Society of Surgical Oncology Consensus Statement: Assessing the Evidence for and Utility of Gene Expression Profiling of Primary Cutaneous Melanoma.

INTRODUCTION: Gene expression profiling (GEP) of primary cutaneous melanoma aims to offer prognostic and predictive information to guide clinical care. Despite limited evidence of clinical utility, these tests are increasingly incorporated into clinical care. METHODS: A panel of melanoma experts from the Society of Surgical Oncology convened to develop recommendations regarding the use of GEP to guide management of patients with melanoma. The use of currently available GEP tests were evaluated in three clinical scenarios: (1) the utility in patient selection for sentinel lymph node biopsy; (2) the utility to guide surveillance; and (3) the utility to inform adjuvant therapy. As a basis for these recommendations, the panel performed a systematic review of the literature, including articles published from January 2012 until August 2023. RESULTS: After review of 137 articles, 50 met the inclusion criteria. These articles included evidence related to three available GEP tests: 31-GEP, CP-GEP, and 11-GEP. The consensus recommendations were finalized using a modified Delphi process. The panel found that current evidence often fails to account for known clinicopathologic risk factors and lacks high-level data. The panel recognizes that the study of GEP tests is still evolving. The integration of GEP into routine clinical practice for predicting sentinel lymph node status and patient prognosis in melanoma is therefore not currently recommended. CONCLUSION: At present, GEP should be considered primarily an investigational tool, ideally used in the context of clinical trials or specialized research settings.

Clinical outcomes of the management of basal cell carcinomas in individuals aged 90 years and over - a retrospective cohort study.

BACKGROUND: A retrospective cohort study was undertaken to examine the management of basal cell carcinoma (BCC) in older patients. OBJECTIVES: The aim was to identify subgroups where intervention could be minimised, based on frailty and trends in survival. METHODS: All patients aged 90 years and over with histologically confirmed BCC during 2017 and 2018 were included within the study (n = 319). RESULTS: Age was the most significant predictor of survival (HR=1.10 (95% CIs: 1.04-1.17); p=0.001). Maximum threshold analysis identified 93 years as the significant age cutpoint. Median survival was 40 months for ≤93 years and 28 months for >93 years (p=0.002). Patients with dementia had a worse survival than those without (median survival: 25 months versus 35 months, respectively; HR=1.92 (95% CIs: 1.18-3.13); p=0.009). There was a statistically significant difference in survival for patients who received treatment for their BCC (n=294) compared those observed (n=25) (median survival 34 months versus 21 months, respectively; HR= 0.54 (95% CIs: 0.34-0.85); p=0.007). All other comorbidities examined had no influence on survival. CONCLUSIONS: This study provides evidence in support of active treatment of BCC in individuals aged ≥90 years, seen in secondary care. Conservative options may be preferable in patients with dementia or those >93 years old.

International Center-Level Variation in Utilization of Completion Lymph Node Dissection and Adjuvant Systemic Therapy for Sentinel Lymph Node-Positive Melanoma at Major Referral Centers.

OBJECTIVE: The aim of this study was to determine overall trends and center-level variation in utilization of completion lymph node dissection (CLND) and adjuvant systemic therapy for sentinel lymph node (SLN)-positive melanoma. SUMMARY BACKGROUND DATA: Based on recent clinical trials, management options for SLN-positive melanoma now include effective adjuvant systemic therapy and nodal observation instead of CLND. It is unknown how these findings have shaped practice or how these contemporaneous developments have influenced their respective utilization. METHODS: We performed an international cohort study at 21 melanoma referral centers in Australia, Europe, and the United States that treated adults with SLN-positive melanoma and negative distant staging from July 2017 to June 2019. We used generalized linear and multinomial logistic regression models with random intercepts for each center to assess center-level variation in CLND and adjuvant systemic treatment, adjusting for patient and disease-specific characteristics. RESULTS: Among 1109 patients, performance of CLND decreased from 28% to 8% and adjuvant systemic therapy use increased from 29 to 60%. For both CLND and adjuvant systemic treatment, the most influential factors were nodal tumor size, stage, and location of treating center. There was notable variation among treating centers in management of stage IIIA patients and use of CLND with adjuvant systemic therapy versus nodal observation alone for similar risk patients. CONCLUSIONS: There has been an overall decline in CLND and simultaneous adoption of adjuvant systemic therapy for patients with SLN-positive melanoma though wide variation in practice remains. Accounting for differences in patient mix, location of care contributed significantly to the observed variation.

