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Background/Objectives: In melanoma management, sentinel lymph node biopsy (SLNB) is used to stage patients and to indicate prognosis. More recently, it has been used to select patients for adjuvant therapy. This study aimed to report knowledge of and attitudes towards SLNB for patients with melanoma among Australian dermatologists. Methods: Mixed methods study using cross‐sectional questionnaires (n = 88) and semi‐structured interviews (n = 13), May–September 2019. Results: Of the dermatologists surveyed, 56% thought SLNB had an important role in melanoma management, 26% were unsure and 18% thought SLNB unimportant. Of the 92% who would discuss SLNB with their patients, the main stated value of SLNB was for assessing eligibility for adjuvant therapies (79%); only 60% indicated SLNB was of value for providing prognostic information, and just over half (53%) thought it could improve staging. Interview data indicated that attitudes towards SLNB are shifting among dermatologists, driven by data from landmark clinical trials and the influence of professional networks. Accordingly, interviewees adopted one of three positions in relation to SLNB: (a) believed in utility of SLNB and adhered to the guidelines; (b) were unconvinced about utility of SLNB but adhered to the guidelines; and (c) were unconvinced about utility of SLNB and did not adhere to the guidelines. Conclusion: Although most of the dermatologists surveyed were familiar with and follow the SLNB recommendations, some disagreement with and distrust of the recommendations was evident. Greater acceptance of the SLNB recommendations appeared to be driven by the improved outcomes demonstrated in stage III patients receiving adjuvant systemic therapy. [ABSTRACT FROM AUTHOR]

Keywords: Melanoma; Surgical oncology EN Melanoma Surgical oncology 208 209 2 08/17/22 20220815 NES 220815 Sentinel lymph node biopsy (SLNB) is a staging procedure for assessing metastatic spread from a primary melanoma to the draining lymph nodes. During 2018 and 2019, 892 of 1855 people diagnosed with invasive melanomas of greater than 1.0 mm thickness (48%) and 151 of 597 with melanomas of 0.8-1.0 mm thickness (25%) underwent SLNB. [Extracted from the article]

Immune checkpoint inhibitors and BRAF-targeted therapy each improve survival in melanoma. Immune changes early during targeted therapy suggest the mechanisms of each drug class could work synergistically. In the non-comparative, randomized, phase 2 NeoTrio trial, we investigated whether targeted therapy could boost the proportion of patients achieving long-term recurrence-free survival with neoadjuvant immunotherapy in resectable stage III BRAF V600 -mutant melanoma. Sixty patients (42% females) were randomized to pembrolizumab alone (n = 20), sequential therapy (dabrafenib plus trametinib followed by pembrolizumab; n = 20) or concurrent (triple) therapy (n = 20), followed by surgery and adjuvant therapy. The primary outcome was pathological response; secondary outcomes included radiographic response, recurrence-free survival, overall survival, surgical outcomes, peripheral blood and tumor analyses and safety. The pathological response rate was 55% (11/20; including six pathological complete responses (pCRs)) with pembrolizumab, 50% (10/20; three pCRs) with sequential therapy and 80% (16/20; ten pCRs) with concurrent therapy, which met the primary outcome in each arm. Treatment-related adverse events affected 75-100% of patients during neoadjuvant treatment, with seven early discontinuations (all in the concurrent arm). At 2 years, event-free survival was 60% with pembrolizumab, 80% with sequential therapy and 71% with concurrent therapy. Recurrences after major pathological response were more common in the targeted therapy arms, suggesting a reduction in response 'quality' when targeted therapy is added to neoadjuvant immunotherapy. Risking the curative potential of immunotherapy in melanoma cannot be justified. Pending longer follow-up, we suggest that immunotherapy and targeted therapy should not be combined in the neoadjuvant setting for melanoma. ClinicalTrials.gov registration: NCT02858921 ., (© 2024. The Author(s).)

Background: Predicting which patients with American Joint Committee on Cancer (AJCC) T1-T2 melanomas will have a positive sentinel lymph node (SLN) is challenging. Melanoma Institute Australia (MIA) developed an internationally validated SLN metastatic risk calculator. This study evaluated the nomogram's impact on T1-T2 melanoma patient management at MIA., Methods: SLN biopsy (SLNB) rates were compared for the pre- and post-nomogram periods of 1 July 2018-30 June 2019 and 1 August 2020-31 July 2021, respectively., Results: Overall, 850 patients were identified (pre-nomogram, 383; post-nomogram, 467). SLNB was performed in 29.0% of patients in the pre-nomogram group and 34.5% in the post-nomogram group (p = 0.091). The overall positivity rate was 16.2% in the pre-nomogram group and 14.9% in the post-nomogram group (p = 0.223). SLNB was performed less frequently in T1a melanoma patients in the pre-nomogram group (1.1%, n = 2/177) than in the post-nomogram group (8.6%, n = 17/198) [p ≤ 0.001]. This increase was particularly for melanomas with a risk score ≥ 5%, with an SLN positivity rate of 11.8% in the post-nomogram group (p = 0.004) compared with zero. For T1b melanomas with a risk score of > 10%, the SLNB rate was 40.0% (8/20) pre-nomogram and 75.0% (12/16) post-nomogram (p = 0.049)., Conclusions: In this specialized center, the SLN risk calculator appears to influence practice for melanomas previously considered low risk for metastasis, with increased use of SLNB for T1a and higher-risk T1b melanomas. Further evaluation is required across broader practice settings. Melanoma management guidelines could be updated to incorporate the availability of nomograms to better select patients for SLNB than previous criteria., (© 2024. The Author(s).)

Background: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial., Patients and Methods: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), with complete resection of the pre-therapy tumour bed at week 12., Results: Between 20 August 2014 and 19 April 2017, 35 patients were enrolled. At data cut-off (17 August 2021), the median follow-up was 60 months [95% confidence interval (CI) 56-72 months]. Overall, 21 of 35 (60%) patients recurred, including 12 (57%) with first recurrence in locoregional sites (followed by later distant recurrence in 6) and 9 (43%) with first recurrence in distant sites, including 3 in the brain. Most recurrences occurred within 2 years, with no recurrences beyond 3 years. At 5 years, recurrence-free survival (RFS) was 40% (95% CI 27% to 60%), distant metastasis-free survival (DMFS) was 57% (95% CI 42% to 76%), and overall survival was 80% (95% CI 67% to 94%). Five-year survival outcomes were stratified by pathological response: RFS was 53% with pathological complete response (pCR) versus 28% with non-pCR (P = 0.087), DMFS was 59% versus 55% (P = 0.647), and overall survival was 88% versus 71% (P = 0.205), respectively., Conclusions: Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of RFS, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare., Competing Interests: Disclosure AMM—advisory boards BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics. RAS—advisory boards MetaOptima Technology Inc., F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, GlaxoSmithKline. RPMS—advisory boards MSD, Novartis, and Qbiotics and speaking honoraria from BMS and Novartis. GVL—consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Immunocore, Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, PHMR Ltd, Pierre Fabre, Provectus, Regeneron. All other authors have declared no conflicts of interest., (Copyright © 2024 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Aims: We aimed to develop a European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) module tailored for patients with advanced (resectable or unresectable stage III/IV) melanoma receiving immune checkpoint inhibitors or targeted therapy., Methods: Following the EORTC QoL Group module development guidelines, we conducted phases 1 and 2 of the development process. In phase 1, we generated a list of health-related (HR)QoL issues through a systematic literature review and semi-structured interviews with healthcare professionals (HCPs) and patients with advanced melanoma. In phase 2, these issues were converted into questionnaire items to create the preliminary module., Results: Phase 1: we retrieved 8006 articles for the literature review, of which 35 were deemed relevant, resulting in 84 HRQoL issues being extracted to create the initial issue list. Semi-structured interviews with 18 HCPs and 28 patients with advanced melanoma resulted in 28 issues being added to the initial issue list. Following EORTC module development criteria, 26 issues were removed, and two issues were added after review by patient advocates. Phase 2: To ensure uniformity and avoid duplication, 16 issues were consolidated into eight items. Additionally, an independent expert contributed one new item, resulting in a preliminary module comprising 80 HRQoL items., Conclusion: We identified a range of HRQoL issues (dry skin, xerostomia, and arthralgia) relevant to patients with stage III/IV melanoma. Future module development phases will refine the questionnaire. Once completed, this module will enable standardized assessment of HRQoL in patients with (locally) advanced melanoma., Competing Interests: Declaration of Competing Interest The authors disclose the following potential conflicts of interest: HE: Member of advisory board for Amgen, Pierre Fabre Nordic, BMS, Merck, and Novartis. Research grants received from SkyLine Dx. LN: received institutional research grants from Merck and Syndax Pharmaceuticals; speaker honoraria from BMS, Johnson&Johnson, MSD, and Novartis; has served on advisory boards for BMS, MSD, Novartis, Pierre Fabre, Sanofi Genzyme, and Zealth; and is a shareholder in SATMEG Ventures AB. ROB: received institutional research grants from BMS, Endomagnetics Ltd (Endomag), and SkyLineDx; speaker honorarium from Roche, Pfizer, and Pierre-Fabre; has served on advisory boards for Amgen, BMS, MSD, BD/BARD, Novartis, Roche, and Sanofi Genzyme; and is a shareholder in SATMEG Ventures. AR: Received consultancy fees from Bristol Myers Squibb, Janssen Pharmaceuticals, and Merck Sharp & Dohme. RS: Received honoraria for advisory board participation from MSD, Novartis and Qbiotics and speaking honoraria from BMS. AvA: Advisory Board / Consultancy Honoraria received from Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Provectus, Sanofi, Sirius Medical, 4SC, Neracare. Research Grants received from Amgen, Merck-Pfizer. All other authors (ME, MvL, JLK, IB, SE, LF, MvH, MJ, JL, ALB, OM, SS, LI, JT, HS, NV, LvdP) declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Neoadjuvant systemic therapy (NAST) for patients with stage III melanoma achieves high major pathologic response rates and high recurrence-free survival rates. This study aimed to determine how NAST with targeted therapies (TTs) and immune checkpoint inhibitors (ICIs) influences surgical outcomes after lymph node dissection in terms of complications, morbidity, and textbook outcomes., Methods: Patients who underwent a lymph node dissection after either NAST in a clinical trial or upfront surgery for stage III melanoma between 2014 and 2022 were identified from an institutional research database., Results: The study included 89 NAST-treated patients and 79 upfront surgery-treated patients. The rate of postoperative complications did not differ between the NAST- and upfront surgery-treated patients (55% vs. 51%; p = 0.643), and steroid treatment for drug toxicity did not influence the complication rate (odds ratio [OR], 1.1; 95% confidence interval [CI], 0.4-3; p = 0.826). No significant differences in postoperative morbidity were observed in terms of seroma (23% vs. 11%; p = 0.570) or lymphedema (36% vs. 51%; p = 0.550). The rate of achieving a textbook outcome was comparable for the two groups (61% vs. 57%; p = 0.641)., Conclusions: The surgical outcomes after lymph node dissections were comparable between the patients who received NAST and those who had upfront surgery, indicating that surgery can be safely performed after NAST with TT or ICI for stage III melanoma., (© 2024. The Author(s).)

