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Australia and New Zealand have the highest incidence and mortality rates for melanoma in the world. Local surgery is still the standard treatment of primary cutaneous melanoma, and it is therefore important that surgeons understand the optimal care pathways for patients with melanoma. Accurate staging is critical to ensure a reliable assessment of prognosis and to guide treatment selection. Sentinel node biopsy (SNB) plays an important role in staging and the provision of reliable prognostic estimates for patients with cutaneous melanoma. Patients with stage III melanoma have a substantial risk of disease recurrence following surgery, leading to poor long-term outcomes. Systemic immunotherapies and targeted therapies, known to be effective for stage IV melanoma, have now also been shown to be effective as adjuvant post-surgical treatments for resected stage III melanoma. These patients should be made aware of this and preferably managed in an integrated multidisciplinary model of care, involving the surgeon, medical oncologists and radiation oncologists. This review considers the impact of a recent update to the American Joint Committee on Cancer (AJCC) staging system, the role of SNB for patients with high-risk primary melanoma and recent advances in adjuvant systemic therapies for high-risk patients. [ABSTRACT FROM AUTHOR]

Australia and New Zealand have the highest incidence and mortality rates for melanoma in the world. Local surgery is still the standard treatment of primary cutaneous melanoma, and it is therefore important that surgeons understand the optimal care pathways for patients with melanoma. Accurate staging is critical to ensure a reliable assessment of prognosis and to guide treatment selection. Sentinel node biopsy (SNB) plays an important role in staging and the provision of reliable prognostic estimates for patients with cutaneous melanoma. Patients with stage III melanoma have a substantial risk of disease recurrence following surgery, leading to poor long‐term outcomes. Systemic immunotherapies and targeted therapies, known to be effective for stage IV melanoma, have now also been shown to be effective as adjuvant post‐surgical treatments for resected stage III melanoma. These patients should be made aware of this and preferably managed in an integrated multidisciplinary model of care, involving the surgeon, medical oncologists and radiation oncologists. This review considers the impact of a recent update to the American Joint Committee on Cancer (AJCC) staging system, the role of SNB for patients with high‐risk primary melanoma and recent advances in adjuvant systemic therapies for high‐risk patients. [ABSTRACT FROM AUTHOR]

Background: Adjuvant dabrafenib plus trametinib therapy improves relapse-free survival in patients with resected stage III melanoma. We aimed to ascertain the proportion of patients who would have a pathological response and a response according to Response Evaluation Criteria in Solid Tumors (RECIST) after neoadjuvant dabrafenib plus trametinib therapy for resectable clinical stage III melanoma.Methods: NeoCombi was a single-arm, open-label, single-centre, phase 2 study done at Melanoma Institute Australia (Sydney, NSW, Australia). Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, clinical stage IIIB-C (American Joint Committee on Cancer [AJCC] 7th edition), BRAFV600-mutant melanoma, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Patients received 150 mg dabrafenib orally, twice daily, plus 2 mg trametinib orally, once daily, for 52 weeks (12 weeks of neoadjuvant therapy before complete resection of the pre-therapy tumour bed, and 40 weeks of adjuvant therapy thereafter). CT and PET scans were done at baseline and before resection. The primary outcomes were the proportion of patients achieving a complete pathological response and the proportion of patients achieving a response according to RECIST at week 12, analysed as per protocol. This trial is registered with ClinicalTrials.gov, NCT01972347, and follow-up of patients is ongoing.Findings: Between Aug 20, 2014, and April 19, 2017, 40 patients were screened, of whom 35 eligible patients were enrolled, received neoadjuvant dabrafenib plus trametinib, and underwent resection. At the data cutoff (Sept 24, 2018), median follow-up was 27 months (IQR 21-36). At resection, 30 (86%) patients achieved a RECIST response; 16 (46%; 95% CI 29-63) had a complete response and 14 (40%; 24-58) had a partial response. Five patients (14%; 95% CI 5-30) had stable disease, and no patients progressed. After resection and pathological evaluation, all 35 patients achieved a pathological response, of whom 17 (49%; 95% CI 31-66) patients had a complete pathological response and 18 (51%; 95% CI 34-69) had a non-complete pathological response. Treatment-related serious adverse events occurred in six (17%) of 35 patients and grade 3-4 adverse events occurred in ten (29%) patients. No treatment-related deaths were reported.Interpretation: Neoadjuvant dabrafenib plus trametinib therapy could be considered in the management of RECIST-measurable resectable stage III melanoma as it led to a high proportion of patients achieving a complete response according to RECIST and a high proportion of patients achieving a complete pathological response, with no progression during neoadjuvant therapy.Funding: GlaxoSmithKline; Novartis; National Health and Medical Research Council, Australia; and Melanoma Institute Australia. [ABSTRACT FROM AUTHOR]

