European e-Delphi process to define expert consensus on electrochemotherapy treatment indications, procedural aspects, and quality indicators in melanoma.

BACKGROUND: Skin metastases are an important co-morbidity in melanoma. Despite broad adoption, electrochemotherapy implementation is hindered by a lack of treatment indications, uncertainty regarding procedural aspects, and the absence of quality indicators. An expert consensus may harmonize the approach among centres and facilitate comparison with other therapies. METHODS: An interdisciplinary panel was recruited for a three-round e-Delphi survey. A literature-based 113-item questionnaire was proposed to 160 professionals from 53 European centres. Participants rated each item for relevance and degree of agreement on a five-point Likert scale, and received anonymous controlled feedback to allow revision. The items that reached concordant agreement in two successive iterations were included in the final consensus list. In the third round, quality indicator benchmarks were defined using a real-time Delphi method. RESULTS: The initial working group included 122 respondents, of whom 100 (82 per cent) completed the first round, thus qualifying for inclusion in the expert panel (49 surgeons, 29 dermatologists, 15 medical oncologists, three radiotherapists, two nurse specialists, two clinician scientists). The completion rate was 97 per cent (97 of 100) and 93 per cent (90 of 97) in the second and third rounds respectively. The final consensus list included 54 statements with benchmarks (treatment indications, (37); procedural aspects, (1); quality indicators, (16)). CONCLUSION: An expert panel achieved consensus on the use of electrochemotherapy in melanoma, with a core set of statements providing general direction to electrochemotherapy users to refine indications, align clinical practices, and promote quality assurance programmes and local audits. The residual controversial topics set future research priorities to improve patient care.

Electrochemotherapy is an effective locoregional therapy for skin metastases from melanoma, a problem faced by almost half of patients with metastatic disease. The lack of comparative studies and the heterogeneity of its clinical application among centres make it challenging to support consistent, evidence-based recommendations. To address this unmet need, a three-round online survey was conducted to establish a consensus on treatment indications, standard operating procedures, and quality indicators. In the survey, a panel of 100 European melanoma experts agreed on 56 statements that can be used to improve patient selection, homogenize treatment application, and monitor outcomes.

Variation in the practice of wide local excision for melanoma in Ireland and the UK: a questionnaire survey.

BACKGROUND: Wide local excision (WLE) is standard practice in the management of melanoma, but no national or international guidelines exist regarding its technique. OBJECTIVES: To assess variation in the practice of WLE and to explore the effect of clinicians' specialty and grade on such variation. METHODS: This was an international, anonymized, cross-sectional study. An online questionnaire was distributed to the Irish Association of Dermatologists, British Association of Dermatologists, British Association of Plastic and Reconstructive and Aesthetic Surgeons, Melanoma Focus and BioGenoMEL members. RESULTS: Of 128 respondents, 57% were dermatologists and 38% plastic surgeons. Most (80%) were consultants. Almost all clinicians learned their technique from colleagues (99%) 'on the job', although 21% also used textbooks or other media as part of WLE training. There was significant variation in planning and performing WLE: 59% considered margins already achieved, 71% marked margins with the skin relaxed. For 1 cm WLE, 84% delineated 1 cm from the edge of the scar; with a greater proportion of plastic surgeons than dermatologists marking from the centre of the scar (P < 0.05). Most followed a longitudinal/oblique axis on the limbs for WLE (81%). Only 40% sent 'dog ears' for histology. Most (70%) incised through the marked line, 27% incised outside it. Most (79%) excised to deep fascia, 18% to the next biological margin. CONCLUSIONS: This study demonstrates significant variation among clinicians performing WLE, an essential component of melanoma management. We postulate that this could have an impact on patient outcomes. A consensus statement should be developed, to achieve more consistency in the practice of WLE.

Extracapsular Spread in Melanoma Lymphadenopathy: Prognostic Implications, Classification, and Management.