Heterogeneous resistance to immunotherapy remains a major challenge in cancer treatment, often leading to disease progression and death. Using CITE-seq and matched 40-plex PhenoCycler tissue imaging, we performed longitudinal multimodal single-cell analysis of tumors from metastatic melanoma patients with innate resistance, acquired resistance, or response to immunotherapy. We established the multimodal integration toolkit to align transcriptomic features, cellular epitopes, and spatial information to provide deeper insights into the tumors. With longitudinal analysis, we identified an "immune-striving" tumor microenvironment marked by peri-tumor lymphoid aggregates and low infiltration of T cells in the tumor and the emergence of MITF + SPARCL1 + and CENPF + melanoma subclones after therapy. The enrichment of B cell-associated signatures in the molecular composition of lymphoid aggregates was associated with better survival. These findings provide further insights into the establishment of microenvironmental cell interactions and molecular composition of spatial structures that could inform therapeutic intervention., Competing Interests: Declaration of interests G.V.L. is a consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd., Pierre Fabre, Provectus, Qbiotics, and Regeneron. R.A.S. has received fees for professional services from SkylineDx BV, IO Biotech ApS, MetaOptima Technology, Roche, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN., Bristol Myers Squibb, Myriad Genetics, and GlaxoSmithKline. I.P.d.S. is on the advisory board of Merck Sharp & Dohme; has received fees for professional services from Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Pierre Fabre; and has had travel support from Bristol Myers Squibb and Merck Sharp & Dohme. R.P.M.S. has received honoraria for advisory board participation from Merck Sharp & Dohme, Novartis, and Qbiotics, and speaking honoraria from Bristol Myers Squibb and Novartis. A.S. has received honoraria for advisory board participation from Nanostring and Phenomic. AI and research support was provided by Nanostring and 10X Genomics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Phase 1-2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy., Methods: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival., Results: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of the patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% among patients in the neoadjuvant group who had a major pathological response, 76.1% among those who had a partial response, and 57.0% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% in the adjuvant group., Conclusions: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: The Evaluation of Groin Lymphadenectomy Extent for Melanoma (EAGLE FM) study sought to address the question of whether to perform inguinal (IL) or ilio-inguinal lymphadenectomy (I-IL) for patients with inguinal nodal metastatic melanoma who have no clinical or imaging evidence of pelvic disease. Primary outcome measure was disease-free survival at 5 years, and secondary endpoints included lymphoedema., Methods: EAGLE FM was designed to recruit 634 patients but closed with 88 patients randomised because of slow recruitment and changes in melanoma management. Lymphoedema assessments occurred preoperatively and at 6, 12, 18, and 24 months postoperatively. Lymphoedema was defined as Inter-Limb Volume Difference (ILVD) > 10%, Lymphoedema Index (L-Dex ® ) > 10 or change of L-Dex ®  > 10 from baseline., Results: Prevalence of leg lymphoedema between the two groups was similar but numerically higher for I-IL at all time points in the first 24 months of follow-up; highest at 6 months (45.9% IL [CI 29.9-62.0%], 54.1% I-IL [CI 38.0-70.1%]) and lowest at 18 months (18.8% IL [CI 5.2-32.3%], 41.4% I-IL [CI 23.5-59.3%]). Median ILVD at 24 months for those affected by lymphoedema was 14.5% (IQR 10.6-18.7%) and L-Dex ® was 12.6 (IQR 9.0-17.2). There was not enough statistical evidence to support associations between lymphoedema and extent of surgery, radiotherapy, or wound infection., Conclusions: Despite a trend for patients who had I-IL to have greater lymphoedema prevalence than IL in the first 24 months after surgery, our study's small sample did not have the statistical evidence to support an overall difference between the surgical groups., (© 2024. Crown.)