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 (≥ 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 (≥ 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. [ABSTRACT FROM AUTHOR]

Background: Patients with primary cutaneous melanomas that are ulcerated and >2 mm in thickness, >4 mm in thickness and those with nodal micrometastases at diagnosis, have few options for adjuvant treatment. Recent studies have suggested a role for vitamin D to delay melanoma recurrence and improve overall prognosis. Methods/Design: This is a pilot placebo-controlled randomised phase II trial to assess the feasibility, safety and toxicity of an oral loading dose of Vitamin D (500,000 IU) followed by an oral dose of 50,000 IU of Vitamin D monthly for 2 years in patients who have been treated for cutaneous melanoma by wide excision of the primary. Patients aged 18 - 79 years who have completed primary surgical treatment and have Stage IIb, IIc, IIIa (N1a, N2a) or IIIb (N1a, N2a) disease are eligible for randomisation 2:1 to active treatment or placebo. The primary endpoints are sufficiency of dose, adherence to study medication and safety of the drug. The secondary endpoints are participation and progression free survival. The study has been approved by the Ethics Review Committee (RPAH Zone) of the Sydney Local Health District, protocol number X09-0138. Discussion: Effective, non-toxic adjuvant therapy for high risk primary melanoma is not currently available. Favorable outcomes of this phase II study will form the basis for a multi-centre phase III study to assess whether the addition of oral high-dose vitamin D therapy in patients who have completed primary treatment for melanoma and are at high risk of recurrence will: 1. prolong time to recurrence within 5 years 2. improve overall survival at 5 years and 3. be both safe and tolerable. Target accrual for the study has been met with 75 patients randomised between December 2010 and August 2014. The Mel-D trial is conducted by the Australia and New Zealand Melanoma Trials Group (ANZMTG 02.09). [ABSTRACT FROM AUTHOR]