BACKGROUND: Extracapsular spread (ECS) is recognized to be a high-risk factor in melanoma patients with macrometastatic (N+) nodal disease; however, ECS risk in sentinel lymph node (SLN) biopsy, micrometastatic stage III disease is ambiguous. OBJECTIVE: The aim of this study was to examine ECS incidence and its prognostic significance. METHODS: A two-center, retrospective analysis of all patients with micro/macrometastatic lymphadenopathy undergoing nodal surgery from 2008 to 2014 was performed. Patient demographics, tumor characteristics, nodal ECS status, and patient outcomes were collected. RESULTS: Overall, 515 patients with nodal disease were identified (males/females = 277/238); median age was 63 years (range 17-94). There was an increased frequency of ECS disease in N+ disease compared with SLN+ disease (52.4% vs. 16.2%; p < 0.0001). The absolute disease-specific survival (DSS) difference for SLN+ patients was approximately 30% at 10 years (66.2% vs. 37.2%; p < 0.0001), and the prognosis of SLN+/ECS+ patients was identical to N+/ECS- patients. Multivariate analysis demonstrated that ECS status was an independent prognostic indicator for DSS (hazard ratio 2.47, 95% confidence interval 1.87-3.26; p < 0.0001) in patients with SLN+ disease. There were significant differences in nodal burden according to ECS status between the SLN+ and N+ subgroups suggestive of differing biology in ECS+ tumors. CONCLUSION: We found that ECS is a significant DSS, progression-free survival, and overall survival indicator in SLN+ and N+ disease. We demonstrated that ECS upstages stage III disease, similar to ulceration in primary melanoma (stage I/II disease). A simplified staging system substituting ECS for N stage accurately stages patients according to prognosis.

The neutrophil-lymphocyte ratio and locoregional melanoma: a multicentre cohort study.

OBJECTIVES: The neutrophil-lymphocyte ratio (NLR) is an inflammatory biomarker which is useful in cancer prognostication. We aimed to investigate the differences in baseline NLR between patients with localised and metastatic cutaneous melanoma and how this biomarker changed over time with the recurrence of disease. METHODS: This multicentre cohort study describes patients treated for Stage I-III cutaneous melanoma over 10 years. The baseline NLR was measured immediately prior to surgery and again at the time of discharge or disease recurrence. The odds ratios (OR) for sentinel node involvement are estimated using mixed-effects logistic regression. The risk of recurrence is estimated using multivariable Cox regression. RESULTS: Overall 1489 individuals were included. The mean baseline NLR was higher in patients with palpable nodal disease compared to those with microscopic nodal or localised disease (2.8 versus 2.4 and 2.3, respectively; p < 0.001). A baseline NLR ≥ 2.3 was associated with 30% higher odds of microscopic metastatic melanoma in the sentinel lymph node [adjusted OR 1.3 (95% CI 1.3, 1.3)]. Following surgery, 253 patients (18.7%) developed recurrent melanoma during surveillance although there was no statistically significant association between the baseline NLR and the risk of recurrence [adjusted HR 0.9 (0.7, 1.1)]. CONCLUSION: The NLR is associated with the volume of melanoma at presentation and may predict occult sentinel lymph metastases. Further prospective work is required to investigate how NLR may be modelled against other clinicopathological variables to predict outcomes and to understand the temporal changes in NLR following surgery for melanoma.

Potentiating Oncolytic Virus-Induced Immune-Mediated Tumor Cell Killing Using Histone Deacetylase Inhibition.

A clinical oncolytic herpes simplex virus (HSV) encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), talimogene laherparepvec, causes regression of injected and non-injected melanoma lesions in patients and is now licensed for clinical use in advanced melanoma. To date, limited data are available regarding the mechanisms of human anti-tumor immune priming, an improved understanding of which could inform the development of future combination strategies with improved efficacy. This study addressed direct oncolysis and innate and adaptive human immune-mediated effects of a closely related HSV encoding GM-CSF (HSVGM-CSF) alone and in combination with histone deacetylase inhibition. We found that HSVGM-CSF supported activation of anti-melanoma immunity via monocyte-mediated type I interferon production, which activates NK cells, and viral maturation of immature dendritic cells (iDCs) into potent antigen-presenting cells for cytotoxic T lymphocyte (CTL) priming. Addition of the histone deacetylase inhibitor valproic acid (VPA) to HSVGM-CSF treatment of tumor cells increased viral replication, viral GM-CSF production, and oncolysis and augmented the development of anti-tumor immunity. Mechanistically, VPA increased expression of activating ligands for NK cell recognition and induced expression of tumor-associated antigens, supporting innate NK cell killing and CTL priming. These data support the clinical combination of talimogene laherparepvec with histone deacetylase inhibition to enhance oncolysis and anti-tumor immunity.

