[Posted 14/Sep/2023]

AUDIENCE: Dermatology, Oncology, Family Medicine

KEY FINDINGS: In addition, Rab7a overexpression is accompanied by reduced migration capacity. Taken together, the study emphasizes that alterations in lysosomal properties facilitate the malignant phenotype and declares the targeting of lysosomal function as a future therapeutic approach.

BACKGROUND: Lysosomes are central in cell homeostasis and participate in macromolecular degradation, plasma membrane repair, exosome release, cell adhesion/migration, and apoptosis. In cancer, alterations in lysosomal function and spatial distribution may facilitate disease progression.

DETAILS: In this study, authors show enhanced lysosomal activity in malignant melanoma cells compared with that in normal human melanocytes. Most lysosomes show perinuclear location in melanocytes, while they are more dispersed in melanoma, with retained proteolytic activity and low pH also in the peripheral population. Rab7a expression is lower in melanoma cells than in melanocytes, and by increasing Rab7a, lysosomes are relocated to the perinuclear region in melanoma. Exposure to the lysosome-destabilizing drug L-leucyl-L-leucine methyl ester causes higher damage in the perinuclear subset of lysosomes in melanomas, whereas differences in subpopulation susceptibility cannot be found in melanocytes. Interestingly, melanoma cells recruit the endosomal sorting complex required for transport-III core protein CHMP4B, involved in lysosomal membrane repair, rather than initiate lysophagy. However, when the perinuclear lysosomal position is promoted by Rab7a overexpression or kinesore treatment, lysophagy is increased.

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

Source: Eriksson, I., Vainikka, L., Waster, P., et al. (2023). Lysosomal Function and Intracellular Position Determine the Malignant Phenotype in Malignant Melanoma. Journal of Investigative Dermatology. 2023; 143 (9): 1769-1778. Published: September, 2023. DOI: 10.1016/j.jid.2023.01.036.

16-Week Results of a Randomized Clinical Trial

[Posted 18/Sep/2024]

AUDIENCE: Dermatology, Family Medicine

KEY FINDINGS: Brodalumab SC 210 mg Q2W demonstrated efficacy in Japanese PPP patients. The most common TEAEs were mild infectious events.

BACKGROUND: Palmoplantar pustulosis (PPP), a refractory skin disease characterized by repeated eruptions of sterile pustules and vesicles on palms and/or soles, involves interleukin-17 pathway activation. Brodalumab, a fully human anti-interleukin-17 receptor A monoclonal antibody, is being investigated for use in PPP treatment. The aim was to assess the efficacy and safety of brodalumab in Japanese PPP patients with moderate or severe pustules/vesicles.

DETAILS: A phase 3, randomized, double-blind, placebo-controlled trial was conducted between July 2019 and August 2022, at 41 centers in Japan. Patients aged 18-70 years with a diagnosis of PPP for >= 24 weeks, a PPP Area Severity Index (PPPASI) score of >= 12, a PPPASI subscore of pustules/vesicles of >= 2, and inadequate response to therapy were included. Participants were randomized 1:1 to receive brodalumab 210 mg or placebo, subcutaneously (SC) at baseline, weeks 1 and 2, and every 2 weeks (Q2W) thereafter until week 16. Changes from baseline to week 16 in the PPPASI total score (primary endpoint) and other secondary skin-related endpoints and safety endpoints were assessed. Of the 126 randomized patients, 50 of 63 in the brodalumab group and 62 of 63 in the placebo group completed the 16-week period. Reasons for discontinuation were adverse event (n = 6), withdrawal by patient/parent/guardian (n = 3), progressive disease (n = 3), and lost to follow-up (n = 1) in the brodalumab group and Good Clinical Practice deviation (n = 1) in the placebo group. Change from baseline in the PPPASI total score at week 16 was significantly higher (p = 0.0049) with brodalumab (least-squares mean [95% confidence interval {CI}] 13.73 [10.91-16.56]) versus placebo (8.45 [5.76-11.13]; difference [95% CI] 5.29 [1.64-8.94]). At week 16, brodalumab showed a trend of rapid improvement versus placebo for PPPASI-50/75/90 response (>= 50%/75%/90% improvement from baseline) and Physician’s Global Assessment 0/1 score: 54% versus 24.2%, 36.0% versus 8.1%, 16.0% versus 0.0%, and 32.0% versus 9.7%, respectively. Infection was the dominant treatment-emergent adverse event (TEAE); the commonly reported TEAEs were otitis externa (25.4%/1.6%), folliculitis (15.9%/3.2%), nasopharyngitis (14.3%/4.8%), and eczema (14.3%/12.9%) in the brodalumab/placebo groups, respectively. The severity of most TEAEs reported was Grade 1 or 2 and less frequently Grade >= 3.