Background: The introduction of adjuvant systemic treatment for patients with high-risk melanomas necessitates accurate staging of disease. However, inconsistencies in outcomes exist between disease stages as defined by the American Joint Committee on Cancer (8th edition). We aimed to develop a tool to predict patient-specific outcomes in people with melanoma rather than grouping patients according to disease stage., Methods: Patients older than 13 years with confirmed primary melanoma who underwent sentinel lymph node biopsy (SLNB) between Oct 29, 1997, and Nov 11, 2013, at four European melanoma centres (based in Berlin, Germany; Amsterdam and Rotterdam, the Netherlands; and Warsaw, Poland) were included in the development cohort. Potential predictors of recurrence-free and melanoma-specific survival assessed were sex, age, presence of ulceration, primary tumour location, histological subtype, Breslow thickness, sentinel node status, number of sentinel nodes removed, maximum diameter of the largest sentinel node metastasis, and Dewar classification. A prognostic model and nomogram were developed to predict 5-year recurrence-free survival on a continuous scale in patients with stage pT1b or higher melanomas. This model was also calibrated to predict melanoma-specific survival. Model performance was assessed by discrimination (area under the time-dependent receiver operating characteristics curve [AUC]) and calibration. External validation was done in a cohort of patients with primary melanomas who underwent SLNB between Jan 30, 1997, and Dec 12, 2013, at the Melanoma Institute Australia (Sydney, NSW, Australia)., Findings: The development cohort consisted of 4071 patients, of whom 2075 (51%) were female and 1996 (49%) were male. 889 (22%) had sentinel node-positive disease and 3182 (78%) had sentinel node-negative disease. The validation cohort comprised 4822 patients, of whom 1965 (41%) were female and 2857 (59%) were male. 891 (18%) had sentinel node-positive disease and 3931 (82%) had sentinel node-negative disease. Median follow-up was 4·8 years (IQR 2·3-7·8) in the development cohort and 5·0 years (2·2-8·9) in the validation cohort. In the development cohort, 5-year recurrence-free survival was 73·5% (95% CI 72·0-75·1) and 5-year melanoma-specific survival was 86·5% (85·3-87·8). In the validation cohort, the corresponding estimates were 66·1% (64·6-67·7) and 83·3% (82·0-84·6), respectively. The final model contained six prognostic factors: sentinel node status, Breslow thickness, presence of ulceration, age at SLNB, primary tumour location, and maximum diameter of the largest sentinel node metastasis. In the development cohort, for the model's prediction of recurrence-free survival, the AUC was 0·80 (95% CI 0·78-0·81); for prediction of melanoma-specific survival, the AUC was 0·81 (0·79-0·84). External validation showed good calibration for both outcomes, with AUCs of 0·73 (0·71-0·75) and 0·76 (0·74-0·78), respectively., Interpretation: Our prediction model and nomogram accurately predicted patient-specific risk probabilities for 5-year recurrence-free and melanoma-specific survival. These tools could have important implications for clinical decision making when considering adjuvant treatments in patients with high-risk melanomas., Funding: Erasmus Medical Centre Cancer Institute., Competing Interests: Declaration of interests RCS reports honoraria (paid to their institution) from Amgen. AAMvdV reports consultancy fees (paid to their institution) from Bristol Myers Squibb, Merck Sharp & Dohme, Sanofi, Pierre Fabre, Ipsen, Eisai, Merck, Pfizer, Novartis, and Roche. RPMS has received honoraria for advisory board participation from Merck Sharp & Dohme, Novartis, and Qbiotics, and speaker fees from Bristol Myers Squibb and Novartis. AHRV has received honoraria from Novartis. RAS has received fees for professional services from MetaOptima Technology, F Hoffmann-La Roche, Evaxion, Provectus, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, Amgen, Bristol Myers Squibb, Myriad Genetics, and GlaxoSmithKline. GVL reports consultancy or advisory fees from Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal, Highlight Therapeutics, Innovent Biologics, Novartis, OncoSec, PHMR, Pierre Fabre, Provectus, Qbiotics, and Regeneron. JFT has received honoraria for advisory board participation from Bristol Myers Squibb, Merck Sharp & Dohme, GlaxoSmithKline, and Provectus, and travel and conference support from GlaxoSmithKline, Provectus, and Novartis. PR reports research funding (paid to their institution) from Merck Sharp & Dohme and Pfizer, and has received honoraria for lectures and advisory board participation from Merck Sharp & Dohme, Bristol Myers Squibb, Novartis, Pierre Fabre, Sanofi, Merck, Philogen, and Blueprint Medicines. UK has received consulting fees from Merck Sharp & Dohme, travel support from Merck Serono and Pfizer, and grants for educational activities from Merck Serono, Bristol Myers Squibb, and Pierre-Fabre. ACJvA reports honoraria for consultancy and serving on advisory boards (all paid to their institution) from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Merck, Pfizer, Neracare, Novartis, Pierre Fabre, Provectus, Sanofi, Sirius Medical, and 4SC, and research grants (paid to their institution) from Amgen, Merck, and Pfizer. DvK has participated on the data and safety monitoring boards of the FAST CABG and Multivessel Talent trials. DJG has served on data and safety monitoring boards for Amgen and Novartis (funds paid to their institution). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Improvements in recurrence-free survival (RFS) were demonstrated in two recent randomized trials for patients with sentinel node (SN)-negative stage IIB or IIC melanoma receiving adjuvant systemic therapy (pembrolizumab/nivolumab). However, adverse events also occurred. Accurate individualized prognostic estimates of RFS and overall survival (OS) would allow patients to more accurately weigh the risks and benefits of adjuvant therapy. Since the current American Joint Committee on Cancer eighth edition (AJCC-8) melanoma staging system focuses on melanoma-specific survival, we developed a multivariable risk prediction calculator that provides estimates of 5- and 10-year RFS and OS for these patients., Methods: Data were extracted from the Melanoma Institute Australia (MIA) database for patients diagnosed with stage II (clinical or pathological) melanoma (n = 3,220). Survival prediction models were developed using multivariable Cox regression analyses (MIA models) and externally validated twice using data sets from the United States and the Netherlands. Each model's performance was assessed using C-statistics and calibration plots and compared with Cox models on the basis of AJCC-8 staging (stage models)., Results: The 5-year and 10-year RFS C-statistics were 0.70 and 0.73 (MIA-model) versus 0.61 and 0.60 (stage-model), respectively. For OS, the 5-year and 10-year C-statistics were 0.71 and 0.75 (MIA-model) compared with 0.62 and 0.61 (stage-model), respectively. The MIA models were well calibrated and externally validated., Conclusion: The MIA models offer accurate and personalized estimates of both RFS and OS in patients with stage II melanoma even in the absence of pathological staging with SN biopsy. These models were robust on external validations and may be used in everyday practice both with (ideally) and without performing SN biopsy to identify high-risk patients for further management strategies. An online tool will be available at the MIA website (Risk Prediction Tools).

Purpose: In sentinel node-positive (SN+ve) melanoma patients, active surveillance with regular ultrasound examination of the node field has become standard, rather than completion lymph node dissection (CLND). A proportion of these patients now receive adjuvant systemic therapy and have routine cross-sectional imaging (computed tomography [CT] or positron emission tomography [PET]/CT). The role of concurrent ultrasound (US) surveillance in these patients is unclear. The purpose of our study was to describe the modality of detection of nodal recurrence in SN+ve node fields., Methods: SN+ve melanoma patients who did not undergo CLND treated at a single institution from January 1, 2016 to December 31, 2020 were included., Results: A total of 225 SN+ve patients with a median follow-up of 23 months were included. Of these, 119 (53%) received adjuvant systemic therapy. Eighty (36%) developed a recurrence at any site; 24 (11%) recurred first in the SN+ve field, of which 12 (5%) were confirmed node field recurrence only at 2 months follow-up. The nodal recurrences were first detected by ultrasound in seven (3%), CT in seven (3%), and PET/CT in seven (3%) patients. All nodal recurrences evident on US were also evident on PET/CT and vice versa., Conclusions: The high rate of recurrences outside the node field and the identification of all US-detected nodal recurrences on concurrent cross-sectional imaging modalities suggest that routine concurrent ultrasound surveillance of the node-positive field may be unnecessary for SN+ve melanoma patients having routine cross-sectional imaging., (© 2023. The Author(s).)

Purpose: This study aimed to investigate the supportive care needs of Australian melanoma patients and their caregivers to form the basis for improving services., Methods: General and melanoma-related supportive care needs in melanoma patients were measured using the SCNS-SF34 and SCNS-M12 respectively, whereas caregivers completed the SCNS-P&C. Patients also completed the MCQ-28 and FCRI-9, with all participants completing the QLQ-C30, DASS-21, and questions measuring utilisation and preference for supportive health services. Multivariable stepwise logistic regression was used to identify variables associated with unmet needs in melanoma patients., Results: A total of 56 early-stage patients, 100 advanced-stage patients, and 37 caregivers participated. At least three-quarters ([Formula: see text] 75%) of each participant group reported at least one unmet need. Of the ten most reported unmet needs in each participant group, at least six ([Formula: see text] 60%) were related to psychological and emotional well-being, with access to a psychologist the most desired service (> 25%). Fear of cancer recurrence was equally prevalent in both patient groups at a level indicative of need for intervention. Advanced-stage patients reported significantly (p < 0.05) more unmet psychological, physical and daily living, and sexuality needs, and significantly (p < 0.05) worse functioning than early-stage patients., Conclusion: Australian melanoma patients and caregivers report substantial unmet supportive care needs, particularly regarding their psychological and emotional well-being. Psychological and emotional well-being services, such as access to a clinical psychologist or implementation of patient-reported outcome measures, should be incorporated into routine melanoma care to address unmet patient and caregiver needs and improve well-being., (© 2023. The Author(s).)

Importance: Ulceration represents a key feature in cutaneous melanoma, contributing to staging according to the current American Joint Committee on Cancer (AJCC) system. However, cases with incipient ulceration do not quite fulfill the AJCC definition of ulceration and are consequently classified as nonulcerated, presenting interpretive difficulty for pathologists. The prognostic implication of incipient ulceration is uncertain., Objective: To evaluate the prognostic significance of incipient ulceration in cutaneous melanoma., Design, Setting, and Participants: This case-control study consisted of resected primary cutaneous melanomas diagnosed between 2005 and 2015, identified from the Melanoma Institute Australia research database and with slides available for review at Royal Prince Alfred Hospital. Slides were reviewed by pathologists experienced in the diagnosis of melanocytic lesions to identify cases (incipient ulceration) and controls (ulcerated or nonulcerated). Incipient ulceration cases were matched at a 1:2 ratio with nonulcerated and ulcerated controls, respectively. Study analysis was conducted from March to June 2023., Main Outcomes: Clinicopathological factors and clinical outcomes: overall survival (OS), melanoma-specific survival (MSS), and recurrence-free survival (RFS) were compared between cases and controls., Results: Of 2284 patients with melanoma identified, 340 patients (median [IQR] age, 69 [24-94] years; 136 [68%] men; median follow-up, 7.2 years) met the criteria. The matched cohort consisted of 40 cases of incipiently ulcerated melanoma matched 1:2 with 80 nonulcerated controls, and 80 ulcerated controls. The median (IQR) Breslow thickness differed significantly between cases and controls; 2.8 (1.7-4.1) mm for incipient cases compared with 1.0 (0.6-2.1) mm and 5.3 (3.5-8.0) mm for nonulcerated and ulcerated melanomas, respectively. Median (IQR) tumor mitotic rate was 5.0 (3.0-9.0) per mm2 in incipiently ulcerated cases compared with 1 (0-3.0) per mm2 in nonulcerated controls and 9 (5.0-14.0) per mm2 in ulcerated controls. Based on the matched cohorts, patients with nonulcerated tumors had significantly better OS (hazard ratio [HR], 0.49; 95% CI, 0.27-0.88; P = .02) and RFS (HR, 0.37; 95% CI, 0.22-0.64; P < .001) than patients with incipient ulceration. The RFS was significantly worse in ulcerated tumors compared with incipiently ulcerated cases (HR, 1.67; 95% CI, 1.07-2.60; P = .03). After adjusting for pathological factors, no statistically significant differences in clinical outcomes were observed between cases and either control group., Conclusions and Relevance: The findings of this case-control study indicate that incipient ulceration in a primary melanoma represents an adverse prognostic feature that should be noted by pathologists in their reports and considered in future guidelines.

