Comparative Performance Analysis of Idylla and Archer in the Detection of Gene Fusions in Spitzoid Melanocytic Tumors.

Melanocytic neoplasms with spitzoid histomorphology are often difficult to classify without identifying genetic drivers such as kinase fusions. Traditional diagnostic methods, such as immunohistochemistry, can yield inconclusive results, and advanced techniques such as the Archer fusion assay are often inaccessible and costly. The Idylla GeneFusion Assay might offer a rapid and cost-effective alternative. This study compared Idylla and Archer in identifying ALK, pan-NTRK, RET, and ROS1 gene fusions. Of the 147 samples where next-generation sequencing did not detect genetic drivers, 89 (60.5%) meeting the tissue requirements were further analyzed using Idylla (Cohort A). Idylla demonstrated a sensitivity of 75% and a specificity of 100% in detecting these fusions. Additionally, among 27 randomly selected cases (Cohort B) that failed to meet the inclusion criteria, Idylla maintained the same levels of sensitivity and specificity. Our findings also show that Idylla can be effectively conducted with isolated RNA, broadening its applicability beyond tissue samples. Although the Idylla assay may not replace more comprehensive molecular assays such as Archer, it could serve as a valuable initial screening tool in diagnosing spitzoid melanocytic tumors.

Towards diagnostic criteria for malignant deep penetrating melanocytic tumors using single nucleotide polymorphism array and next-generation sequencing.

Cutaneous deep penetrating melanocytic neoplasms frequently simulate melanoma and might occasionally progress to metastatic melanoma. Distinguishing deep penetrating nevi (DPN) and deep penetrating melanocytomas (DPM) from malignant deep penetrating tumors (MDPT) is difficult based on histopathology alone, and diagnostic criteria for MDPT are currently lacking. Using a molecular workup, we aimed to provide readily available diagnostic tools for classification of deep penetrating tumors. We used clinical follow-up and Single Nucleotide Polymorphism (SNP) array for tumor classification of 20 deep penetrating neoplasms to identify associations with histopathological, immunohistochemistry, and NGS findings. Ten neoplasms were classified as MDPT, four as DPM, and six as DPN. Two MDPT showed metastases. The following parameters were statistically significantly associated with MDPT: severe nuclear atypia (risk ratio [RR] 2.9, p < 0.05), absence of a nevus component (RR 10.0, p = 0.04), positive PRAME expression (RR 9.0, p = 0.02), complete loss of p16 expression (RR 3.5, p = 0.003), TERT-p and APC mutations (RR 11.0, p = 0.01 and RR 2.7, p = 0.002, respectively), and ≥1 additional pathogenic mutation (RR 9.0, p = 0.02). Ki-67 expression ≥ 5% was not significantly associated with MDPTs, although it was <5% in all DPNs. Three MDPT did not show nuclear ß-catenin expression despite having a CTNNB1 (n = 2) or an APC mutation (n = 1). Our findings suggest that complete loss of p16 and positive PRAME expression, a driver mutation in APC, ≥ 1 additional pathogenic mutation, especially in TERT-p, support an MDPT diagnosis in deep penetrating neoplasms. Besides severe nuclear atypia and possibly severe inflammation, we did not identify specific histopathological criteria for malignancy. Non-aberrant nuclear ß-catenin expression might not exclude a deep penetrating signature in MDPT.

Risk of myocardial infarction in patients with atrial fibrillation using vitamin K antagonists, aspirin or direct acting oral anticoagulants.

AIM: Direct-acting oral anticoagulants (DOACs) have become available for the prevention of stroke in patients with atrial fibrillation (AF). Conflicting results have been published on the risk of acute myocardial infarction (AMI) with the use of DOACs in comparison with vitamin K antagonists (VKAs). The objective of the present study was to evaluate the risk of AMI in patients with AF who are exposed to either VKAs, DOACs or low-dose (< 325 mg) aspirin. METHODS: We conducted a population-based cohort study using data from the Clinical Practice Research Datalink (2008-2014). The study population (n = 30 146) consisted of all patients ≥18 years with a diagnosis of AF who were new users of VKAs, DOACs (rivaroxaban and dabigatran) or aspirin. Cox proportional hazards models were used to estimate the hazard ratio (HR) of AMI for users of DOACs or aspirin vs. VKA. Adjustments were made for age, gender, lifestyle, risk factors, comorbidity and other drugs. RESULTS: The risk of AMI was doubled when we compared current use of DOACs with current use of VKAs [adjusted HR 2.11; 95% confidence interval (CI) 1.08, 4.12] and for current users of aspirin vs. current VKA users (adjusted HR 1.91; 95% CI 1.45, 2.51). CONCLUSIONS: There is a twofold increase in the risk of AMI for users of DOACs, in comparison with VKAs, in AF therapy. In addition, the results suggested that in patients with AF, the incidence of AMI is higher during aspirin monotherapy than during the use of VKAs.

Diving with psychotropic medication: review of the literature and clinical considerations.