Baseline Neutrophil-Lymphocyte and Platelet-Lymphocyte Ratios as Biomarkers of Survival in Cutaneous Melanoma: A Multicenter Cohort Study.

BACKGROUND: In the peripheral blood, the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) change in response to malignancy. These biomarkers are associated with adverse outcomes in numerous cancers, but the evidence is limited in relation to melanoma. This study sought to investigate the association between these biomarkers and survival in Stages I-III cutaneous melanoma. METHODS: This multicenter cohort study investigated a consecutive series of patients who underwent wide excision of biopsy-proven cutaneous melanoma and sentinel lymph node biopsy during a 10-year period. The baseline NLR and PLR were calculated immediately before sentinel lymph node biopsy. Adjusted hazard ratios (HRs) for overall and melanoma-specific survival were generated. RESULTS: Overall, 1351 patients were included in the study. During surveillance, 184 of these patients died (14%), with 141 of the deaths (77%) attributable to melanoma. Worse overall survival was associated with a baseline NLR lower than 2.5 [HR 2.2; 95% confidence interval (CI) 2.0 to 2.3; p < 0.001] and a baseline PLR lower than 100 (HR 1.8; 95% CI 1.7 to 1.8; p < 0.001). Melanoma-specific survival also was worse, with a baseline NLR lower than 2.5 (HR 1.9; 95% CI 1.6 to 2.2; p < 0.001) and a baseline PLR lower than 100 (HR 1.9; 95% CI 1.7 to 2.2; p < 0.001). The 5-year survival for patients with sentinel lymph node metastases and a low NLR and PLR was approximately 50%. CONCLUSION: This study provides important new data on biomarkers in early-stage melanoma, which contrast with biomarker profiles in advanced disease. These biomarkers may represent the host inflammatory response to melanoma and therefore could help select patients for adjuvant therapy and enhanced surveillance.

1 Versus 2-cm Excision Margins for pT2-pT4 Primary Cutaneous Melanoma (MelMarT): A Feasibility Study.

BACKGROUND: There is a lack of consensus regarding optimal surgical excision margins for primary cutaneous melanoma > 1 mm in Breslow thickness (BT). A narrower surgical margin is expected to be associated with lower morbidity, improved quality of life (QoL), and reduced cost. We report the results of a pilot international study (MelMarT) comparing a 1 versus 2-cm surgical margin for patients with primary melanoma > 1 mm in BT. METHODS: This phase III, multicentre trial [NCT02385214] administered by the Australia & New Zealand Medical Trials Group (ANZMTG 03.12) randomised patients with a primary cutaneous melanoma > 1 mm in BT to a 1 versus 2-cm wide excision margin to be performed with sentinel lymph node biopsy. Surgical closure technique was at the discretion of the treating surgeon. Patients' QoL was measured (FACT-M questionnaire) at baseline, 3, 6, and 12 months after randomisation. RESULTS: Between January 2015 and June 2016, 400 patients were randomised from 17 centres in 5 countries. A total of 377 patients were available for analysis. Primary melanomas were located on the trunk (56.9%), extremities (35.6%), and head and neck (7.4%). More patients in the 2-cm margin group required reconstruction (34.9 vs. 13.6%; p < 0.0001). There was an increased wound necrosis rate in the 2-cm arm (0.5 vs. 3.6%; p = 0.036). After 12 months' follow-up, no differences were noted in QoL between groups. DISCUSSION: This pilot study demonstrates the feasibility of a large international RCT to provide a definitive answer to the optimal excision margin for patients with intermediate- to high-risk primary cutaneous melanoma.