Copyright © Springer Nature. All rights reserved.

Source: Okubo, Y., Kobayashi, S., Murakami, M., et al. (2024). Efficacy and Safety of Brodalumab, an Anti-interleukin-17 Receptor A Monoclonal Antibody, for Palmoplantar Pustulosis: 16-Week Results of a Randomized Clinical Trial. Am J Clin Dermatol. 2024; 25(5): 837-847. Published: September, 2024. DOI: 10.1007/s40257-024-00876-x.

A Critical Examination of Existing Knowledge

[Posted 29/Aug/2024]

AUDIENCE: Dermatology, Family Medicine

KEY FINDINGS: This review highlights the need for additional research because of the lack of standardized reporting of clinical effects in the studies under scrutiny. A deeper exploration of the pathophysiology focusing on dietary modifications and their potential associations with HS severity is essential. Furthermore, it is crucial to recognize that patients' willingness to experiment with new diets makes them vulnerable to fraudulent interventions, highlighting the importance of evidence-based dietary guidance.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic condition that can overwhelm patients, and the effectiveness of supplementary dietary treatments remains uncertain. The primary aim of this review is to explore the connection between diet and HS progression. However, it is imperative to note that the evidence supporting a substantial role of the diet in HS remains weak. Dietary alterations alone should not be considered independent solutions for managing HS.

DETAILS: Medical therapy continues to be indispensable for adequate treatment. Research indicates that the Mediterranean lifestyle and diet may provide cost-effective and beneficial adjustments when combined with traditional therapies. Conversely, foods with a high glycemic index and dairy could worsen HS symptoms, conceivably through mechanisms linked to insulin resistance and inflammation. Zinc, known for its antioxidant properties, shows promise as an adjunct therapy. Moreover, evidence suggests a connection between vitamin D deficiency and HS severity, although the findings are inconclusive. Brewer's yeast-free diet, B12 supplementation, intermittent fasting, and reducing the intake of refined sugar and dairy merit further investigation.

Copyright © John Wiley & Sons Ltd. All rights reserved.

Source: Vural, S., Baskurt, D., Yildirici, S., et al. (2024). Evaluating Dietary Considerations in Hidradenitis Suppurativa: A Critical Examination of Existing Knowledge. International Journal of Dermatology. 2024; 63(8): 987-998. Published: July, 2024. DOI: XX10.1111/ijd.17101XX.

[Posted 22/Jul/2024]

AUDIENCE: General Surgery, Dermatology, Family Medicine

KEY FINDINGS: Skin graft reperfusion is a protracted process that evolves differently in the graft centre and periphery, influenced by postoperative time and anatomic location. A better knowledge of this process can potentially enhance the development of strategies to induce vessel ingrowth into tissue-engineered skin substitutes.

BACKGROUND: Under optimal conditions, afferent and efferent human skin graft microcirculation can be restored 8-12 days postgrafting. Still, the evidence about the reperfusion dynamics beyond this period in a dermato-oncologic setting is scant. Authors aimed to characterise the reperfusion of human skin grafts over 4 weeks according to the necrosis extension (less than 20%, or 20%-50%) and anatomic location using laser speckle contrast imaging (LSCI).

DETAILS: Over 16 months, all eligible adults undergoing skin grafts following skin cancer removal on the scalp, face and lower limb were enroled. Perfusion was assessed with LSCI on the wound margin (control skin) on day 0 and on the graft surface on days 7, 14, 21 and 28. Graft necrosis extension was determined on day 28. Forty-seven grafts of 47 participants were analysed. Regardless of necrosis extension, graft perfusion equalled the control skin by day 7, surpassed it by day 21, and stabilised onwards. Grafts with less than 20% necrosis on the scalp and lower limb shared this reperfusion pattern and had a consistently better-perfused centre than the periphery for the first 21 days. On the face, the graft perfusion did not differ from the control skin from day 7 onwards, and there were no differences in reperfusion within the graft during the study.

