Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma.

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.).

Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer.

BACKGROUND: The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood. METHODS: We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use. RESULTS: Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 [noninferiority margin, -8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not. CONCLUSIONS: A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.).

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.

The Effect of Neoadjuvant Systemic Therapy on Surgical Outcomes After Lymph Node Dissections for Stage III Melanoma; An Australian Cohort.

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.

Impact of an Online Risk Calculator for Sentinel Node Positivity on Management of Patients with T1 and T2 Melanomas.

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.

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.

Risk factors for subsequent primary melanoma in patients with previous melanoma: a systematic review and meta-analysis.

BACKGROUND: Compared with the general population, people with a previous melanoma are at increased risk of developing another primary melanoma. Understanding the risk factors associated with multiple primary melanomas can inform patient education and tailored surveillance. OBJECTIVES: To examine the risk factors for subsequent primary melanoma in people with a previous melanoma, by conducting a systematic review and meta-analysis of the available data. METHODS: A systematic literature search was conducted in CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), Embase and MEDLINE. Studies that reported a risk estimate or raw frequencies and conducted between 1982 and August 2022 were included. Adjusted risk estimates were prioritized over univariable risk estimates. PRISMA reporting guidelines were followed. Random effects meta-analysis was conducted to derive pooled estimates. Quality assessment was conducted by two researchers using the Newcastle-Ottawa scale. GRADE was used to rate the certainty and quality of the evidence. RESULTS: Data from 27 studies involving 413 181 participants were pooled and analysed. Risk factors assessed included age and sex, environmental, lifestyle, phenotypic, genetic and histopathological factors, and there was wide variation in how they were categorized and analysed. Independent risk factors identified from pooled analyses included male sex [hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.40-1.53], increasing age per 10 years (HR 1.19, 95% CI 1.14-1.24), light skin colour (HR 1.44, 95% CI 1.23-1.70), family history [odds ratio (OR) 1.79, 95% CI 1.25-2.56], CDKN2A mutation (OR 5.29, 95% CI 2.70-10.37), a high or moderate naevus count [OR 2.63 (95% CI 1.61-4.30) and OR 1.64 (95% CI 1.07-2.51), respectively], one or more atypical naevi (OR 3.01, 95% CI 1.52-5.97), first lesions occurring on the head or neck, lentigo maligna subtype (HR 1.16, 95% CI 1.15-1.17), other subtype (HR 1.14, 95% CI 1.03-1.27) and inadequate sun protection (HR 1.85, 95% CI 0.98-3.50). Based on the GRADE criteria, there was high to very low confidence in the pooled effect estimates. CONCLUSIONS: This meta-analysis identified several consistent, independent risk factors for the development of subsequent primary melanoma. These findings will help stratify the risk of subsequent melanoma, tailor skin-check schedules and inform patient education.

Dermoscopy of Lentiginous Melanomas and Equivocal Benign Pigmented Macules of the Scalp: A Case-Control Multicentric Study.

INTRODUCTION: Although the dermoscopic features of facial lentiginous melanomas (LM), including lentigo maligna and lentigo maligna melanoma, have been extensively studied, the literature about those located on the scalp is scarce. This study aims to describe the dermoscopic features of scalp LM and assess the diagnostic accuracy of dermoscopy to discriminate them from equivocal benign pigmented macules. METHODS: Consecutive cases of scalp LM and histopathology-proven benign but clinically equivocal pigmented macules (actinic keratoses, solar lentigos, seborrhoeic keratoses, and lichen planus-like keratoses) from four referral centres were included. Dermoscopic features were analysed by two blinded experts. The diagnostic performance of a predictive model was assessed. RESULTS: 56 LM and 44 controls were included. Multiple features previously described for facial and extrafacial LM were frequently identified in both groups. Expert's sensitivity to diagnose scalp LM was 76.8% (63.6-87.0) and 78.6% (65.6-88.4), with specificity of 54.5% (38.9-69.6) and 56.8% (41.0-71.7), and fair agreement (kappa coefficient 0.248). The strongest independent predictors of malignancy were (OR, 95% CI) chaos of colour (15.43, 1.48-160.3), pigmented reticular lines (14.96, 1.68-132.9), increased density of vascular network (3.45, 1.09-10.92), and perifollicular grey circles (2.89, 0.96-8.67). The predictive model achieved 85.7% (73.8-93.6) sensitivity, 61.4% (45.5-75.6) specificity, and 81.5 (73.0-90.0) area under curve to discriminate benign and malignant lesions. A diagnostic flowchart was proposed, which should improve the diagnostic performance of dermoscopy. CONCLUSION: Both facial and extrafacial dermoscopic patterns can be identified in scalp LM, with considerable overlap with benign pigmented macules, leading to low specificity and interobserver agreement on dermoscopy.