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. 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). 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. 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. Erasmus Medical Centre Cancer Institute. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: In 2015, the public media in Australia reported a series of life stories of victims who had been subjected to inappropriate behaviors in their surgical careers, bringing the profession into disrepute. Currently, limited data are available in the medical literature on discrimination, bullying and harassment (DBH) in surgery. This significant information gap prompted a systematic review to compile relevant information about DBH in surgical practice and training, in particular, its prevalence and impact.Methods: A literature search was conducted using the MEDLINE, EMBASE and PubMed databases (May 1929-October 2017). Studies identified were appraised with standard selection criteria. Data points were extracted, and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.Results: Eight studies, comprising 5934 participants, were examined. Discrimination occurred in a pooled estimate of 22.4% [95% Confidence Interval (CI) = 14.0-33.9%]. One of the papers reported the prevalence of bullying using two methods including Revised Negative Acts Questionnaire and a definition by Einarsen. Pooled estimate of incidence rate was thus 37.7% (95% CI = 34.0-41.5%) and 40.3% (95% CI = 34.7-46.2%), respectively. In terms of harassment, pooled prevalence was 31.2% (95% CI = 10.0-65.0%).Conclusions: DBH is a significant issue in surgery. The true incidence of these issues may remain underestimated. Actions are being taken by professional bodies to create a positive culture in surgery. The effectiveness of these strategies is yet to be determined. More studies are warranted to investigate the magnitude of these issues given their psychological impact, and more importantly to monitor the effectiveness of current measures. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Most subsequent new primary or recurrent melanomas might be self-detected if patients are trained to systematically self-examine their skin and have access to timely medical review (patient-led surveillance). Routinely scheduled clinic visits (clinician-led surveillance) is resource-intensive and has not been shown to improve health outcomes; fewer visits may be possible if patient-led surveillance is shown to be safe and effective. The MEL-SELF trial is a randomised controlled trial comparing patient-led surveillance with clinician-led surveillance in people who have been previously treated for localised melanoma.Methods: Stage 0/I/II melanoma patients (n = 600) from dermatology, surgical, or general practice clinics in NSW Australia, will be randomised (1:1) to the intervention (patient-led surveillance, n = 300) or control (usual care, n = 300). Patients in the intervention will undergo a second randomisation 1:1 to polarised (n = 150) or non-polarised (n = 150) dermatoscope. Patient-led surveillance comprises an educational booklet, skin self-examination (SSE) instructional videos; 3-monthly email/SMS reminders to perform SSE; patient-performed dermoscopy with teledermatologist feedback; clinical review of positive teledermoscopy through fast-tracked unscheduled clinic visits; and routinely scheduled clinic visits following each clinician's usual practice. Clinician-led surveillance comprises an educational booklet and routinely scheduled clinic visits following each clinician's usual practice. The primary outcome, measured at 12 months, is the proportion of participants diagnosed with a subsequent new primary or recurrent melanoma at an unscheduled clinic visit. Secondary outcomes include time from randomisation to diagnosis (of a subsequent new primary or recurrent melanoma and of a new keratinocyte cancer), clinicopathological characteristics of subsequent new primary or recurrent melanomas (including AJCC stage), psychological outcomes, and healthcare use. A nested qualitative study will include interviews with patients and clinicians, and a costing study we will compare costs from a societal perspective. We will compare the technical performance of two different models of dermatoscope (polarised vs non-polarised).Discussion: The findings from this study may inform guidance on evidence-based follow-up care, that maximises early detection of subsequent new primary or recurrent melanoma and patient wellbeing, while minimising costs to patients, health systems, and society.Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12621000176864 . Registered on 18 February 2021. [ABSTRACT FROM AUTHOR]

Merkel cell carcinoma of the skin is a rare but aggressive malignancy, which predominantly affects older adults with fair skin. Isolated limb infusion (ILI) using melphalan and actinomycin D was first developed as a minimally invasive treatment option to treat unresectable metastatic melanoma confined to the limb. We report on a 62-year-old male with in-transit metastases (ITMs) treated with ILI to highlight the ongoing role this treatment has when all other therapies have been exhausted. At presentation, the patient had widespread ITMs in the right leg. Positron emission tomography scan demonstrated recurrent disease in the thigh and pelvis, and it was decided to treat the patient with ILI. The patient progressed well in the immediate post-operative period. The patient was able to mobilize from Day 6 post-ILI and was discharged on Day 10. There was an immediate clinical response seen in the lesions, with necrosis developing in the larger lesions. [ABSTRACT FROM AUTHOR]