Risk Stratification of Sentinel Node Metastasis Disease Burden and Phenotype in Stage III Melanoma Patients.

BACKGROUND: Currently, all patients with American Joint Committee on Cancer (AJCC) pT2b-pT4b melanomas and a positive sentinel node biopsy are now considered for adjuvant systemic therapy without consideration of the burden of disease in the metastatic nodes. METHODS: This was a retrospective cohort analysis of 1377 pT1-pT4b melanoma patients treated at an academic cancer center. Standard variables regarding patient, primary tumor, and sentinel node characteristics, in addition to sentinel node metastasis maximum tumor deposit size (MTDS) in millimeters and extracapsular spread (ECS) status, were analyzed for predicting disease-specific survival (DSS). RESULTS: The incidence of SN+ was 17.3% (238/1377) and ECS was 10.5% (25/238). Increasing AJCC N stage was associated with worse DSS. There was no difference in DSS between the IIIB and IIIC groups. Subgroup analyses showed that the optimal MTDS cut-point was 0.7 mm for the pT1b-pT4a SN+ subgroups, but there was no cut-point for the pT4b SN+ subgroup. Patients with MTDS <0.7 mm and no ECS had similar survival outcomes as the N0 patients with the same T stage. Nodal risk categories were developed using the 0.7 mm MTDS cut-point and ECS status. The incidence of low-risk disease, according to the new nodal risk model, was 22.3% (53/238) in the stage III cohort, with 49% (26/53) in the pT2b-pT3a and pT3b-pT4a subgroups and none in the pT4b subgroup. Similar outcomes were observed for overall and distant metastasis-free survival. CONCLUSION: We propose a more granular classification system, based on tumor burden and ECS status in the sentinel node, that identifies low-risk patients in the AJCC IIIB and IIIC subgroups who may otherwise be observed.

Prognostic Significance of Sentinel Lymph Node Status in Thick Primary Melanomas (> 4 mm).

BACKGROUND: The key prognostic factors for staging patients with primary cutaneous melanoma are Breslow thickness, ulceration, and sentinel lymph node (SLN) status. The multicenter selective lymphadenectomy trial (MSLT-I) verified SLN status as the most important prognostic factor for patients with intermediate-thickness melanoma (Breslow thickness, 1-4 mm). Although most international guidelines recommend SLN biopsy (SLNB) also for patients with thick (> 4 mm, pT4) melanomas, its prognostic role has been questioned. The primary aim of this study was to establish whether SLN status is prognostic in T4 melanoma tumors. METHODS: Data for all patients with a diagnosis of primary invasive cutaneous melanoma of Breslow thickness greater than 1 mm in Sweden between 2007 and 2020 were retrieved from the Swedish Melanoma Registry, a large prospective population-based registry. A multivariable Cox proportional hazard model for melanoma-specific survival (MSS) was constructed based on Breslow thickness stratified for SLN status. RESULTS: The study enrolled 10,491 patients, 1943 of whom had a Breslow thickness greater than 4 mm (pT4). A positive SLN was found for 34% of these pT4 patients. The 5-year MSS was 71%, and the 10-year MSS was 62%. There was a statistically significant difference in MSS between the patients with a positive SLN and those with a negative SLN (hazard ratio of 2.4 (95% confidence interval CI 1.6-3.5) for stage T4a and 2.0 (95% CI 1.6-2.5) for satage T4b. CONCLUSION: Sentinel lymph node status gives important prognostic information also for patients with thick (> 4 mm) melanomas, and the authors thus recommend that clinical guidelines be updated to reflect this.