Introduction: The COVID-19 pandemic caused rapid implementation of telehealth for melanoma follow-up care in Australia. This study explores Australian melanoma patients and clinicians' level of satisfaction with telehealth., Methods: A cross-sectional study was conducted across three specialist melanoma centres in Sydney, Australia. Melanoma patients (all stages) and clinicians completed mixed methods surveys seeking socio-demographic and clinical information and questionnaires to assess satisfaction with telehealth. Additionally, patients completed measures of quality of life, fear of cancer recurrence and trust in their oncologist. Patients and clinicians provided open-ended responses to qualitative questions about their perceptions of telehealth., Results: One hundred and fifteen patients and 13 clinicians responded to surveys. Telephone was used by 109 (95%) patients and 11 (85%) clinicians. Fifty-seven (50%) patients and nine (69%) clinicians preferred face-to-face consultations, 38 (33%) patients and 3 (23%) clinicians preferred a combination of face-to-face and telehealth consultations. Five (4%) patients and nil clinicians preferred telehealth consultations. Patients diagnosed with early-stage melanoma, using telehealth for the first time, who have lower trust in their oncologist, and having higher care delivery, communication and supportive care concerns were likely to report lower satisfaction with telehealth. Open-ended responses were consistent between patients and clinicians, who reported safety, convenience and improved access to care as major benefits, while identifying personal, interpersonal, clinical and system-related disadvantages., Discussion: While telehealth has been widely implemented during COVID-19, the benefits identified by patients and clinicians may extend past the pandemic. Telehealth may be considered for use in conjunction with face-to-face consultations to provide melanoma follow-up care., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Male-pattern baldness (MPB) is related to dysregulation of androgens such as testosterone. A previously observed relationship between MPB and skin cancer may be due to greater exposure to ultraviolet radiation or indicate a role for androgenic pathways in the pathogenesis of skin cancers. We dissected this relationship via Mendelian randomization (MR) analyses, using genetic data from recent male-only meta-analyses of cutaneous melanoma (12,232 cases; 20,566 controls) and keratinocyte cancers (KCs) (up to 17,512 cases; >100,000 controls), followed by stratified MR analysis by body-sites. We found strong associations between MPB and the risk of KC, but not with androgens, and multivariable models revealed that this relationship was heavily confounded by MPB single nucleotide polymorphisms involved in pigmentation pathways. Site-stratified MR analyses revealed strong associations between MPB with head and neck squamous cell carcinoma and melanoma, suggesting that sun exposure on the scalp, rather than androgens, is the main driver. Men with less hair covering likely explains, at least in part, the higher incidence of melanoma in men residing in countries with high ambient UV., (© 2023. Springer Nature Limited.)

Purpose: This study characterizes intratumoral macrophage populations within baseline melanoma biopsies from patients with advanced melanoma who received either anti-PD-1 monotherapy or a combination with anti-CTLA-4. Particularly, FcγRIIIa (CD16)-expressing macrophage densities were investigated for associations with response and progression-free survival., Experimental Design: Patients with advanced melanoma who received either anti-PD-1 monotherapy or combination anti-PD-1 and anti-CTLA-4 were retrospectively identified. Macrophage populations were analyzed within baseline melanoma biopsies via multiplex IHC in relation to treatment outcomes., Results: Patients who responded to combination immune checkpoint inhibitor contained higher CD16+ macrophage densities than those who did not respond (196 vs. 7 cells/mm2; P = 0.0041). There was no diffidence in CD16+ macrophage densities in the PD-1 monotherapy-treated patients based on response (118 vs. 89 cells/mm2; P = 0.29). A significantly longer 3-year progression-free survival was observed in combination-treated patients with high intratumoral densities of CD16+ macrophages compared with those with low densities (87% vs. 42%, P = 0.0056, n = 40). No association was observed in anti-PD-1 monotherapy-treated patients (50% vs. 47%, P = 0.4636, n = 50). Melanoma biopsies with high densities of CD16+ macrophages contained upregulated gene expression of critical T-cell recruiting chemokines (CXCL9, CXCL10, and CXCL11)., Conclusions: Our data demonstrate that tumor microenvironments enriched with CD16+ macrophages are favorable for response to combination anti-PD-1 and anti-CTLA-4 therapy but not anti-PD-1 monotherapy. These data provides a potential biomarker of response for combination immunotherapies in patients with metastatic melanoma. See related commentary by Smithy and Luke, p. 2345., (©2023 American Association for Cancer Research.)

Background and Objectives: Adjuvant radiotherapy (RT) can be given to melanoma patients following salvage surgery for node field recurrence after a previous regional node dissection, but the value of this treatment strategy is poorly documented. This study evaluated long-term node field control and survival of patients treated in this way in an era before effective adjuvant systemic therapy became available., Methods: Data for 76 patients treated between 1990 and 2011 were extracted from an institutional database. Baseline patient characteristics, treatment details and oncological outcomes were analysed., Results: Adjuvant RT with conventional fractionation (median dose 48 Gy in 20 fractions) was given to 43 patients (57%) and hypofractionated RT (median dose 33 Gy in 6 fractions) to 33 patients (43%). The 5-year node field control rate was 70%, 5-year recurrence-free survival 17%, 5-year melanoma-specific survival 26% and 5-year overall survival 25%., Conclusions: Salvage surgery with adjuvant RT achieved node field control in 70% of melanoma patients with node field recurrence following a prior node dissection. However, disease progression at distant sites was common and survival outcomes were poor. Prospective data will be required to assess outcomes for contemporary combinations of surgery, adjuvant RT and systemic therapy., (© 2023 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Aim: We conducted a systematic review and evidence gap mapping to explore the existing supportive care interventions and their impact on well-being outcomes for melanoma patients and caregivers., Methods: We searched MEDLINE, Embase, Web of Science Index Medicus, CINAHL, Lilacs, CENTRAL (Cochrane Library) and PsycINFO in December 2022, including interventional studies assessing the effectiveness of any supportive care intervention among melanoma patients and/or their caregivers., Findings: Twenty studies were included in this review. These studies consisted of randomised controlled trials (n = 11, 55%), pre-post studies (n = 7, 35%) and quasi-experimental trials (n = 2, 10%). All studies originated from high-income countries and focused primarily on melanoma patients, with no studies identified that focused solely on caregivers. Educational interventions were the most common (n = 7, 35%), followed by psychoeducational interventions (n = 6, 30%) and psychotherapeutic interventions (n = 4, 20%). Nearly all included studies (n = 18, 90%) reported a positive effect of the intervention on the primary outcome of interest; however, most studies (n = 17, 85%) were judged to be at moderate or high risk of bias. Due to heterogeneity of study designs, intervention characteristics and outcome measures, meta-analysis was not conducted., Implications: Supportive care interventions have positive impacts on melanoma patient well-being outcomes, while being acceptable and feasible to conduct. More research is needed regarding supportive care interventions for melanoma caregivers. Future research should focus on eliminating sources of bias through rigorous methodology, with the development of standardised outcome measures for psychosocial outcomes to facilitate future meta-analyses., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Gene expression profiling is increasingly being utilised as a diagnostic, prognostic and predictive tool for managing cancer patients. Single-sample scoring approach has been developed to alleviate instability of signature scores due to variations from sample composition. However, it is a challenge to achieve comparable signature scores across different expressional platforms., Methods: The pre-treatment biopsies from a total of 158 patients, who have received single-agent anti-PD-1 (n = 84) or anti-PD-1 + anti-CTLA-4 therapy (n = 74), were performed using NanoString PanCancer IO360 Panel. Multiple immune-related signature scores were measured from a single-sample rank-based scoring approach, singscore. We assessed the reproducibility and the performance in reporting immune profile of singscore based on NanoString assay in advance melanoma. To conduct cross-platform analyses, singscores between the immune profiles of NanoString assay and the previous orthogonal whole transcriptome sequencing (WTS) data were compared through linear regression and cross-platform prediction., Results: singscore-derived signature scores reported significantly high scores in responders in multiple PD-1, MHC-1-, CD8 T-cell-, antigen presentation-, cytokine- and chemokine-related signatures. We found that singscore provided stable and reproducible signature scores among the repeats in different batches and cross-sample normalisations. The cross-platform comparisons confirmed that singscores derived via NanoString and WTS were comparable. When singscore of WTS generated by the overlapping genes to the NanoString gene set, the signatures generated highly correlated cross-platform scores (Spearman correlation interquartile range (IQR) [0.88, 0.92] and r 2 IQR [0.77, 0.81]) and better prediction on cross-platform response (AUC = 86.3%). The model suggested that Tumour Inflammation Signature (TIS) and Personalised Immunotherapy Platform (PIP) PD-1 are informative signatures for predicting immunotherapy-response outcomes in advanced melanoma patients treated with anti-PD-1-based therapies., Conclusions: Overall, the outcome of this study confirms that singscore based on NanoString data is a feasible approach to produce reliable signature scores for determining patients' immune profiles and the potential clinical utility in biomarker implementation, as well as to conduct cross-platform comparisons, such as WTS., (© 2023. The Author(s).)