Background: Mitotic rate is a strong, independent prognostic factor in patients with melanoma. However, incorporating it into the melanoma staging system has proved challenging.Methods: The prognostic impact of mitotic rate was assessed in a melanoma cohort comprising 5050 patients from 2 geographically distinct populations. Computer-generated cut points for mitotic rate were constructed to determine its impact on melanoma-associated survival using Kaplan-Meier and multivariate regression analyses. The impact of mitotic rate also was assessed in randomly split training and validation sets.Results: Mitotic rate had a nonlinear impact on survival, as evidenced by unequally spaced cut points. An index incorporating these cut points that was constructed from one population produced significantly more accurate predictions of survival in the other population than using the entire scale of mitotic rate. An index constructed from the combined cohort was found to be independently predictive of survival, with an impact comparable to that of ulceration. Optimal high-versus-low cut points for mitotic rate were generated separately for each T category (<2 mitoses/mm2 vs ≥2 mitoses/mm2 for T1 melanoma, <4 mitoses/mm2 vs ≥4 mitoses/mm2 for T2 melanoma, <6 mitoses/mm2 vs ≥6/mitoses/mm2 for T3 melanoma, and <7 mitoses/mm2 vs ≥7 mitoses/mm2 for T4 melanoma). Using Kaplan-Meier analysis, elevated mitotic rate was found to have an impact on survival comparable to that of ulceration within each T category. Application of the index for mitotic rate that was constructed from the training data set demonstrated an independent impact in the validation data set, with a significance similar to that of ulceration.Conclusions: The results of the current study demonstrated the comparable prognostic impact of mitotic rate and ulceration, providing support for its reincorporation into the T category. [ABSTRACT FROM AUTHOR]

Direct lymphatic drainage from the skin of the anterior chest and breast to internal mammary lymph nodes does not normally occur. Preoperative lymphoscintigraphy was performed in a 55-year-old man with a 3.7 mm-thick primary melanoma on his right anterior chest, who had undergone surgery and radiotherapy to successfully treat a localized lymphosarcoma in his right axilla 35 years earlier. The sentinel node in the lower right internal mammary chain, in the 5th interspace, was removed at the same time as the primary melanoma site was widely excised, and micrometastatic melanoma was subsequently identified in it. Second-tier nodes in the 4th and 3rd right interspaces were therefore removed, and adjuvant radiotherapy was given to the entire internal mammary node chain. This case demonstrates that major disturbance of normal lymphatic drainage pathways can result from previous surgery and/or radiotherapy. Also, the rarity of this drainage pattern indicates that attempts to identify sentinel nodes in breast cancer patients by injecting tracer into the skin overlying a tumour rather than into the breast tissue immediately adjacent to it are likely to be inaccurate in some patients, because cutaneous injection will not demonstrate the sentinel nodes in the internal mammary chain that are present in up to 40% of patients with a breast cancer. [ABSTRACT FROM AUTHOR]

Background: The results of the DeCOG‐SLT and MSLT‐II studies, published in 2016 and mid‐2017, indicated no survival benefit from completion lymph node dissection (CLND) in melanoma patients with positive sentinel nodes (SNs). Subsequently, several studies have been published reporting a benefit of adjuvant systemic therapy in patients with stage III melanoma. The current study assessed how these findings influenced management of SN‐positive patients in a dedicated melanoma treatment centre. Methods: SN‐positive patients treated at Melanoma Institute Australia between July 2017 and December 2018 were prospectively identified. Surgeons completed a questionnaire documenting the management of each patient. Information on patients, primary tumours, SNs, further treatment and follow‐up was collected from patient files, the institutional research database and pathology reports. Results: During the 18‐month study period, 483 patients underwent SN biopsy. A positive SN was found in 61 (13%). Two patients (3%) requested CLND because of anxiety about observation in view of unfavourable primary tumour and SN characteristics. The other 59 patients (97%) were followed with a four‐monthly ultrasound examination of the relevant lymph node field(s). Two of them (3%) developed an isolated nodal recurrence after 4 and 11 months of follow‐up. Fifty‐seven patients (93%) were seen following the publication of the first two adjuvant systemic therapy studies in November 2017; 46 (81%) were referred to a medical oncologist to discuss adjuvant systemic therapy, which 32 (70%) chose to receive. Conclusion: At Melanoma Institute Australia most patients with an involved SN are now managed without CLND. The majority are referred to a medical oncologist and receive adjuvant systemic therapy. [ABSTRACT FROM AUTHOR]