Machine-learning algorithm to predict multidisciplinary team treatment recommendations in the management of basal cell carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) is the most common human cancer. Facial BCCs most commonly occur on the nose and the management of these lesions is particularly complex, given the functional and complex implications of treatment. Multidisciplinary team (MDT) meetings are routinely held to integrate expertise from dermatologists, surgeons, oncologists, radiologists, pathologists and allied health professionals. The aim of this research was to develop a supervised machine-learning algorithm to predict MDT recommendations for nasal BCC to potentially reduce MDT caseload, provide automatic decision support and permit data audit in a health service context. METHODS: The study population included all consecutive patients who were discussed at skin cancer-specialised MDT (SSMDT) with a diagnosis of nasal BCC between January 1, 2015 and December 31, 2015. We conducted analyses for gender, age, anatomical location, histological subtype, tumour size, tumour recurrence, anticoagulation, pacemaker, immunosuppressants and therapeutic modalities (Mohs surgery, conventional excision or radiotherapy). We used S-statistic computing language to develop a supervised machine-learning algorithm. RESULTS: We found that 37.5% of patients could be reliably predicted to be triaged to Mohs micrographic surgery (MMS), based on tumour location and age. Similarly, the choice of conventional treatment (surgical excision or radiotherapy) by the MDT could be reliably predicted based on the patient's age, tumour phenotype and lesion size. Accordingly, the algorithm reliably predicted the MDT decision outcome of 45.1% of nasal BCCs. CONCLUSIONS: Our study suggests that the machine-learning approach is a potentially useful tool for predicting MDT decisions for MMS vs conventional surgery or radiotherapy for a significant group of patients. We suggest that utilising this algorithm gives the MDT more time to consider more complex patients, where multiple factors, including recurrence, financial costs and cosmetic outcome, contribute to the final decision, but cannot be reliably predicted to determine that outcome. This approach has the potential to reduce the burden and improve the efficiency of the specialist skin MDT and, in turn, improve patient care, reduce waiting times and reduce the financial burden. Such an algorithm would need to be updated regularly to take into account any changes in patient referral patterns, treatment options or local clinical expertise. CLINICAL TRIAL REGISTRATION: lPLAS_20-21_A08.

PGC-1α induced mitochondrial biogenesis in stromal cells underpins mitochondrial transfer to melanoma.

INTRODUCTION: Progress in the knowledge of metabolic interactions between cancer and its microenvironment is ongoing and may lead to novel therapeutic approaches. Until recently, melanoma was considered a glycolytic tumour due to mutations in mitochondrial-DNA, however, these malignant cells can regain OXPHOS capacity via the transfer of mitochondrial-DNA, a process that supports their proliferation in-vitro and in-vivo. Here we study how melanoma cells acquire mitochondria and how this process is facilitated from the tumour microenvironment. METHODS: Primary melanoma cells, and MSCs derived from patients were obtained. Genes' expression and DNA quantification was analysed using Real-time PCR. MSC migration, melanoma proliferation and tumour volume, in a xenograft subcutaneous mouse model, were monitored through bioluminescent live animal imaging. RESULTS: Human melanoma cells attract bone marrow-derived stromal cells (MSCs) to the primary tumour site where they stimulate mitochondrial biogenesis in the MSCs through upregulation of PGC1a. Mitochondria are transferred to the melanoma cells via direct contact with the MSCs. Moreover, inhibition of MSC-derived PGC1a was able to prevent mitochondrial transfer and improve NSG melanoma mouse tumour burden. CONCLUSION: MSC mitochondrial biogenesis stimulated by melanoma cells is prerequisite for mitochondrial transfer and subsequent tumour growth, where targeting this pathway may provide an effective novel therapeutic approach in melanoma.