Patient demographic characteristics and risk factors associated with sun protection behaviours in specialist melanoma clinics.

OBJECTIVE: We investigated the association between sun protection behaviours and demographic and melanoma risk characteristics of patients attending Australian melanoma specialist clinics. This may assist in targeting and tailoring melanoma prevention patient education for people at high-risk and specific population subgroups. METHODS: A cross-sectional analysis of questionnaire data collected from participants attending the dermatology clinics at two major melanoma centres in Sydney, Australia between February 2021 and September 2023. The primary outcome was Sun Protection Habits (SPH) index (a summary score measured as habitual past month use of sunscreen, hats, sunglasses, a shirt with sleeves that covers the shoulders, limiting midday sun exposure and seeking shade, using a Likert scale). The primary analysis considered the SPH index and its component items scored as continuous. RESULTS: Data from 883 people were analysed. Factors associated with less frequent sun protection behaviours overall included male gender, no personal history of melanoma, lower perceived risk, lower calculated 10-year risk of developing melanoma, and no private health insurance. People aged >61 years reported lower use of sunscreen but higher use of hats and sleeved-shirts compared with people in the younger age group. There was no difference in overall sun protection behaviours according to family history of melanoma, country of birth or by lifetime melanoma risk among people without a personal history of melanoma. CONCLUSIONS: These findings highlight the potential for targeting high-risk individuals with less frequent use of sun protection for patient education, public health messaging and ultimately improving sun protection behaviours.

FDG PET/CT Prognostic Markers in Patients with Advanced Melanoma Treated with Ipilimumab and Nivolumab.

Background Despite improved response to combined ipilimumab and nivolumab (hereafter, IpiNivo) treatment for advanced melanoma, many patients exhibit primary or acquired resistance. This, combined with high risk of immune-related adverse events, makes identifying markers predictive of outcomes desirable. Purpose To investigate the prognostic value of fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/CT parameters at baseline and as part of response monitoring in patients with advanced melanoma undergoing IpiNivo treatment. Materials and Methods This was a single-center retrospective study of adult patients with melanoma who received IpiNivo. Baseline FDG PET/CT parameters that included metabolic tumor volume (MTV), tumor stage, mutation status, Eastern Cooperative Oncology Group performance score, lactate dehydrogenase level, and treatment line were correlated with overall survival in univariable and multivariable Cox regression analyses. Treatment response as determined with FDG PET/CT was correlated with overall survival. Results In total, 122 patients (median age, 61 years [IQR, 51-69 years]; 89 men) were included; 78% (95 of 122) had an Eastern Cooperative Oncology Group score of 0, 52% (45 of 86) had an elevated lactate dehydrogenase level, 39% (48 of 122) had a metastatic stage of M1c and 45% (55 of 122) M1d, 45% (55 of 122) had BRAF V600E/K mutation, and the median MTV was 42 mL. Patients with a higher than median MTV at baseline FDG PET/CT had a lower 12-month survival rate compared with those with a lower than median MTV (43% [95% CI: 32, 58] vs 66% [95% CI: 55, 79], P < .001). In multivariable analysis, higher versus lower than median MTV, Eastern Cooperative Oncology Group performance scores of 1-2 versus 0, and subsequent versus first-line IpiNivo treatment were independently associated with overall survival (hazard ratio [HR]: 1.68 [95% CI: 1.02, 2.78], P = .04; 3.1 [95% CI: 1.8, 5.4], P < .001; and 11.2 [95% CI: 3.4, 37.1], P = .002, respectively). The 12-month overall survival rate was lower in patients with progressive disease than in those without progression (35% [95% CI: 24, 51] vs 90% [95% CI: 83, 99]; HR, 7.3 [95% CI: 3.9, 13.3]; P < .001). Conclusion Baseline fluorine 18 fluorodeoxyglucose PET/CT metabolic tumor volume was an independent prognostic marker in patients with advanced melanoma who received ipilimumab and nivolumab treatment. © RSNA, 2023 Supplemental material is available for this article.

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.

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.

Melanomas in children and adolescents: Clinicopathologic features and survival outcomes.