Importance: Refining eligibility guidelines may identify more appropriate patients to undergo useful medical procedures., Objective: To improve cost-effectiveness in selecting patients with melanoma for sentinel lymph node biopsy (SLNB)., Design, Setting, and Participants: This hybrid prognostic study/decision analytical model was conducted among patients with melanoma who were eligible for SLNB at 2 melanoma centers from Australia and the US from 2000 to 2014. Participants consisted of 2 cohorts of patients with melanoma undergoing SLNB and a cohort of eligible patients without SLNB. Individualized probabilities of SLNB positivity generated by a patient-centered methodology (PCM) were compared with those generated by conventional multiple logistic regression analysis investigating 12 prognostic factors. Prognostic accuracy was assessed by the area under the receiver operating characteristic curve (AUROC) for each methodology and by matched-pair analyses., Interventions: Triaging appropriate patients to undergo SLNB., Main Outcomes and Measures: Total number of SLNBs performed (giving total cost) vs number of SLNB-positive outcomes (a measure of effectiveness) was evaluated. Improved cost-effectiveness through judicious patient selection was interpreted as increased numbers of SLNB-positive outcomes achieved, decreased numbers of SLNBs performed, or both outcomes simultaneously., Results: Among 7331 patients with melanoma, SLNB outcomes were assessed in 3640 Australian patients (2212 males [60.8%]; 2447 aged >50 years [67.2%]) and 1342 US patients (774 males [57.7%]; 885 aged >50 years [66.0%]); 2349 patients eligible for SLNB who did not undergo the procedure were included in the simulation. PCM-generated probabilities achieved an AUROC of 0.803 in predicting SLNB positivity in the Australian cohort and 0.826 in the US cohort, higher than corresponding AUROCs generated by conventional logistic regression analysis. In simulation, adopting many SLNB-positive probabilities as minimally acceptable patient-selection criteria resulted in fewer procedures performed or increased the expected numbers of positive SLNBs. A minimally acceptable PCM-generated probability of 8.7% elicited the same number of SLNBs as historically performed (3640 SLNBs), with 1066 positive SLNBs (29.3%), constituting an improvement of 287 additional positive SLNBs compared with 779 actual positive SLNBs (36.8% improvement). In contrast, adopting a 23.7% PCM-generated minimum cutoff probability resulted in performing 1825 SLNBs, or 1815 fewer SLNBs than the actual experience (49.9%). It resulted in the same expected number of positive results (779 SLNBs), for a 42.7% positivity rate., Conclusions and Relevance: This prognostic study/decision analytical model found that the PCM approach outperformed conventional multiple logistic regression analysis in predicting which patients would have positive results on SLNB. These findings suggest that systematically producing and exploiting more accurate SLNB-positivity probabilities could improve the selection of patients with melanoma for SLNB compared with using established guidelines, thus improving the cost-effectiveness of the selection process. Eligibility guidelines to undergo SLNB should include a context-tailored minimum cutoff probability.

Basal cell carcinomas (BCCs) are human beings' most common malignant tumors. Most are easily managed by surgery or topical therapies, and metastasis is rare. Although BCCs can become locally advanced, metastatic BCCs are very uncommon and may be biologically distinct. We assessed the clinicopathologic characteristics of 17 patients with metastatic BCC and pursued whole-exome sequencing of tumor and germline DNA from 8 patients. Genomic profiling revealed aberrant activation of Hedgehog signaling and alterations in GLI transcriptional regulators and Notch and Hippo signaling. Matched local recurrences of primary BCCs and metastases from 3 patients provided evidence of a clonal origin in all cases. Mutations associated with YAP inhibition were found exclusively in 2 hematogenously-spread lung metastases, and metastatic BCCs were enriched for mutations in the YAP/TAZ-binding domain of TEAD genes. Accordingly, YAP/TAZ nuclear localization was associated with metastatic types and Hippo mutations, suggesting an enhanced oncogenic role in hematogenously-spread metastases. Mutations in RET, HGF, and phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) signaling were enriched compared with a cohort of low clinical-risk BCCs. Our results implicate Hippo and PI3K/AKT dysregulation in metastatic progression of BCCs, making these potential therapeutic targets in metastatic disease. The common clonal origin of matched recurrent and metastatic BCCs suggests that molecular profiling can assist in determining the nature/origin of poorly differentiated metastatic tumors of uncertain type. Genes and pathways enriched for mutations in this cohort are candidate drivers of metastasis and can be used to identify patients at high risk of metastasis who may benefit from aggressive local treatment and careful clinical follow-up., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Neoadjuvant ipilimumab plus nivolumab has yielded high response rates in patients with macroscopic stage III melanoma. These response rates translated to high short-term survival rates. However, data on long-term survival and disease recurrence are lacking., Patients and Methods: In OpACIN, 20 patients with macroscopic stage III melanoma were randomized to ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w four cycles of adjuvant or split two cycles of neoadjuvant and two adjuvant. In OpACIN-neo, 86 patients with macroscopic stage III melanoma were randomized to arm A (2× ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w; n = 30), arm B (2× ipilimumab 1 mg/kg plus nivolumab 3 mg/kg q3w; n = 30), or arm C (2× ipilimumab 3 mg/kg q3w plus 2× nivolumab 3 mg/kg q2w; n = 26) followed by surgery., Results: The median recurrence-free survival (RFS) and overall survival (OS) were not reached in either trial. After a median follow-up of 69 months for OpACIN, 1/7 patients with a pathologic response to neoadjuvant therapy had disease recurrence. The estimated 5-year RFS and OS rates for the neoadjuvant arm were 70% and 90% versus 60% and 70% for the adjuvant arm. After a median follow-up of 47 months for OpACIN-neo, the estimated 3-year RFS and OS rates were 82% and 92%, respectively. The estimated 3-year RFS rate for OpACIN-neo was 95% for patients with a pathologic response versus 37% for patients without a pathologic response (P < 0.001). In multiple regression analyses, pathologic response was the strongest predictor of disease recurrence. Of the 12 patients with distant disease recurrence after neoadjuvant therapy, 5 responded to subsequent anti-PD-1 and 8 to targeted therapy, although 7 patients showed progression after the initial response., Conclusions: Updated data confirm the high survival rates after neoadjuvant combination checkpoint inhibition in macroscopic stage III melanoma, especially for patients with a pathologic response. Pathologic response is the strongest surrogate marker for long-term outcome., Competing Interests: Disclosure AMM reports an advisory role for Bristol-Myers Squibb, MSD Oncology, Novartis, Pierre Fabre, QBiotics, and Roche. RPMS reports an advisory role for Merck Sharpe & Dohme, Novartis, and QBiotics; and was a speaker for Bristol-Myers Squibb. WJvH reports an advisory role for Amgen, Bristol-Myers Squibb, and Sanofi. BAvdW reports employment with Bristol-Myers Squibb. RAS reports an advisory role for Amgen, Bristol-Myers Squibb, Evaxion Biotech, GlaxoSmithKline, Merck Sharp & Dohme, Myriad Genetics, NeraCare GmbH, Novartis Australia, Novartis, Provectus Biopharmaceuticals Australia, QBiotics, and Roche; has received compensation for travel expenses from Bristol-Myers Squibb and Novartis Australia; has received honoraria from GlaxoSmithKline, Harvard Medical School, and Wake Forest School of Medicine; and has received research funding from the Australian National Health and Medical Research Council. JBAGH reports an advisory role for Achilles Therapeutics, BioNTech, Bristol-Myers Squibb, Immunocore, Instil Bio, Iovance Biotherapeutics, Ipsen, Molecular Partners, MSD Oncology, Neogene Therapeutics, Novartis, PokeAcell, Roche/Genentech, Sanofi, Third Rock Ventures, and T-Knife; has received research funding, paid to the institute, from Amgen, Asher Biotherapeutics, BioNTech, Bristol-Myers Squibb, MSD, Neon Therapeutics, and Novartis; and is stockowner of Neogene Therapeutics. TNS reports an advisory role for Allogene Therapeutics, Asher Bio, Celsius, Merus, Neogene Therapeutics, Scenic Biotech, and Third Rock Ventures; and is stockowner of Allogene Therapeutics, Asher Bio, Celsius, Merus, Neogene Therapeutics, Scenic Biotech, and Third Rock Ventures. ACJvA reports an advisory role for 4SC, Bristol-Myers Squibb, Amgen, Merck/Pfizer, Novartis, MSD Oncology, Pierre Fabre, Provectus, Sanofi, and Sirius Medical; and received research funding, all paid to the institute, from Amgen and Merck/Pfizer. GVL reports an advisory role for Agenus, Amgen, Array BioPharma, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Evaxion Biotech A/S, Hexal, Highlight Therapeutics, Innovent Biologics, Merck Sharp & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus Australia, QBiotics, and Regeneron; and has received honorarium from Bristol-Myers Squibb and Pierre Fabre. CUB reports research funding from Bristol-Myers Squibb, Novartis, and NanoString, all paid to the institute; has an advisory role for Bristol-Myers Squibb, MSD Oncology, Roche/Genentech, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, Genmab, Pierre Fabre, and Third Rock Ventures; and is stockowner of Uniti Cars and Immagene. All other authors have declared no conflicts of interest., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: The clinical significance of sentinel nodes (SNs) in the triangular intermuscular space (TIS) of patients with melanoma is poorly understood. This study aimed to determine their incidence and positivity rate, and to report their management and patient outcomes., Methods: This was a single-institution retrospective cohort study of patients with unilateral or bilateral TIS SNs on lymphoscintigraphy treated between 1992 and 2017. Recurrence-free survival was analyzed., Results: Lymphoscintigraphy identified TIS SNs in 266 patients. They were bilateral in 17 patients. Of the 2296 patients with a melanoma on the upper back, 259 (11%) had TIS SNs. Procurement of SNs was not attempted in 122 (43%) of the 283 cases and failed in 11 cases (7%). An SN was successfully retrieved from the TIS in 145 patients (53%) and contained metastasis in 18 of 150 TIS SNs. This was the only positive SN in 12 patients (8%), upstaging all of them. Of the 18 patients with a positive SN in the TIS, 9 (50%) underwent completion axillary lymph node dissection, but no additional involved nodes were found in any of these patients. Recurrence in the TIS was observed in six patients (5%), none of whom had their TIS SN surgically pursued previously., Conclusions: Lymphoscintigraphy showed TIS SNs in 11% of patients with melanomas on their upper back. In such cases, retrieval of TIS SNs is required for accurate staging and to minimize the risk of TIS recurrence., (© 2022. Society of Surgical Oncology.)