Follow-up Schedule for Patients With Sentinel Node-negative Cutaneous Melanoma (The MELFO Study): An International Phase III Randomized Clinical Trial.

OBJECTIVES AND DESIGN: The MELFO (MELanoma FOllow-up) study is an international phase III randomized controlled trial comparing an experimental low-intensity schedule against current national guidelines. BACKGROUND: Evidence-based guidelines for the follow-up of sentinel node-negative melanoma patients are lacking. METHODS: Overall, 388 adult patients diagnosed with sentinel node-negative primary melanoma patients were randomized in cancer centers in the Netherlands and United Kingdom between 2006 and 2016. The conventional schedule group (control: n=196) was reviewed as per current national guidelines. The experimental schedule group (n=192) was reviewed in a reduced-frequency schedule. Quality of life was the primary outcome measurement. Detection rates and survival outcomes were recorded. Patient satisfaction rates and compliance with allocated schedules were compared. RESULTS: At 5 years, both arms expressed high satisfaction with their regimens (>97%). This study found no significant group effect on any patient-reported outcome measure scores between the follow-up protocols. In total, 75/388 (19.4%) patients recurred, with no difference in incidence found between the 2 arms (hazard ratio=0.87, 95% confidence interval: 0.54-1.39, P =0.57). Self-examination was the method of detection for 25 experimental patients and 32 control patients (75.8% vs. 76.2%; P =0.41). This study found no difference in any survival outcomes between the 2 study arms (disease-free survival: hazard ratio=1.00, 95% confidence interval: 0.49-2.07, P =0.99). CONCLUSIONS: A reduced-intensity, American Joint Committee on Cancer (AJCC) stage-adjusted follow-up schedule for sentinel node-negative melanoma patients is a safe strategy, and patient self-examination is effective for recurrence detection with no evidence of diagnostic delay. Patients' acceptance is very high.

Effectiveness of SPECT/CT Imaging for Sentinel Node Biopsy Staging of Primary Cutaneous Melanoma and Patient Outcomes.

PURPOSE: Coregistered SPECT/CT can improve accuracy of sentinel node biopsy (SNB) for staging melanoma. This benefit has implications for pathology services and surgical practice with increased diagnostic and surgical workload. The purpose of this study was to investigate the effectiveness of SPECT/CT imaging. METHODS: SNB data were collected over a 10-year period. Preoperative SLN mapping was performed by using planar lymphoscintigraphy (LSG) for all patients (n = 1522) and after October 2015, patients underwent a second co-registered SPECT/CT scan (n = 559). The patients were stratified according to the imaging protocol. The number of nodes and nodal basins were assessed. The reasons for cancellation also were assessed. RESULTS: A total of 95% (1446/1522) of patients underwent a successful SNB procedure. Significantly more sentinel nodes were identified by the SPECT/CT protocol (3 vs. 2; p < 0.0001). More patients were cancelled in the SPECT/CT cohort (9.3% vs. 2.5%; p < 0.0001). Head & neck, lower limb, and AJCC IB primaries were significantly less likely to proceed to SNB. SPECT/CT identified significantly more positive SNBs (20.9% vs. 16.5%; p = 0.038). SPECT/CT imaging was associated with improved disease-free (hazard ratio [HR] = 0.74; 95% confidence interval [CI]: 0.54-1.0); p = 0.048) and disease-specific survival (HR = 0.48; 95% CI: 0.3-0.78; p = 0.003). Patients who did not proceed to SNB had a significantly increased nodal relapse rate (23.5% vs. 6.8%; HR = 3.4; 95% CI: 1.9-6.2; p < 0.0001) compared with those who underwent SNB. CONCLUSIONS: This large cohort study confirms the increased accuracy of SPECT/CT for identifying SLN metastases, which would appear to have a significant therapeutic benefit, although an increased risk of cancellation of the SNB procedure on the day of surgery.

Predictors of Sentinel Lymph Node Metastasis in Patients with Thin Melanoma: An International Multi-institutional Collaboration.