Correction to: 1 Versus 2-cm Excision Margins for pT2-pT4 Primary Cutaneous Melanoma (MelMarT): A Feasibility Study.

In the original article John F. Thompson was inadvertently omitted as an author. The author list is updated as shown in this correction.

The unpredictability of lymphatic drainage from the ear in melanoma patients, and its implications for management.

BACKGROUND: The ear is known to have variable lymphatic drainage. The purpose of this study was to define better the lymphatic drainage patterns of the ear by correlating the location of primary tumors, classified according to the embryologically derived anatomical subunits of the ear, with their mapped sentinel nodes (SNs) identified by lymphoscintigraphy (LS). METHODS: Lymphatic drainage data for patients with a primary melanoma of the ear were reviewed and correlated with the precise primary melanoma site. RESULTS: Between 1993 and 2010, LS was performed in 111 patients with a primary melanoma on the ear, identifying 281 SNs in 195 lymph node (LN) fields. The mean numbers of SNs and LN fields identified by LS per patient were 2.65 and 1.76. SN biopsy was performed in 71 patients (64 %). The mean number of SNs removed was 2.36. The 111 ear melanomas were mostly located on the helical rim (55 %), followed by the lobule (24.3 %). The five different primary ear sites drained mainly to SNs in level CII, level CV and the preauricular region. Drainage was most often to level CII (36.4 %). Drainage to the contralateral neck was not observed. CONCLUSIONS: Lymphatic drainage of the ear has no predictable pattern and can be to SNs anywhere in the ipsilateral neck. Most commonly drainage is to cervical level II and the preauricular and postauricular LN fields. LS defines the lymphatic drainage pattern in individual melanoma patients and is essential for accurate SN identification and reliable SN biopsy.

MelRisk: Using neutrophil-to-lymphocyte ratio to improve risk prediction models for metastatic cutaneous melanoma in the sentinel lymph node.

BACKGROUND: Identifying metastatic melanoma in the sentinel lymph node (SLN) is important because 80% of SLN biopsies are negative and 11% of patients develop complications. The neutrophil-to-lymphocyte ratio (NLR), a biomarker of micrometastatic disease, could improve prediction models for SLN status. We externally validated existing models and developed 'MelRisk' prognostic score to better predict SLN metastasis. METHODS: The models were externally validated using data from a multicenter cohort study of 1,251 adults. Additionally, we developed and internally validated a new prognostic score `MelRisk', using candidate predictors derived from the extant literature. RESULTS: The Karakousis model had a C-statistic of 0.58 (95% CI, 0.54-0.62). The Sondak model had a C-statistic of 0.57 (95% CI 0.53-0.61). The MIA model had a C-statistic of 0.60 (95% CI. 0.56-0.64). Our 'MelRisk' model (which used Breslow thickness, ulceration, age, anatomical site, and the NLR) showed an adjusted C-statistic of 0.63 (95% CI, 0.56-0.64). CONCLUSION: Our prediction tool is freely available in the Google Play Store and Apple App Store, and we invite colleagues to externally validate its performance .

Less is more: A systematic review and meta-analysis of the outcomes of radical versus conservative primary resection in anorectal melanoma.

INTRODUCTION: Anorectal melanoma (ARM) is a rare disease with a poor prognosis. There is no consensus as to the optimal primary surgical treatment for ARM, with advocates for both radical (abdominoperineal resection [APR]) and conservative strategies (wide local excision [WLE]). Here, we report a systematic review of studies comparing outcomes between these strategies. METHODS: Studies comparing APR with WLE in patients with ARM were included, and a systematic review using the Grading of Recommendations, Assessment, Development and Evaluation methodology was performed. Outcomes deemed critical included overall survival, disease-free survival, local recurrence and quality of life. RESULTS: Forty studies were identified, of which 27 were suitable for inclusion. Twenty-three studies compared overall survival between WLE and APR, with no difference in outcomes noted (risk ratio [RR]: 0.80, 95% confidence interval [CI]: 0.60-1.07, p = 0.13). Seven studies compared disease-free survival, with no difference in outcomes noted (RR: 1.08, 95% CI: 0.61-1.91, p = 0.79). A total of 19 studies compared local recurrence rates, with again no significant difference in outcomes noted (RR: 0.71, 95% CI: 0.44-1.14, p = 0.16). None of the studies identified reported quality of life-related outcomes. CONCLUSION: There is no evidence to suggest that a radical primary surgical strategy improves outcomes in ARM. Therefore, given the well-documented morbidity associated with APR, WLE with regular surveillance for local recurrence should be the primary strategy in most patients.