BACKGROUND: Melanomas in the first 2 decades of life are uncommon and poorly understood. OBJECTIVE: To assess clinicopathologic features and survival of children (≤11 years) and adolescents (12-19 years) diagnosed with melanoma. METHODS: A pooled cohort of 514 patients was analyzed (397 Dutch, 117 Australian; 62 children, 452 adolescents). Pathology reports were reevaluated to determine melanoma subtypes. Multivariable Cox models were generated for recurrence-free survival (RFS) and overall survival (OS). RESULTS: Melanoma subtypes were conventional melanoma (superficial spreading, nodular, desmoplastic, and acral lentiginous), spitzoid melanoma, and melanoma associated with a congenital nevus in 428, 78, and 8 patients, respectively. Ten-year RFS was 91.5% (95% confidence interval [CI], 82.4%-100%) in children and 86.4% (95% CI, 82.7%-90.3%) in adolescents (P = .32). Ten-year OS was 100% in children and 92.7% (95% CI, 89.8%-95.8%) in adolescents (P = .09). On multivariable analysis possible only for the adolescent cohort due to the small number of children, ulceration status, and anatomic site were associated with RFS and OS, whereas age, sex, mitotic index, sentinel node status and melanoma subtype were not. Breslow thickness >4 mm was associated with worse RFS. LIMITATIONS: Retrospective study. CONCLUSIONS: Survival rates for children and adolescents with melanomas were high. Ulceration, head or neck location and Breslow thickness >4 mm predicted worse survival in adolescents.

Development and validation of risk calculators for people with "thin" melanomas on their skin to predict the likelihood that their cancer will return: a plain language summary of publication.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article describing the development of risk calculators for use in people who develop a type of melanoma on their skin called "thin" melanoma to predict the likelihood that their cancer will return. The article was originally published in the Journal of Clinical Oncology in 2021. HOW WERE THE CALCULATORS DEVELOPED?: Calculations were performed to predict the chance of people with thin melanomas surviving without their melanoma recurring. Three graphical prediction calculators (called nomograms) were developed, along with easy-to-use online calculators using the same underlying calculation methods. The model was developed using data for 25,930 Dutch people diagnosed with thin melanomas (called the "development set"). To test its ability to predict melanoma recurrence, it was then compared with data for 2,968 Australian people with melanoma (the "validation set"). The calculators developed in the Dutch patients were found to accurately predict the risk of melanoma recurring for people with melanoma in the Australian "validation" group. WHAT DO THE RESULTS MEAN?: The calculators provide estimates of the risk of the melanoma returning for people with thin melanomas. The easy-to-use online calculators are freely available on a smartphone, tablet or computer, and will assist in providing accurate estimates of recurrence risks for individuals with thin melanomas, allowing more intensive follow-up of those whose predicted risk of their melanoma returning is high.

Clinical management of melanocytic tumours of uncertain malignant potential (MelTUMPs), including melanocytomas: A systematic review and meta-analysis.

Little guidance is currently available for managing patients with melanocytic tumours of uncertain or low malignant potential (MelTUMPs, including melanocytomas), in particular the optimal excision margins and whether to offer sentinel node biopsy (SNB). The objective of this review was to evaluate excision margins and the prognostic utility of SNB by systematic review of the literature and meta-analysis. PRISMA guidelines were followed. Medline, EMBASE and Cochrane databases were searched to October 2021 for studies of patients with MelTUMPs reporting excision margins and/or SNB-positivity. Meta-analysis was performed on the SNB-positivity rate using a random effects model, followed by sensitivity analyses on subgroups. 111 primary studies reported excision margins and/or SNB data for 1962 patients. Follow-up was available for 1649 patients: 1561 (94.7%) were alive without disease at last review, 53 (3.2%) had developed further disease, 29 (1.8%) had died of metastatic disease (melanoma) and six (0.4%) died of unrelated causes. SNB was performed in 837 patients. The pooled positivity rate on meta-analysis was 32% (95% CI: 23-44%). Clinical outcome could be correlated with excision margin in only 171 patients (60% of those with known follow up) and was therefore not analysed further. Evidence indicating the ideal excision margins for MelTUMPs was lacking. SNB had a high positivity rate despite very low rates of recurrence or melanoma-related death. Consequently, SNB should not be offered routinely for MelTUMPs (including melanocytomas), due to its lack of prognostic utility for this tumour type (high certainty of evidence).

In vivo reflectance confocal microscopy can detect the invasive component of lentigo maligna melanoma: Prospective analysis and case-control study.