BACKGROUND: Consideration of sentinel lymph node biopsy (SLNB) is recommended for patients with T1b melanomas and T1a melanomas with high-risk features; however, the proportion of patients with actionable results is low. We aimed to identify factors predicting SLNB positivity in T1 melanomas by examining a multi-institutional international population. METHODS: Data were extracted on patients with T1 cutaneous melanoma who underwent SLNB between 2005 and 2018 at five tertiary centers in Europe and Canada. Univariable and multivariable logistic regression analyses were performed to identify predictors of SLNB positivity. RESULTS: Overall, 676 patients were analyzed. Most patients had one or more high-risk features: Breslow thickness 0.8-1 mm in 78.1% of patients, ulceration in 8.3%, mitotic rate > 1/mm2 in 42.5%, Clark's level ≥ 4 in 34.3%, lymphovascular invasion in 1.4%, nodular histology in 2.9%, and absence of tumor-infiltrating lymphocytes in 14.4%. Fifty-three patients (7.8%) had a positive SLNB. Breslow thickness and mitotic rate independently predicted SLNB positivity. The odds of positive SLNB increased by 50% for each 0.1 mm increase in thickness past 0.7 mm (95% confidence interval [CI] 1.05-2.13) and by 22% for each mitosis per mm2 (95% CI 1.06-1.41). Patients who had one excised node (vs. two or more) were three times less likely to have a positive SLNB (3.6% vs. 9.6%; odds ratio 2.9 [1.3-7.7]). CONCLUSIONS: Our international multi-institutional data confirm that Breslow thickness and mitotic rate independently predict SLNB positivity in patients with T1 melanoma. Even within this highly selected population, the number needed to diagnose is 13:1 (7.8%), indicating that more work is required to identify additional predictors of sentinel node positivity.

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.

Active surveillance of patients who have sentinel node positive melanoma: An international, multi-institution evaluation of adoption and early outcomes after the Multicenter Selective Lymphadenectomy Trial II (MSLT-2).

BACKGROUND: For patients with sentinel lymph node (SLN)-positive cutaneous melanoma, the Second Multicenter Selective Lymphadenectomy trial demonstrated equivalent disease-specific survival (DSS) with active surveillance using nodal ultrasound versus completion lymph node dissection (CLND). Adoption and outcomes of active surveillance in clinical practice and in adjuvant therapy recipients are unknown. METHODS: In a retrospective cohort of SLN-positive adults treated at 21 institutions in Australia, Europe, and the United States from June 2017 to November 2019, the authors evaluated the impact of active surveillance and adjuvant therapy on all-site recurrence-free survival (RFS), isolated nodal RFS, distant metastasis-free survival (DMFS), and DSS using Kaplan-Meier curves and Cox proportional hazard models. RESULTS: Among 6347 SLN biopsies, 1154 (18%) were positive and had initial negative distant staging. In total, 965 patients (84%) received active surveillance, 189 (16%) underwent CLND. Four hundred thirty-nine patients received adjuvant therapy (surveillance, 38%; CLND, 39%), with the majority (83%) receiving anti-PD-1 immunotherapy. After a median follow-up of 11 months, 220 patients developed recurrent disease (surveillance, 19%; CLND, 22%), and 24 died of melanoma (surveillance, 2%; CLND, 4%). Sixty-eight patients had an isolated nodal recurrence (surveillance, 6%; CLND, 4%). In patients who received adjuvant treatment without undergoing prior CLND, all isolated nodal recurrences were resectable. On risk-adjusted multivariable analyses, CLND was associated with improved isolated nodal RFS (hazard ratio [HR], 0.36; 95% CI, 0.15-0.88), but not all-site RFS (HR, 0.68; 95% CI, 0.45-1.02). Adjuvant therapy improved all-site RFS (HR, 0.52; 95% CI, 0.47-0.57). DSS and DMFS did not differ by nodal management or adjuvant treatment. CONCLUSIONS: Active surveillance has been adopted for most SLN-positive patients. At initial assessment, real-world outcomes align with randomized trial findings, including in adjuvant therapy recipients. LAY SUMMARY: For patients with melanoma of the skin and microscopic spread to lymph nodes, monitoring with ultrasound is an alternative to surgically removing the remaining lymph nodes. The authors studied adoption and real-world outcomes of ultrasound monitoring in over 1000 patients treated at 21 centers worldwide, finding that most patients now have ultrasounds instead of surgery. Although slightly more patients have cancer return in the lymph nodes with this strategy, typically, it can be removed with delayed surgery. Compared with up-front surgery, ultrasound monitoring results in the same overall risk of melanoma coming back at any location or of dying from melanoma.