Ano-uro-genital mucosal melanoma UK national guidelines.

Ano-uro-genital (AUG) mucosal melanomas are rare cancers associated with poor outcomes and limited evidence-based management. The United Kingdom AUG mucosal melanoma guideline development group used an evidence-based systematic approach to make recommendations regarding the diagnosis, treatment and surveillance of patients diagnosed with AUG mucosal melanomas. The guidelines were sent for international peer review, and are accredited by The National Institute for Health and Clinical Excellence (NICE). A summary of the key recommendations is presented. The full documents are available on the Melanoma Focus website.

Pathological review of primary cutaneous malignant melanoma by a specialist skin cancer multidisciplinary team improves patient care in the UK.

AIMS: The National Institute for Health and Care Excellence advocated the development of specialist skin cancer multidisciplinary teams (SSMDTs) for the management of higher risk invasive skin cancers in the UK. The interobserver variability in the histopathological assessment of primary cutaneous malignant melanoma (PCMM) is well recognised. METHODS: We evaluated the discordance rates in the assessment of the histopathological criteria of PCMM based on the eighth American Joint Committee on Cancer (AJCC) melanoma staging system and subsequent change in prognosis and management following pathology review by an SSMDT. RESULTS: 353 cases of PCMM were referred to our SSMDT between April 2015 and May 2016. Cases in which there was a discrepancy in one or more histological parameters following expert review were collected retrospectively. Of 341 eligible cases, there were 94 (27.6%) in which there was an alteration in any parameter. There was interobserver agreement in final diagnosis in 96.8%, Breslow thickness in 86.8%, ulceration in 98.2%, microsatellites in 98.5%, tumour mitotic rate in 88.9%, histological subtype in 92.4%, growth phase in 98.5%, angiolymphatic invasion in 97.7%, perineural invasion in 98.8%, regression in 95.3% and tumour-infiltrating lymphocytes in 95.0%. A corresponding change in AJCC stage occurred in 23 cases (6.7%), with a resulting change in clinical management in 10 cases (2.9%). CONCLUSIONS: Disagreements in the pathological assessment of PCMM can have significant clinical implications for a small number of patients. Our findings highlight the value of the SSMDT for high-quality care of patients with melanoma in the UK.

Neuropathic pain and quality of life after wide local excision and sentinel lymph node biopsy for melanoma: a multicentre study.

Wide local excision and sentinel lymph node biopsy is the mainstay of treatment for patients with melanoma. As survival outcomes improve, longer term quality of life questions become more pertinent and this study aims to assess the factors which may play a role following surgery. A total of, 221 patients who underwent wide local excision and sentinel lymph node biopsy for melanoma (AJCC stage I and II) were recruited from three UK centres. These patients completed a patient outcome questionnaire, which included demographic and treatment data as well as quality of life and pain questionnaires. Pain was the only significant factor influencing the quality of life with a negative correlation seen between pain and quality of life scores (P<0.001). In total, 34% of patients reported pain at their surgical site and four (1.8%) patients scored as high risk for neuropathic pain. Patients experiencing pain were significantly younger that those not reporting pain (median 55.0 vs. 63.5 years, P<0.001). Length of time since surgery did not correlate with pain nor quality of life scores. Our results suggest that following this common procedure a sizeable proportion of patients experience pain and poorer quality of life which does not improve with time. The level of pain experienced is clinically significant and merits evaluation and treatment in this group of patients who are increasingly surviving their melanoma diagnosis. Further investigation into potential prophylactic measures is suggested.