Aims: Indoleamine 2,3‐dioxygenase (IDO), an immunomodulatory enzyme, facilitates immune escape by tumours and promotes tumour progression. IDO inhibitors with and without additional anti‐PD‐1 therapy have been evaluated in recent and ongoing melanoma clinical trials, but IDO expression in melanoma tumours, and therefore its potential role as a predictive biomarker remains unknown. This study sought to evaluate IDO expression in immunotherapy‐naive metastatic melanoma patients in order to determine patterns of expression in corresponding primary melanomas, locoregional metastases and distant metastases. Methods and results: Here, we evaluated IDO expression using immunohistochemistry in 99 melanoma tumour samples from 43 immunotherapy‐naive patients with metastatic melanoma to determine patterns of expression in primary melanomas (n = 29), locoregional metastases (n = 36) and distant metastases (n = 34). Thirty‐seven per cent of patients demonstrated tumour IDO expression in at least one specimen. Twelve of 35 patients (34%) with longitudinal specimens (i.e. two or more separate specimens from different disease stages in the same patient) displayed heterogeneous IDO staining between samples. Tumour IDO expression positively correlated with tumour‐infiltrating lymphocyte (TIL) score as well as the number of IDO‐expressing mononuclear cells in the primary melanoma (P < 0.0001 and P = 0.0011, respectively) and nodal metastases (P = 0.049 and P = 0.037, respectively), but not in distant metastases. Furthermore, tumour IDO expression correlated positively with PD‐L1 expression by melanoma cells among all specimens (P = 0.0073). Conclusions: Therefore, while assessment of tumour IDO expression warrants evaluation in melanoma patient cohorts treated with IDO inhibitors dosed at levels proven to inhibit the target by pharmacodynamic assessment, its utility as a biomarker may be limited by intertumoral heterogeneity. [ABSTRACT FROM AUTHOR]

BACKGROUND: Targeted therapy and immunotherapy agents for advanced melanoma are associated with novel toxicities. Melanoma clinical nurse consultants (CNCs) provide multifaceted clinical care. OBJECTIVES: The objective was to evaluate the type of support, excluding clinic and inpatient care, provided by CNCs for patients not enrolled in a clinical trial. METHODS: A prospective review of CNC support provided during a 12-week period was conducted. FINDINGS: From May to August 2015, 105 patients attended clinic, and 72 received CNC support. Initial patient encounters with CNCs were documented (n = 150), as well as additional interactions (n = 291). The most common problem identified per initial encounter was symptom/drug toxicity. The most common therapy-related concern was related to anti-programmed cell death protein 1 immunotherapy and BRAF plus MEK inhibition. CNC interventions commonly involved clinical advice and counseling and care coordination. [ABSTRACT FROM AUTHOR]

Background and aims BRAF or NRAS mutations occur in approximately 60% of cutaneous melanomas, and the identification of such mutations underpins the appropriate selection of patients who may benefit from BRAF and MEK inhibitor targeted therapies. The utility of immunohistochemistry ( IHC) to detect NRASQ61L mutations is currently unknown. This study sought to assess the sensitivity and specificity of anti-BRAFV600E ( VE1), anti-NRASQ61R ( SP174) and anti-NRASQ61L (26193) antibodies for mutation detection in a large series of cases. Methods and results Mutation status was determined using the OncoCarta assay in 754 cutaneous melanomas. IHC with the anti-BRAFV600E antibody was performed in all cases, and the anti-NRASQ61R and anti-NRASQ61L antibodies were assessed in a subset of 302 samples utilizing tissue microarrays. The staining with the anti-BRAFV600E and anti-NRASQ61R antibodies was diffuse, homogeneous and cytoplasmic. The anti-NRASQ61L antibody displayed variable intensity staining, ranging from weak to strong in NRASQ61L mutant tumours. The sensitivity and specificity for anti-BRAFV600E was 100 and 99.3%, anti-NRASQ61R was 100 and 100% and anti-NRASQ61L was 82.6 and 96.2%, respectively. Conclusions The use of IHC is a fast, efficient and cost-effective method to identify single specific mutations in melanoma patients. BRAFV600E and NRASQ61R antibodies have high sensitivity and specificity; however, the NRASQ61L antibody appears less sensitive. IHC can help to facilitate the timely, appropriate selection and treatment of metastatic melanoma patients with targeted therapies. Detection of melanoma-associated mutations by IHC may also provide evidence for a diagnosis of melanoma in metastatic undifferentiated neoplasms lacking expression of melanoma antigens. [ABSTRACT FROM AUTHOR]