Copyright © Wiley Periodicals LLC. All rights reserved

Source: Pinho, A., Brinca, A., Xara, J., et al. (2024). Postoperative Time and Anatomic Location Influence Skin Graft Reperfusion Assessed With Laser Speckle Contrast Imaging. Lasers in Surgery and Medicine. 2024; 56(6): 564-573. Published: August, 2024. DOI: 10.1002/lsm.23815.

[Posted 20/May/2024]

AUDIENCE: Dermatology, Family Medicine

KEY FINDINGS: MTX is a valuable, cost-effective option for long-term treatment of psoriasis although drug survival is not comparable with that of biological treatments. Studies are needed to better understand the best dosing regimen to use, with the aim of achieving the best clinical outcomes and the lowest rate of side effects with this drug.

BACKGROUND: Methotrexate (MTX) is a systemic therapy largely used for moderate-severe psoriasis. There is a lack of data on its use in daily practice and particularly on its long-term effectiveness and survival in psoriasis.

DETAILS: Authors performed a single-centered, retrospective, observational study to evaluate the drug survival of MTX in patients with psoriasis, treated in monotherapy with MTX between March 2015 and March 2022. Clinical and demographic characteristics were extracted from files of the patients. The drug survival was analyzed using Kaplan-Meier survival curves, considering separately overall discontinuation, discontinuation due to MTX ineffectiveness, and discontinuation due to adverse events. Multivariable Cox regression analyses were carried out including clinically meaningful variables. A total of 199 patients were included; 148 (74.4%) suspended MTX during the observation period. The reasons for discontinuation were adverse events (39.2%), ineffectiveness (38.5%), remission of psoriasis (12.2%), and other reasons (10.1%). Average duration of therapy was 10.1 months. Patients who remained on therapy after 1, 2, and 5 years of treatment were respectively 46.9, 35.6, and 29.3%. Positive predictive factors for therapy continuation were increasing age and the use of > 15 mg of MTX for a period > 3 months; the only negative predictive factor was the clinical variant of palmoplantar pustular.

Copyright © John Wiley & Sons Ltd. All rights reserved.

Source: Caldarola, G., De Luca, E., Mariani, M., et al. (2024). Drug Survival of Methotrexate and Predictor Factors for Discontinuation in Psoriasis. Int J Dermatol. 2024; 62(5): 649-656. Published: May, 2024. DOI: 10.1111/ijd.16652.

[Posted 8/May/2024]

AUDIENCE: Dermatology, Oncology, Family Medicine

KEY FINDINGS: Both groups, KTRs and ICs, exhibited similar primary tumor grades and metastasis evolution, but KTRs had a higher prevalence of lymphovascular invasion. Metastasis of cSCC was more common in males with low skin phototype, in KTRs, particularly on the head and neck. The study suggests a possible link between lymphovascular invasion and metastasis development in KTRs.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the most common skin malignancy in kidney transplant recipients (KTRs) as a result of immunosuppression.

DETAILS: A worldwide increase in kidney transplantation justifies the determination of prognostic biomarkers by collecting detailed patient data on metastasis development. This study aims to characterize the clinical, epidemiological, and histopathological profiles of KTRs who developed metastasis of cSCC. Authors conducted a retrospective single-center study on 18 KTRs and 21 immunocompetent patients (ICs) with metastatic cSCC, using data from 2004 to 2021. ICs were older (median age 70.5 years) than KTRs (median age: 59.5 years). Both groups were predominantly male with Fitzpatrick skin phototype I/II. The primary tumor appeared around 83.5 ; months post-transplant, usually in sun-exposed areas (61.1%), though some non-exposed areas in ICs (23.8%) contradicted literature findings. KTRs took longer to develop metastasis (median: 11.0 months) compared to ICs (median: 5.5 months). The mean size of the primary tumor was smaller in KTRs (2.50 cm2) compared to ICs (4.55 cm²). The main lymph node chain affected by metastasis was parotid lymph nodes in KTRs (27.8%) and cervical/axillar lymph nodes in ICs (both 19.0%).

Copyright © John Wiley & Sons Ltd. All rights reserved.

Source: Alves, F. F. C., de Jesus, L. C. B., Cristelli, M. P., et al. (2024). Metastasis Of Skin Squamous Cell Carcinoma In Kidney Transplant Recipients. Int J Dermatol. 2024; 63(5): 560-564. Published: March, 2024. DOI: 10.1111/ijd.17029.