Mitochondrial oxidative phosphorylation in cutaneous melanoma.

The Warburg effect in tumour cells is associated with the upregulation of glycolysis to generate ATP, even under normoxic conditions and the presence of fully functioning mitochondria. However, scientific advances made over the past 15 years have reformed this perspective, demonstrating the importance of oxidative phosphorylation (OXPHOS) as well as glycolysis in malignant cells. The metabolic phenotypes in melanoma display heterogeneic dynamism (metabolic plasticity) between glycolysis and OXPHOS, conferring a survival advantage to adapt to harsh conditions and pathways of chemoresistance. Furthermore, the simultaneous upregulation of both OXPHOS and glycolysis (metabolic symbiosis) has been shown to be vital for melanoma progression. The tumour microenvironment (TME) has an essential supporting role in promoting progression, invasion and metastasis of melanoma. Mesenchymal stromal cells (MSCs) in the TME show a symbiotic relationship with melanoma, protecting tumour cells from apoptosis and conferring chemoresistance. With the significant role of OXPHOS in metabolic plasticity and symbiosis, our review outlines how mitochondrial transfer from MSCs to melanoma tumour cells plays a key role in melanoma progression and is the mechanism by which melanoma cells regain OXPHOS capacity even in the presence of mitochondrial mutations. The studies outlined in this review indicate that targeting mitochondrial trafficking is a potential novel therapeutic approach for this highly refractory disease.

Quantitative and Spatial Analysis of CD8+/PD-1 Tumor-Infiltrating Lymphocytes as a Predictive Biomarker for Clinical Response of Melanoma In-Transit Metastases to Topical Immunotherapy.

BACKGROUND: Melanoma in-transit metastases (ITMs) are a challenge to treat and associated with systemic disease and poor prognosis. Topical diphencyprone (DPCP), a potent contact sensitizer, is an established treatment for melanoma ITMs. This exploratory study investigated the utility of BRAF mutation status, CD8, PD-1, PD-L1, and TILs distribution as biomarkers for response of ITMs to topical immunotherapy (DPCP). METHODS: The ITM deposits of 40 patients treated with DPCP were subjected to biomarker analysis for BRAF status, CD8 and PD-1 expression on tumor-infiltrating lymphocytes (TILs), and tumor PD-L1 expression. Response to DPCP and overall survival (OS) were compared by biomarker status. RESULTS: After 12 weeks, 10 patients (25%) had a complete response, 12 patients (30%) had a partial response, and 18 patients (45%) had no response. No significant association was found between any individual biomarker and response to DPCP or OS. The BRAF mutation rate was 25% (10/40). All the patients with a complete response had BRAF wild-type tumor. Peritumoral CD8+ T-cells were associated with complete response (P = 0.041). Both CD8+ and PD-1 expressions were highly correlated (P < 0.0001), and the highest levels of PD-1 expression were detected at the peritumoral interface (P = 0.0004). Only two cases were PD-L1-positive, and both had a complete response to DPCP (P = 0.043). CONCLUSION: Patients who have BRAF wild-type tumor are more likely to experience a complete response to DPCP. Peritumoral TILs and PD-1 expressions may predict a better response to DPCP. Expression of PD-L1 may be associated with a complete response to DPCP. A larger prospective study is required.