Melanoma is difficult to treat once it becomes metastatic. However, the precise ancestral relationship between primary tumors and their metastases is not well understood. We performed whole-exome sequencing of primary melanomas and multiple matched metastases from eight patients to elucidate their phylogenetic relationships. In six of eight patients, we found that genetically distinct cell populations in the primary tumor metastasized in parallel to different anatomic sites, rather than sequentially from one site to the next. In five of these six patients, the metastasizing cells had themselves arisen froma common parental subpopulation in the primary, indicating that the ability to establish metastases is a late-evolving trait. Interestingly, we discovered that individual metastases were sometimes founded by multiple cell populations of the primary that were genetically distinct. Such establishment of metastases by multiple tumor subpopulations could help explain why identical resistance variants are identified in different sites after initial response to systemic therapy. One primary tumor harbored two subclones with different oncogenic mutations in CTNNB1, which were both propagated to the same metastasis, raising the possibility that activation of wingless-type mouse mammary tumor virus integration site (WNT) signaling may be involved, as has been suggested by experimental models. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint therapies have significantly improved the survival of patients with metastatic melanoma, however approximately 50% of patients exhibit no response. Understanding the underlying clinical, pathologic and genetic factors associated with failed response to immunotherapies is key to identifying therapeutic strategies to overcome resistance. Here, we investigated the baseline tumour characteristics of patients with innate resistance to anti-PD-1-based immunotherapies. This study is the first on non-responders to integrate detailed clinical and molecular analyses and has identified two distinct clusters of patients with clinically relevant key targetable proteins. While immune checkpoint inhibitors targeting the CTLA-4 and PD-1 receptors have significantly improved outcomes of many patients with metastatic melanoma, there remains a group of patients who demonstrate no benefit. In this study, we sought to characterise patients who do not respond to anti-PD-1-based therapies based on their clinical, genetic and immune profiles. Forty patients with metastatic melanoma who did not respond to anti-PD-1 +/− anti-CTLA-4 treatment were identified. Targeted RNA sequencing (n = 37) was performed on pretreatment formalin-fixed paraffin-embedded (FFPE) melanoma specimens. Patients clustered into two groups based on the expression profiles of 26 differentially expressed genes: an immune gene rich group (n = 17) expressing genes associated with immune and T cell signalling, and a second group (n = 20) expressing genes associated with metabolism, signal transduction and neuronal signalling. Multiplex immunohistochemistry validated significantly higher densities of tumour-infiltrating lymphocytes (TILs) and macrophages in the immune gene-rich group. This TIL-high subset of patients also demonstrated higher expression of alternative immune-regulatory drug targets compared to the TIL-low group. Patients were also subdivided into rapid progressors and other progressors (cut-off 2 mo progression-free survival), with significantly lower TILs (p = 0.04) and CD68+ macrophages (p = 0.0091) in the rapid progressors. Furthermore, a trend towards a higher tumour burden was observed in rapid progressors (p = 0.06). These data highlight the need for a personalised and multilayer (clinical and molecular) approach for identifying the most appropriate treatments for anti-PD-1 resistant patients and provides insight into how individual treatment strategies can be achieved. [ABSTRACT FROM AUTHOR]

