Melanoma Institute Australia

ABSTRACTThere have only been a limited number of case reports that have described vulval lichen sclerosus in patients receiving immune checkpoint inhibitor (ICI) therapy. We describe 11 cases of vulval lichen sclerosus in patients with melanoma treated with ICIs, and in nine of these cases, the lichen sclerosus symptoms began after ICI commencement. This represents the largest reported series to date and highlights the need for clinician awareness of this potential immune‐related adverse effect.

Neoadjuvant ipilimumab plus nivolumab has become standard therapy for stage III melanoma based on the NADINA trial, although long-term data are lacking. In the phase 2 PRADO cohort of OpACIN-neo, 99 patients with stage III macroscopic melanoma received this regimen. Here we report first-time 5-year survival data: 71% event-free survival, 74% relapse-free survival, 79% distant metastasis-free survival and 86% overall survival. Ongoing grade 1-2 immune-related adverse events occurred in 69% of patients alive, predominantly vitiligo and hypothyroidism. Major pathologic response (MPR), high tumor mutational burden (TMB), high interferon-gamma (IFNγ) signature and programmed cell death ligand 1 (PD-L1) expression of 1% or higher were associated with favorable outcomes. Combined high TMB, IFNγ and PD-L1 expression yielded 100% MPR and 100% 5-year event-free survival, whereas triple low expression had only 18% MPR and 41% event-free survival. Our findings demonstrate favorable long-term outcomes for patients with an MPR and identify IFNγ and PD-L1 as promising baseline biomarkers. ClinicalTrials.gov identifier: NCT02977052 .

ABSTRACTBackgroundNext‐generation sequencing (NGS) is becoming more commonly used for diagnosis in dermatopathology. It's critical to appraise its efficacy and limitations. Distinguishing benign deep penetrating nevi (DPN) from deep penetrating like‐melanoma (DPN‐M) is a challenging diagnostic scenario even for experienced dermatopathologists.MethodsWe sent a two‐phase survey (pre‐and postgenomics) to 32 experienced dermatopathologists to evaluate 39 diagnostically challenging cases from the DPN/WNT‐activated family of melanocytic neoplasms.ResultsWith NGS data, interobserver agreement improved from 0.41 to 0.51 (p < 0.0001) in distinguishing DPN‐M from nonmelanoma cases. Overall diagnostic accuracy improved, mostly driven by a 16% increase in accurate diagnosis of DPN‐M. However, in two cases, the inclusion of genomics shifted the majority vote from a correct to an incorrect diagnosis. A total of 218 diagnostic changes occurred between Survey 1 and 2. Among the changes, 132 votes moved toward the correct diagnosis while 86 moved toward an incorrect diagnosis. The shift in voting which resulted in improved diagnostic accuracy was statistically significant (p = 0.0001).ConclusionsNGS has the potential to improve interobserver agreement and diagnostic accuracy. We provide guidance on the utilization of bioinformatic data to maximize its benefits and improve diagnostic accuracy and interobserver agreement.

Background. Adjuvant targeted therapy (ATT) with a combination of dabrafenib and trametinib after radical surgical treatment in patients with stage III skin melanoma (SM) with a BRAF V600 mutation reduces the risk of disease recurrence. The effectiveness of this approach has been demonstrated in randomized clinical trials, and also confirmed in several large non-Russian real-world (RW) studies. Aim. To evaluate, in RW settings, the effectiveness of ATT with a combination of dabrafenib and trametinib after definitive surgical treatment in patients with BRAF V600-positive SM in Russia. Materials and methods. The RATIONALE study is a prospective, non-interventional, multicenter RW study. The follow-up duration for the study was 1 year. Patients with SM older than 18 years who had previously started dabrafenib and trametinib therapy no more than 8 weeks prior to Visit 1 were included in the study. The paper presents results from the analysis of Cohort 1 only (patients who received dabrafenib and trametinib in the adjuvant setting). Results. The cohort included 214 patients with BRAF V600-mutated SM of stages IIIA–D and IV resectable. At the time of therapy initiation, the majority of patients were stage IIIc (54.7%) or IIIb (22.0%). The most common mutation – BRAF V600E – occurred in 66.3% of cases, while the second most common variant – BRAF V600 not otherwise specified – was detected in 31.3%. One-year overall survival for all included patients was 94%, one-year relapse-free survival was 84%, and one-year distant metastasis-free survival was 86%. No previously listed adverse events were reported. Adverse events led to therapy discontinuation in only 11.7% of cases. ATT did not reduce patients' quality of life. In the subgroup analysis, the effectiveness of the combination of dabrafenib and trametinib after removal of distant metastases (equivalent to stage IV resectable) was found, in particular, the one-year relapse-free survival rate was 83%, and the one-year overall survival rate was 100%, which is comparable to these indicators for stage IIIB-D (72–86 and 78–100%, respectively). Conclusion. The effectiveness and favorable safety profile of the combination of dabrafenib and trametinib in ATT after radical surgical treatment was confirmed in a population of Russian patients with SM in the RW settings.

<h2>Abstract</h2> The Personalized Response-directed surgery and Adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma (PRADO trial) is an international, multicenter, single arm, non-randomized prospective phase 2 trial that investigated neoadjuvant immunotherapy (ipi-nivo) in patients with macroscopic stage III melanoma. Depending on tumor response after index lymph node resection (ILN), patients were offered follow up only (major pathologic response, MPR ≤10% viable melanoma); therapeutic lymph node dissection (TLND) without adjuvant therapy (partial pathologic response, pPR; 11-50% viable tumor cells), and finally, TLND +/- adjuvant radiotherapy to the nodal field, followed by adjuvant systemic therapy (pathologic non response (pNR; >50% viable tumor cells), and switch to BRAF/MEK inhibition in case of a BRAF V600 mutation. Primary endpoints were confirmation of pathologic response rate (pRR) of the ipi-nivo; to investigate whether TLND can be safely omitted in patients achieving MPR, with the hypothesis that MPR is durable and transcends the need for TLND. <h3>Results</h3> showed that MPR could be achieved 61% of patients and TLND could safely be omitted in these patients with significantly lower surgical morbidity and better QoL, with durable DFS and DMFS at 2 years. Summarizing, the PRADO trial showed that in macroscopic stage III melanoma 2 doses of neoadjuvant ipi-nivo leads to a high MPR rate and suggests TLND can be safely omitted in favor of ILN. Validation of this concept will follow in MSLT-3.

Careful selection of skin lesions that require expert evaluation is important for early skin cancer detection. Yet challenges include lack of cost-effective asymptomatic screening, geographical inequality in access to specialty dermatology, and long wait times due to exam inefficiencies and staff shortages. Machine learning models trained on high-quality dermoscopy photos have been shown to aid clinicians in diagnosing individual, hand-selected skin lesions. In contrast, models designed for triage have been less explored due to limited datasets that represent a broader net of skin lesions. 3D total body photography is an emerging technology used in dermatology to document all apparent skin lesions on a patient for skin cancer monitoring. A multi-institutional and global project collected over 900,000 lesion crops off 3D total body photos for an online grand challenge in machine learning. Here we summarize the results of the competition, 'ISIC 2024 - Skin Cancer Detection with 3D-TBP', demonstrate superiority of a model that utilized intra-patient context against a prior published approach, and explore clinical plausibility of automated atypical skin lesion triage through an ablation study.