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.

Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma.

BACKGROUND: Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. METHODS: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. RESULTS: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. CONCLUSIONS: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .).

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.

Improved Perioperative Seroma and Complication Rates Following the Application of a 2-Layer Negative Pressure Wound Therapy System After Inguinal Lymphadenectomy for Metastatic Cutaneous Melanoma.

BACKGROUND: Perioperative complications following inguinal lymphadenectomy, including seroma formation, are frequent. We have employed a 2-layer negative pressure wound therapy (2-LNPWT) as a method to reduce seroma rate and perioperative complications. We present the outcome of our initial experience with 2-LNPWT and compare the outcomes of its use with traditional closed suction drains (CSDs). MATERIALS AND METHODS: A non-randomised retrospective case-control series was analysed. Surgeons performing inguinal lymphadenectomy for metastatic cutaneous melanoma utilised either the 2-LNPWT therapy or traditional CSDs according to their practice preference. RESULTS: The study included 111 patients. The cohorts were well matched for gender, disease burden, body mass index and comorbidities. The 2-LNPWT technique was associated with significantly better postoperative outcomes than CSD, in terms of incidence of seroma formation (26.9% vs 49.4%; p < 0.03), period of drainage (15 days vs 20 days; p = 0.005) and return to theatre rate (0% vs 15.3%; p = 0.03). The overall seroma rate was 44.1%. The only significant association with seroma initiation was the type of drainage system used (2-LNPWT 31.2% vs CSD 58.3%; p < 0.03; OR 3.0). The method of drainage did not alter the course of an established seroma. There was no significant difference in overall or disease-specific survival detected between the 2 groups. CONCLUSION: This retrospective non-randomised case control study has demonstrated the safe use of a novel application of negative pressure wound therapy that significantly reduced the incidence of seroma formation and postoperative complication rate for inguinal lymphadenectomy for melanoma.

The MelFo Study UK: Effects of a Reduced-Frequency, Stage-Adjusted Follow-Up Schedule for Cutaneous Melanoma 1B to 2C Patients After 3-Years.

BACKGROUND: Evidence-based guidelines for follow-up treatment of American Joint Committee on Cancer (AJCC) stages 1B to 2C melanoma patients are lacking. The MELanoma FOllow-up study is an international phase 3 randomized trial, and the 3-year interim data were recently reported from the Netherlands. The study was undertaken concurrently with a British cohort for comparison and validation of the Dutch study. METHODS: The study enrolled and stratified 207 patients by AJCC stage. The conventional schedule group (CSG; n = 103) cohort was reviewed as per UK guidelines. The experimental schedule group (ESG; n = 104) cohort was reviewed in a reduced-frequency nurse-led, consultant-supervised clinic. Quality of life (QoL) was measured at baseline (T1), a 1 year (T2), and at 3 years (T3) using the State-Trait Anxiety Inventory, the Cancer Worry Scale, the Impact-of-Event Scale, and the Mental and Physical Component scales (PCS/MCS) of the RAND-36. RESULTS: Of the 207 QoL questionnaires, 170 (82.1%) were completed at T3. Both cohorts expressed high satisfaction (> 93%) with their regimens. At T3, no significant group effect was found on any patient-reported outcome measures scores, indicating no QoL difference between the follow-up protocols. Recurrence had developed in 33 patients Conventional follow-up (CFU), 16 [15.5%]; Experimental follow-up (EFU), 17 [16.3%]. Self-examination was the method of detection for 12 ESG patients (70.6%) and 11 CSG patients (68.8%). The melanoma-specific survival was identical. CONCLUSION: The UK 3-year data were consistent with the previous Dutch report. The reduced follow-up strategy was shown to be safe, with significant resource usage benefits for national cancer services. Patient anxiety levels were not increased by a less-intensive follow-up regimen, and acceptance was high. The study data indicate that patient self-examination is very effective for recurrence detection.