Introduction: Melanoma surveillance photography (MSP) is a comprehensive surveillance method that comprises two- or three-dimensional total body photography with tagged digital dermoscopy, performed at prescribed intervals. It has the potential to reduce unnecessary biopsies and enhance early detection of melanoma, but it is not yet standard care for all high-risk patients in Australia. This protocol describes a randomised controlled trial (RCT) designed to evaluate the clinical impact and cost-effectiveness of using MSP for the surveillance of individuals at ultra-high or high risk of melanoma from a health system perspective., Methods and Design: This is a registry-based, unblinded, multi-site, parallel-arm RCT that will be conducted over 3 years. We aim to recruit 580 participants from three Australian states: Victoria, New South Wales and Queensland, via state cancer registries or direct referral from clinicians. Eligible participants within 24 months of a primary cutaneous melanoma diagnosis will be randomised 1:1 to receive either MSP in addition to their routine clinical surveillance (intervention group) or routine clinical surveillance without MSP (control group). Most participants will continue surveillance with their usual care provider, and the frequency of follow-up visits in both groups will depend on the stage of their primary melanoma and risk factors. The primary outcome measure of the study is the number of unnecessary biopsies (i.e. false positives, being cases where a lesion is biopsied due to suspected melanoma on clinical examination, either with or without MSP, but the resulting histopathology finding is negative for melanoma). Secondary outcomes include the evaluation of health economic outcomes, quality of life and patient acceptability. Two sub-studies will explore the benefit of MSP in high-risk patients prior to a melanoma diagnosis and the diagnostic performance of MSP in the teledermatology setting compared to the en face clinical setting., Discussion: This trial will determine the clinical efficacy, cost-effectiveness and affordability of MSP to facilitate policy decision-making at the national and local levels, across primary and specialist care., Trial Registration: ClinicalTrials.gov NCT04385732 . Registered on May 13, 2020., (© 2023. The Author(s).)

Resistance to immune checkpoint inhibitor therapies in melanoma is common and remains an intractable clinical challenge. In this study, we comprehensively profile immune checkpoint inhibitor resistance mechanisms in short-term tumor cell lines and matched tumor samples from melanoma patients progressing on immune checkpoint inhibitors. Combining genome, transcriptome, and high dimensional flow cytometric profiling with functional analysis, we identify three distinct programs of immunotherapy resistance. Here we show that resistance programs include (1) the loss of wild-type antigen expression, resulting from tumor-intrinsic IFNγ signaling and melanoma de-differentiation, (2) the disruption of antigen presentation via multiple independent mechanisms affecting MHC expression, and (3) immune cell exclusion associated with PTEN loss. The dominant role of compromised antigen production and presentation in melanoma resistance to immune checkpoint inhibition highlights the importance of treatment salvage strategies aimed at the restoration of MHC expression, stimulation of innate immunity, and re-expression of wild-type differentiation antigens., (© 2023. The Author(s).)

Desmoplastic melanoma (DM) is an uncommon subtype of melanoma with distinct clinicopathological features. It is classified into pure desmoplastic melanoma (PDM) when the proportion of desmoplastic melanoma is ≥90% of the dermally-invasive component, and mixed desmoplastic melanoma (MDM) when the proportion of desmoplastic melanoma is <90%. Studies have reported a lower sentinel lymph node biopsy (SLNB)-positivity rate in PDM compared to MDM and non-DM. As a result, some have recommended not performing SLNB in PDM patients. When PDM is identified in a partial biopsy of a melanoma, there is a risk that sampling bias may under-recognise MDM, but to the best of our knowledge this has not been previously assessed or quantified. The aim of this study was to assess the concordance of the proportion of desmoplastic melanoma in an initial partial biopsy of PDM with the proportion in the entire tumour following complete excision, in patients with cutaneous melanoma. A secondary aim was to determine how frequently this potentially resulted in a patient not receiving a SLNB. Seventy-eight cases of cutaneous melanoma were identified from the Melanoma Institute Australia (MIA) database and 23 cases from the Memorial Sloan Kettering Cancer Centre (MSKCC), where an initial biopsy contained PDM and a subsequent wide excision had residual invasive melanoma. Clinicopathological features were analysed in all patients, including whether a SLNB was performed, the results of SLNB, and any subsequent recurrence. Ninety percent (91/101) of cases were still classified as PDM in the complete wide excision specimen while 10% (10/101) of cases were reclassified as MDM, which was a significant change in classification of final desmoplastic melanoma subtype (p<0.001). The proportion of desmoplastic melanoma was also significantly different between the initial and excisional biopsies (p=0.004). Forty-eight (48/101) patients had a SLNB, of which two (4.5%) were positive for metastatic melanoma; both cases were PDM in the excision specimen. Of the 10 cases demonstrating MDM in the excision specimen, the initial biopsy was a punch biopsy in six cases, shave biopsy in two cases and subcutaneous tissue was sampled in two patients (one punch biopsy, one incisional biopsy). Four of these 10 patients underwent SLNB which was negative in all cases. Twenty-two patients developed recurrence in the follow-up period (median 30 months, range 1-192 months), three with MDM in their excision specimen. One patient did not have a SLNB and developed regional lymph node recurrence. In this study there was a 10% risk that the percentage of desmoplastic melanoma in an initial biopsy of PDM was not representative of the entire lesion, resulting in reclassification as MDM in the excision specimen. If a SLNB is not performed in such cases, a positive SLNB may be missed (one patient in our study) which could impact treatment options for the patient. We recommend caution in not offering a SLNB in the setting of an initial biopsy of PDM if the biopsy is small compared with the overall lesion. If a SLNB is not procured at the time of wide excision in such cases, the SLNs should still be mapped by lymphoscintigraphy to facilitate careful follow up and to enable earlier detection and treatment of nodal disease., (Copyright © 2023 Royal College of Pathologists of Australasia. All rights reserved.)