BACKGROUND: Lentigo maligna (LM), a form of melanoma in situ, has no risk of causing metastasis unless dermal invasive melanoma (LMM) supervenes. Furthermore, the detection of invasion impacts prognosis and management. OBJECTIVE: To assess the accuracy of RCM for the detection of invasion component on LM/LMM lesions. METHODS: In the initial case-control study, the performance of one expert in detecting LMM at the time of initial RCM assessment of LM/LMM lesions was recorded prospectively (n = 229). The cases were assessed on RCM-histopathology correlation sessions and a panel with nine RCM features was proposed to identify LMM, which was subsequently tested in a subset of initial cohort (n = 93) in the matched case-control study by two blinded observers. Univariable and multivariable logistic regression models were performed to evaluate RCM features predictive of LMM. Reproducibility of assessment of the nine RCM features was also evaluated. RESULTS: A total of 229 LM/LMM cases evaluated by histopathology were assessed blindly and prospectively by an expert confocalist. On histopathology, 210 were LM and 19 were LMM cases. Correct identification of an invasive component was achieved for 17 of 19 LMM cases (89%) and the absence of a dermal component was correctly diagnosed in 190 of 210 LM cases (90%). In the matched case-control (LMM n = 35, LM n = 58), epidermal and junctional disarray, large size of melanocytes and nests of melanocytes were independent predictors of LMM on multivariate analysis. The interobserver analysis demonstrated that these three features had a fair reproducibility between the two investigators (K = 0.4). The multivariable model including those three features showed a high predictive performance AUC = 74% (CI 95% 64-85%), with sensitivity of 63% (95% CI 52-78%) and specificity of 79% (CI 95% 74-88%), and likelihood ratio of 18 (p-value 0.0026). CONCLUSION: Three RCM features were predictive for identifying invasive melanoma in the background of LM.

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.

Clinicopathological Characteristics Predicting Further Recurrence and Survival Following Resection of In-Transit Melanoma Metastases.

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.

The Impact of Surveillance Imaging Frequency on the Detection of Distant Disease for Patients with Resected Stage III Melanoma.

BACKGROUND: It is not known whether there is a survival benefit associated with more frequent surveillance imaging in patients with resected American Joint Committee on Cancer stage III melanoma. OBJECTIVE: The aim of this study was to investigate distant disease-free survival (DDFS), melanoma-specific survival (MSS), post distant recurrence MSS (dMSS), and overall survival for patients with resected stage III melanoma undergoing regular computed tomography (CT) or positron emission tomography (PET)/CT surveillance imaging at different intervals. PATIENTS AND METHODS: A closely followed longitudinal cohort of patients with resected stage IIIA-D disease treated at a tertiary referral center underwent 3- to 4-monthly, 6-monthly, or 12-monthly surveillance imaging between 2000 and 2017. Survival outcomes were estimated using the Kaplan-Meier method, and log-rank tests assessed the significance of survival differences between imaging frequency groups. RESULTS: Of 473 patients (IIIA, 19%; IIIB, 31%; IIIC, 49%; IIID, 1%) 30% underwent 3- to 4-monthly imaging, 10% underwent 6-monthly imaging, and 60% underwent 12-monthly imaging. After a median follow-up of 6.2 years, distant recurrence was recorded in 252 patients (53%), with 40% detected by surveillance CT or PET/CT, 43% detected clinically, and 17% with another imaging modality. Median DDFS was 5.1 years (95% confidence interval 3.9-6.6). Among 139 IIIC patients who developed distant disease, the median dMSS was 4.4 months shorter in those who underwent 3- to 4-monthly imaging than those who underwent 12-monthly imaging. CONCLUSION: Selecting patients at higher risk of distant recurrence for more frequent surveillance imaging yields a higher proportion of imaging-detected distant recurrences but is not associated with improved survival. A randomized comparison of low versus high frequency imaging is needed.

Evaluation of the Indications for Sentinel Node Biopsy in Early-Stage Melanoma with the Advent of Adjuvant Systemic Therapy: An International, Multicenter Study.

BACKGROUND: Patients presenting with early-stage melanoma (AJCC pT1b-pT2a) reportedly have a relatively low risk of a positive SNB (~5-10%). Those patients are usually found to have low-volume metastatic disease after SNB, typically reclassified to AJCC stage IIIA, with an excellent prognosis of ~90% 5-year survival. Currently, adjuvant systemic therapy is not routinely recommended for most patients with AJCC stage IIIA melanoma. The purpose was to assess the SN-positivity rate in early-stage melanoma and to identify primary tumor characteristics associated with high-risk nodal disease eligible for adjuvant systemic therapy METHODS: An international, multicenter retrospective cohort study from 7 large-volume cancer centers identified 3,610 patients with early primary cutaneous melanomas 0.8-2.0 mm in Breslow thickness (pT1b-pT2a; AJCC 8th edition). Patient demographics, primary tumor characteristics, and SNB status/details were analyzed. RESULTS: The overall SNB-positivity rate was 11.4% (412/3610). Virtually all SNB-positive patients (409/412; 99.3%) were reclassified to AJCC stage IIIA. Multivariate analysis identified age, T-stage, mitotic rate, primary site and subtype, and lymphovascular invasion as independent predictors of sentinel node status. A mitotic rate of >1/mm2 was associated with a significantly increased SN-positivity rate and was the only significant independent predictor of high-risk SNB metastases (>1 mm maximum diameter). CONCLUSIONS: The new treatment paradigm brings into question the role of SNB for patients with early-stage melanoma. The results of this large international cohort study suggest that a reevaluation of the indications for SNB for some patients with early-stage melanoma is required.