This review discusses the safety concerns associated with diving while using psychotropic medication and the limited literature available on the topic. Despite the risks, some divers continue to dive while taking these medications, and their reasons for doing so are unclear. The exact mechanisms of action of these drugs in hyperbaric environments are poorly understood. While current standards and advice for fitness-to-dive assessments are based on limited evidence and expert opinion, developing evidence-based strategies could improve patient care and optimise diving safety. This review appraises relevant literature in diving medicine and provides clinical perspectives for diving physicians conducting fitness-to-dive assessments on patients using psychotropic medication.

[Melanocytoma, an intermediate entity between nevus and melanoma: implications of the WHO classification of melanocytic skin tumours]. / Melanocytoom, intermediair tussen naevus en melanoom.

The WHO classification of melanocytic skin tumours published in 2018 describes a new classification with nine different pathways based on molecular driver mutations, localization, clinical context and solar damage. The dichotomous concept of benign (nevus) versus malignant (melanoma) is replaced by a gradual concept starting with a benign nevus with progression into low to high grade intermediate melanocytic lesions, called melanocytoma, and ending at melanoma. The current European recommendation is (re-)excision with 2-5mm margin of low grade melanocytoma and with 5-10mm margin of high grade melanocytoma. Low grade melanocytoma needs no follow-up. For high grade melanocytoma a follow-up for at least 5 years every 6 months is recommended. Routine sentinel node procedure is not indicated. If diagnosis melanoma cannot be ruled out the lesions have to be treated as melanoma. Correct classification of a melanocytoma is a diagnostic challenge, but of high importance for therapeutic choices and prognosis.

Genome-wide copy number variations as molecular diagnostic tool for cutaneous intermediate melanocytic lesions: a systematic review and individual patient data meta-analysis.

Cutaneous intermediate melanocytic neoplasms with ambiguous histopathological features are diagnostically challenging. Ancillary cytogenetic techniques to detect genome-wide copy number variations (CNVs) might provide a valuable tool to allow accurate classification as benign (nevus) or malignant (melanoma). However, the CNV cut-off value to distinguish intermediate lesions from melanoma is not well defined. We performed a systematic review and individual patient data meta-analysis to evaluate the use of CNVs to classify intermediate melanocytic lesions. A total of 31 studies and 431 individual lesions were included. The CNV number in intermediate lesions (median 1, interquartile range [IQR] 0-2) was significantly higher (p<0.001) compared to that in benign lesions (median 0, IQR 0-1) and lower (p<0.001) compared to that in malignant lesions (median 6, IQR 4-11). The CNV number displayed excellent ability to differentiate between intermediate and malignant lesions (0.90, 95% CI 0.86-0.94, p<0.001). Two CNV cut-off points demonstrated a sensitivity and specificity higher than 80%. A cut-off of ≥3 CNVs corresponded to 85% sensitivity and 84% specificity, and a cut-off of ≥4 CNVs corresponded to 81% sensitivity and 91% specificity, respectively. This individual patient data meta-analysis provides a comprehensive overview of CNVs in cutaneous intermediate melanocytic lesions, based on the largest pooled cohort of ambiguous melanocytic neoplasms to date. Our meta-analysis suggests that a cut-off of ≥3 CNVs might represent the optimal trade-off between sensitivity and specificity in clinical practice to differentiate intermediate lesions from melanoma.

Topical Ivermectin in the Treatment of Papulopustular Rosacea: A Systematic Review of Evidence and Clinical Guideline Recommendations.

INTRODUCTION: Rosacea is a chronic inflammatory skin disease with different phenotypes. There is accumulating evidence that the commensal Demodex mite is linked to papulopustular rosacea. Established treatment options, including topical metronidazole, azelaic acid, and tetracyclines, are thought to work through their anti-inflammatory effects. However, none of these therapies have been shown to be curative and are associated with frequent relapses. Therefore, new and improved treatment options are needed. Topical ivermectin 1.0% cream is a new option having both anti-inflammatory and acaricidal activity against Demodex mites which might pave the way to a more etiologic approach. Its use has now been widely adopted by clinical guidelines. The objective was to review the evidence and clinical guideline recommendations concerning ivermectin 1.0% cream in the treatment of papulopustular rosacea. METHODS: A systematic review of both medical literature and clinical guideline recommendations was conducted. Numbers needed to treat (NNT) were calculated for relevant dichotomous outcomes (e.g., relapse rate and achieving full lesion clearance) to compare ivermectin with other established treatment options for rosacea. RESULTS: The search identified three randomized trials, three extension studies, and two meta-analyses. Ivermectin has only been tested in moderate-to-severe papulopustular rosacea. Ivermectin is an effective treatment option for papulopustular rosacea and seems to be more effective than metronidazole (NNT = 10.5) at 12 weeks of treatment. Although ivermectin was numerically more effective than metronidazole at week 36 in preventing relapse (NNT = 17.5), relapse after discontinuation of treatment in both groups was common with 62.7% and 68.4% of patients relapsing. Based on limited generalizability of available evidence, clinical guidelines have yielded different treatment algorithms and, in some areas, conflicting recommendations. CONCLUSION: Topical ivermectin is an effective option in the treatment of papulopustular rosacea. Although ivermectin seems to be more effective than topical metronidazole, with both treatment options about two-thirds of patient relapsed within 36 weeks after discontinuation of treatment. More research is needed to establish the clinical benefit of ivermectin's acaricidal action in preventing relapse compared to other non-etiologic treatment approaches.