Melanoma is a cancer of melanocytes, with multiple subtypes based on body site location. Cutaneous melanoma is associated with skin exposed to ultraviolet radiation; uveal melanoma occurs in the eyes; mucosal melanoma occurs in internal mucous membranes; and acral melanoma occurs on the palms, soles, and nail beds. Here, we present the largest whole-genome sequencing study of melanoma to date, with 570 tumors profiled, as well as methylation and RNA sequencing for subsets of tumors. Uveal melanoma is genomically distinct from other melanoma subtypes, harboring the lowest tumor mutation burden and with significantly mutated genes in the G-protein signaling pathway. Most cutaneous, acral, and mucosal melanomas share alterations in components of the MAPK, PI3K, p53, p16, and telomere pathways. However, the mechanism by which these pathways are activated or inactivated varies between melanoma subtypes. Additionally, we identify potential novel germline predisposition genes for some of the less common melanoma subtypes., Significance: This is the largest whole-genome analysis of melanoma to date, comprehensively comparing the genomics of the four major melanoma subtypes. This study highlights both similarities and differences between the subtypes, providing insights into the etiology and biology of melanoma. This article is highlighted in the In This Issue feature, p. 2711., (©2022 The Authors; Published by the American Association for Cancer Research.)

The gut microbiota shapes the response to immune checkpoint inhibitors (ICIs) in cancer, however dietary and geographic influences have not been well-studied in prospective trials. To address this, we prospectively profiled baseline gut (fecal) microbiota signatures and dietary patterns of 103 trial patients from Australia and the Netherlands treated with neoadjuvant ICIs for high risk resectable metastatic melanoma and performed an integrated analysis with data from 115 patients with melanoma treated with ICIs in the United States. We observed geographically distinct microbial signatures of response and immune-related adverse events (irAEs). Overall, response rates were higher in Ruminococcaceae-dominated microbiomes than in Bacteroidaceae-dominated microbiomes. Poor response was associated with lower fiber and omega 3 fatty acid consumption and elevated levels of C-reactive protein in the peripheral circulation at baseline. Together, these data provide insight into the relevance of native gut microbiota signatures, dietary intake and systemic inflammation in shaping the response to and toxicity from ICIs, prompting the need for further studies in this area., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The SunSafe Student Ambassador Program (SSSAP) in Australia uses the peer-to-peer learning environment to educate high-school students about sun-safety., Aims: To assess whether the SSSAP would improve knowledge, attitudes and behaviours towards sun safety in high-school students and whether this would be sustained at 3 months., Methods: An assessment survey was delivered before, immediately after and 3 months after participation in the SSSAP in 2019., Results: In total, 503 participants completed the pre-presentation survey, 274 completed the post-presentation survey, and 218 completed both. Immediately following presentation, the total composite score for all 18 knowledge questions increased from a mean ± SD of 11.8 ± 3.5 to 13.8 ± 4.7 (P < 0.001). There was strong evidence for an improvement in one attitude-based question 'Is it healthy to have a tan?' (P < 0.01) and one behaviour question about wearing sunscreen daily (P = 0.02). After 3 months, 235 students were matched to their pre-presentation survey. The composite score of all knowledge questions had improved from 11.2 ± 3.5 to 12.1 ± 4.5 (out of a total of 18) (P < 0.01). There was also an improvement in two attitude questions 'Do you feel better when you have a tan?' (P = 0.03) and 'Is it healthy to have a tan?' (very strong evidence: P < 0.001), and evidence for a reduction in time spent outdoors on a weekday (P = 0.04)., Conclusion: The SSSAP was associated with improvements in knowledge, attitude and behaviour towards sun safety immediately and at 3 months post-presentation. Further research is required to determine whether these positive effects are sustained and whether they ultimately reduce skin cancers., (© 2022 British Association of Dermatologists.)

Background: Sentinel node biopsy (SN biopsy) is a surgical procedure used to accurately stage patients with primary melanoma at high risk of recurrence. Although Australian Melanoma Management Guidelines recommend SN biopsy be considered in patients with melanomas > 1 mm thick, SN biopsy rates in Australia are reportedly low. Our objective was to identify factors impacting the acceptance, adoption and adherence to the Australian SN biopsy guideline recommendations., Methods: Opinions of Australian key informants including clinicians, representatives from melanoma education and training providers, professional associations and colleges, and melanoma advocacy organisations were collected through semi-structured interviews (n = 29) and from publicly released statements (n = 14 news articles). Data analysis involved inductive and deductive thematic analysis using Flottorp's determinants framework., Results: A complex interplay of contemporary and historical factors was identified as influencing acceptance, adoption and adherence to the SN biopsy guideline recommendations at the individual, guideline, patient, organisational and social levels. Expert and peer opinion leaders have played an important role in facilitating or inhibiting adoption of guideline recommendations, as have financial incentives driven by healthcare-funding policies and non-financial incentives including professional identity and standing. Of critical importance have been the social and knowledge boundaries that exist between different professional groups to whom the guidelines apply (surgeons, dermatologists and primary care practitioners) with adherence to the guideline recommendations having the potential to shift work across professional boundaries, altering a clinician's workflow and revenue. More recently, the emergence of effective immunotherapies and targeted therapies for patients at high risk of recurrence, the emergence of new opinion leaders on the topic (in medical oncology), and patient demands for accurate staging are playing crucial roles in overcoming the resistance to change created by these social and knowledge boundaries., Conclusions: Acceptance and adherence to SN biopsy guideline recommendations in Australia over the past 20 years has involved a process of renegotiation and reframing of the evidence for SN biopsy in melanoma by clinicians from different professional groups and networks. This process has helped to refine the evidence for SN biopsy and our understanding of appropriate adoption. New effective systemic therapies have changed the balance towards accepting guideline recommendations., (© 2022. The Author(s).)

Background: In-transit metastases (ITMs) affect approximately 4% of patients with cutaneous melanoma. This study sought to identify clinical and pathological characteristics that predict further recurrence and survival following resection of ITMs., Patients and Methods: Patients (n = 573) who underwent surgical resection of their first presentation of ITM following previous surgical treatment of an American Joint Committee on Cancer (AJCC) stage I-II melanoma between 1969 and 2017 were identified from an institutional database. Clinicopathological predictors of patterns of recurrence and survival following ITM resection were sought., Results: The median time of ITM development was 2.4 years after primary melanoma resection. ITMs were most frequently located on the lower limb (51.0%). The most common melanoma subtype associated with ITM development was nodular melanoma (44.1%). After surgical resection of a first ITM, 65.4% of patients experienced recurrent disease. Most recurrences were locoregional (44.7%), with distant metastasis occurring in 23.9% of patients. Lower limb ITMs were more frequently associated with subsequent ITMs [odds ratio (OR) 2.41, p = 0.0002], and the lowest risk of distant metastasis (p < 0.0001) compared with other primary sites. Primary melanomas and ITM on head and neck, as well as the presence of ulceration, were associated with worse survival., Conclusions: Recurrence after surgical resection of a first ITM was common. Patterns of recurrence differed according to anatomical site; further ITM recurrences were more likely for lower limb ITMs, which were also associated with longer distant recurrence-free survival. Distant metastasis was more common for ITM on the head and neck, with worse survival., (© 2022. Crown.)

Background: The role of germline genetic factors in determining survival from cutaneous melanoma (CM) is not well understood., Objective: To perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS., Methods: We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia, a high ultraviolet (UV) radiation setting (MIA; 5,762 patients with melanoma; 800 melanoma deaths) and UK Biobank (UKB: 5,220 patients with melanoma; 241 melanoma deaths), and combined them in a fixed-effects meta-analysis. Significant (P < 5 × 10-8) results were investigated in the Leeds Melanoma Cohort (LMC; 1,947 patients with melanoma; 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts., Results: Two loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, HR = 2.09, 95%CI = 1.61-2.71, P = 2.08 × 10-8) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR = 2.38, 95%CI = 1.77-3.21, P = 1.07 × 10-8) on chromosome 7. While neither SNP replicated in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets. After adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR = 0.88, 95% CI = 0.83-0.94, P = 6.93 × 10-5; I2 = 88%). However, this was only driven by the high UV setting cohort (MIA HR = 0.84, 95% CI = 0.78-0.90)., Conclusion: We found two loci potentially associated with MSS. Increased genetic susceptibility to develop CM is associated with improved MSS in a high UV setting., (© 2022. The Author(s).)