Detection of melanoma-associated mutations using circulating tumor DNA (ctDNA) from plasma is a potential alternative to using genomic DNA from invasive tissue biopsies. In this study, we developed a custom melanoma next-generation sequencing (NGS) panel which includes 123 amplicons in 30 genes covering driver and targetable mutations and alterations associated with treatment resistance. Analysis of a cohort of 74 stage III and IV treatment-naïve melanoma patients revealed that sensitivity of ctDNA detection was influenced by the amount of circulating-free DNA (cfDNA) input and stage of melanoma. At the recommended cfDNA input quantity of 20 ng (available in 28/74 patients), at least one cancer-associated mutation was detected in the ctDNA of 84% of stage IV patients and 47% of stage III patients with a limit of detection for mutant allele frequency (MAF) of 0.2%. This custom melanoma panel showed significant correlation with droplet digital PCR (ddPCR) and provided a more comprehensive melanoma mutation profile. Our custom panel could be further optimized by replacing amplicons spanning the TERT promoter, which did not perform well due to the high GC content. To increase the detection rate to 90% of stage IV melanoma and decrease the sensitivity to 0.1% MAF, we recommend increasing the volume of plasma to 8 mL to achieve minimal recommended cfDNA input and the refinement of poorly performing amplicons. Our panel can also be expanded to include new targetable and treatment resistance mutations to improve the tracking of treatment response and resistance in melanoma patients treated with systemic drug therapies. [ABSTRACT FROM AUTHOR]

The use of circulating tumor DNA (ctDNA) to monitor cancer progression and response to therapy has significant potential but there is only limited data on whether this technique can detect the presence of low frequency subclones that may ultimately confer therapy resistance. In this study, we sought to evaluate whether whole-exome sequencing (WES) of ctDNA could accurately profile the mutation landscape of metastatic melanoma. We used WES to identify variants in matched, tumor-derived genomic DNA (gDNA) and plasma-derived ctDNA isolated from a cohort of 10 metastatic cutaneous melanoma patients. WES parameters such as sequencing coverage and total sequencing reads were comparable between gDNA and ctDNA. The mutant allele frequency of common single nucleotide variants was lower in ctDNA, reflecting the lower read depth and minor fraction of ctDNA within the total circulating free DNA pool. There was also variable concordance between gDNA and ctDNA based on the total number and identity of detected variants and this was independent of the tumor biopsy site. Nevertheless, established melanoma driver mutations and several other melanoma-associated mutations were concordant between matched gDNA and ctDNA. This study highlights that WES of ctDNA could capture clinically relevant mutations present in melanoma metastases and that enhanced sequencing sensitivity will be required to identify low frequency mutations. [ABSTRACT FROM AUTHOR]

Background: Patients may decide to undertake shared care with a general practitioner (GP) during follow-up after treatment for localised melanoma. Routine imaging tests for surveillance may be commonly used despite no evidence of clinical utility. This study describes the frequency of shared care and routine tests during follow-up after treatment for localised melanoma.Methods: We randomly sampled 351 people with localised melanoma [American Joint Cancer Committee (AJCC) substages 0 - II] who had not had recurrent or new primary melanoma diagnosed from a total of 902 people diagnosed and treated for localised melanoma at a specialist centre in 2014. We interviewed participants by telephone about their experience of follow-up in the past year, and documented the proportion of patients who were undertaking shared care follow-up with a GP. We also recorded the frequency and type of investigations during follow-up. We calculated weighted estimates that are representative of the full inception cohort.Results: Of the 351 people who were invited to participate, 230 (66%) people consented to the telephone interview. The majority undertook shared care follow-up with a GP (61%). People who choose to have shared care follow-up with a GP are more likely to be male (p = 0.006), have lower AJCC stage (p for trend = 0.02), reside in more remote areas (p for trend< 0.001), and are less likely to have completed secondary school (p < 0.001). Few people saw a non-doctor health practitioner as part of their follow-up (9%). Many people report undergoing tests for melanoma, much of which may be routine tests for surveillance (37%).Conclusions: The majority of people treated for a first primary localised melanoma at a specialist centre, without recurrent or new melanoma, choose to undertake shared care follow-up with a GP. Many appear to have routine diagnostic imaging as part of their melanoma surveillance. [ABSTRACT FROM AUTHOR]