10.1016/j.jid.2023.07.009.