Background: The liver is a known site of resistance to immunotherapy and the presence of liver metastases is associated with shorter progression-free and overall survival (OS) in melanoma, while lung metastases have been associated with a more favorable outcome. There are limited data available regarding the immune microenvironment at different anatomical sites of melanoma metastases. This study sought to characterize and compare the tumor immune microenvironment of liver, brain, lung, subcutaneous (subcut) as well as lymph node (LN) melanoma metastases., Methods: We analyzed OS in 1924 systemic treatment-naïve patients with AJCC (American Joint Committee on Cancer) stage IV melanoma with a solitary site of organ metastasis. In an independent cohort we analyzed and compared immune cell densities, subpopulations and spatial distribution in tissue from liver, lung, brain, LN or subcut sites from 130 patients with stage IV melanoma., Results: Patients with only liver, brain or bone metastases had shorter OS compared to those with lung, LN or subcutaneous and soft tissue metastases. Liver and brain metastases had significantly lower T-cell infiltration than lung (p=0.0116 and p=0.0252, respectively) and LN metastases (p=0.0116 and p=0.0252, respectively). T cells were further away from melanoma cells in liver than lung metastases (p=0.0335). Liver metastases displayed unique T-cell profiles, with a significantly lower proportion of programmed cell death protein-1+ T cells compared to all other anatomical sites (p<0.05), and a higher proportion of TIM-3+ T cells compared to LN (p=0.0004), subcut (p=0.0082) and brain (p=0.0128) metastases. Brain metastases had a lower macrophage density than subcut (p=0.0105), liver (p=0.0095) and lung (p<0.0001) metastases. Lung metastases had the highest proportion of programmed death ligand-1+ macrophages of the total macrophage population, significantly higher than brain (p<0.0001) and liver metastases (p=0.0392)., Conclusions: Liver and brain melanoma metastases have a significantly reduced immune infiltrate than lung, subcut and LN metastases, which may account for poorer prognosis and reduced immunotherapy response rates in patients with liver or brain metastases. Increased TIM-3 expression in liver metastases suggests TIM-3 inhibitor therapy as a potential therapeutic opportunity to improve patient outcomes., Competing Interests: Competing interests: MSC reports personal fees from BMS, Merck Sharp & Dohme, Novartis, Roche, Amgen, Pierre-Fabre and Ideaya. RPMS has received honoraria for advisory board participation from MSD, Novartis and Qbiotics and speaking honoraria from BMS and Novartis. JFT has received honoraria for advisory board participation from BMS Australia, MSD Australia, GSK and Provectus, and travel and conference support from GSK, Provectus and Novartis. AMM has served on advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre and QBiotics. GVL is consultant advisor for Agenus Inc, Amgen Inc, Array Biopharma Inc, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA Inc, Merck Sharpe & Dohme (Australia) Pty Limited, Merck Sharpe & Dohme, Novartis Pharma AG, OncoSec Medical Australia, PHMR Limited, Pierre Fabre, Provectus Australia, Qbiotics Group Limited, Regeneron Pharmaceuticals Inc. RAS has received fees for professional services from F. Hoffmann-La Roche, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, Amgen, Bristol Myers Squibb, Myriad Genetics and GlaxoSmithKline. IPS had travel support by BMS and MSD, and speaker fee by Roche, Bristol Myers Squibb and Merck Sharpe & Dohme. All remaining authors declared no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

While the tumor immune microenvironment (TIME) of metastatic melanoma has been well characterized, the primary melanoma TIME is comparatively poorly understood. Additionally, although the association of tumor-infiltrating lymphocytes with primary melanoma patient outcome has been known for decades, it is not considered in the current AJCC melanoma staging system. Detailed immune phenotyping of advanced melanoma has revealed multiple immune biomarkers, including the presence of CD8+ T-cells, for predicting response to immunotherapies. However, in primary melanomas, immune biomarkers are lacking and CD8+ T-cells have yet to be extensively characterized. As recent studies combining immune features and clinicopathologic characteristics have created more accurate predictive models, this study sought to characterize the TIME of primary melanomas and identify predictors of patient outcome. We first phenotyped CD8+ T cells in fresh stage II primary melanomas using flow cytometry (n = 6), identifying a CD39+ tumor-resident CD8+ T-cell subset enriched for PD-1 expression. We then performed Opal multiplex immunohistochemistry and quantitative pathology-based immune profiling of CD8+ T-cell subsets, along with B cells, NK cells, Langerhans cells and Class I MHC expression in stage II primary melanoma specimens from patients with long-term follow-up (n = 66), comparing patients based on their recurrence status at 5 years after primary diagnosis. A CD39+CD103+PD-1- CD8+ T-cell population (P2) comprised a significantly higher proportion of intratumoral and stromal CD8+ T-cells in patients with recurrence-free survival (RFS) ≥5 years vs those with RFS <5 years (p = 0.013). Similarly, intratumoral B cells (p = 0.044) and a significantly higher B cell density at the tumor/stromal interface were associated with RFS. Both P2 and B cells localized in significantly closer proximity to melanoma cells in patients who remained recurrence-free (P2 p = 0.0139, B cell p = 0.0049). Our results highlight how characterizing the TIME in primary melanomas may provide new insights into how the complex interplay of the immune system and tumor can modify the disease outcomes. Furthermore, in the context of current clinical trials of adjuvant anti-PD-1 therapies in high-risk stage II primary melanoma, assessment of B cells and P2 could identify patients at risk of recurrence and aid in long-term treatment decisions at the point of primary melanoma diagnosis., Competing Interests: JFT has received honoraria for advisory board participation from BMS Australia, MSD Australia, GSK and Provectus Inc, and travel and conference support from GSK, Provectus Inc and Novartis. GVL is consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Evaxion Biotech A/S, Hexel AG, Highlight Therapeutics S.L., Merck Sharpe and Dohme, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, Specialised Therapeutics Australia Pty Ltd. RAS has received fees for professional services from F. Hoffmann-La Roche Lt​d, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp and Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, GlaxoSmithKline. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor HPS declared a past co-authorship with the author RAS., (Copyright © 2022 Attrill, Lee, Tasker, Adegoke, Ferguson, da Silva, Saw, Thompson, Palendira, Long, Ferguson, Scolyer and Wilmott.)

Testing for BRAF mutations in metastatic melanoma is pivotal to identifying patients suitable for targeted therapy and influences treatment decisions regarding single agent versus combination immunotherapy. Knowledge of BRAF V600E immunohistochemistry (IHC) results can streamline decisions during initial oncology consultations, prior to DNA-based test results. In the absence of formal guidelines that require pathologist initiated ('reflex') BRAF mutation testing, our institution developed a local protocol to perform BRAF V600E IHC on specimens from all stage III/IV melanoma patients when the status is otherwise unknown. This study was designed to evaluate the application of this protocol in a tertiary referral pathology department. A total of 408 stage III/IV melanoma patients had tissue specimens accessioned between 1 January and 31 March in three consecutive years (from 2019 to 2021), reported by 32 individual pathologists. The BRAF mutation status was established by pathologists in 87% (352/408) of cases. When a prior BRAF mutation status was previously known, as confirmed in linked electronic records (202/408), this status had been communicated by the clinician on the pathology request form in 1% of cases (3/202). Pathologists performed BRAF V600E IHC in 153 cases (74% of cases where the status was unknown, 153/206) and testing was duplicated in 5% of cases (20/408). Reflex BRAF IHC testing was omitted in 26% of cases (53/206), often on specimens with small volume disease (cytology specimens or sentinel node biopsies) despite adequate tissue for testing. Incorporating BRAF IHC testing within routine diagnostic protocols of stage III/IV melanoma was both feasible and successful in most cases. Communication of a patient's BRAF mutation status via the pathology request form will likely improve implementation of pathologist initiated BRAF mutation testing and may result in a reduction of duplicate tests. To improve pathologist reflex testing rates, we advocate for the use of an algorithmic approach to pathologist initiated BRAF mutation testing utilising both IHC and DNA-based methodologies for stage III/IV melanoma patients., (Copyright © 2022 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Primary scalp melanomas are associated with a higher rate of brain metastasis than primary cutaneous melanomas occurring at other head and neck and body sites, but the reason is unclear. Spread to brain parenchyma via emissary veins draining from the scalp to dural sinuses has been suggested. We sought to examine the locations of metastases from primary scalp and nonscalp head and neck melanomas to determine whether there was anatomical evidence supporting direct venous spread to the brain. Data from patients who developed distant metastases from cutaneous head and neck melanomas (CHNMs) between 2000 and 2018 were analyzed. Anatomical sites of primary scalp melanomas and their respective intracranial metastases were compared. Times to first brain and nonbrain metastases were investigated for scalp and nonscalp primary CHNMs. Of 693 patients with CHNMs, 244 developed brain metastases: 109 (44.7%) had scalp primaries and 135 (55.3%) had nonscalp primaries. There was no significant association between anatomical sites of scalp primary melanomas and brain metastases (Cramer's V = 0.21; Chi-square P = 0.63). Compared with nonscalp CHNMs, scalp melanomas had no greater propensity for the brain as the first distant metastatic site ( P = 0.52) but had a shorter time to both brain metastasis (76.3 vs. 168.5 months; P < 0.001) and nonbrain metastasis (22.6 vs. 35.8 months; P < 0.001). No evidence was found to support a direct vascular pathway for metastatic spread of scalp melanomas to the brain. The increased incidence of brain metastases from scalp melanomas is probably driven by aggressive biological mechanisms., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)