Development and validation of a novel model to predict recurrence-free survival and melanoma-specific survival after sentinel lymph node biopsy in patients with melanoma: an international, retrospective, multicentre analysis.

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.

Predicting Recurrence-Free and Overall Survival for Patients With Stage II Melanoma: The MIA Calculator.

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).

Role of Concurrent Ultrasound Surveillance of Sentinel Node-Positive Node Fields in Melanoma Patients Having Routine Cross-Sectional Imaging.

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.

Prognostic Significance of Incipient Ulceration in Primary Cutaneous Melanoma.

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.

Telehealth follow-up consultations for melanoma patients during the COVID-19 pandemic: Patient and clinician satisfaction.

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.

Uncovering the complex relationship between balding, testosterone and skin cancers in men.

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.

Supportive care needs in Australian melanoma patients and caregivers: results from a quantitative cross-sectional survey.

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.

Improving Selection for Sentinel Lymph Node Biopsy Among Patients With Melanoma.

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.

Cross-platform comparison of immune signatures in immunotherapy-treated patients with advanced melanoma using a rank-based scoring approach.

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 r2 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.

A systematic review with evidence mapping of supportive care interventions for melanoma patients and caregivers.

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.

Adjuvant radiotherapy after salvage surgery for melanoma recurrence in a node field following a previous lymph node dissection.

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.

Study protocol for a randomised controlled trial to evaluate the use of melanoma surveillance photography to the Improve early detection of MelanomA in ultra-hiGh and high-risk patiEnts (the IMAGE trial).

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.

The molecular and functional landscape of resistance to immune checkpoint blockade in melanoma.

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.

Genomic Profiling of Metastatic Basal cell Carcinoma Reveals Candidate Drivers of Disease and Therapeutic Targets.

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 3­kinase (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.

Intratumoral CD16+ Macrophages Are Associated with Clinical Outcomes of Patients with Metastatic Melanoma Treated with Combination Anti-PD-1 and Anti-CTLA-4 Therapy.

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.

Vulvar Melanoma.

This case report describes an ulcerated, erythematous, and hyperpigmented periurethral nodule with surrounding irregular macular hyperpigmentation.

Prognostic Significance and Management of Sentinel Nodes in the Triangular Intermuscular Space of Patients with Melanoma.

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.

Factors influencing acceptance, adoption and adherence to sentinel node biopsy recommendations in the Australian Melanoma Management Guidelines: a qualitative study using an implementation science framework.

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.

Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting.

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.