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Background: Advancements in managing stage III melanoma have involved the implementation of adjuvant therapies alongside a simultaneous decrease in the utilization of completion lymph node dissection (CLND) following positive sentinel node biopsy (SLNB). Methods: This retrospective study from the University of Turin's Dermatology Clinic analyzed relapse-free survival (RFS) and overall survival (OS) among stage III melanoma patients (n = 157) who underwent CLND after positive SLNB versus those who did not receive such procedure. Results: Patients without CLND had a median RFS of 49 months (95% CI 42-NA), while CLND recipients showed 51 months (95% CI 31-NA) (p = 0.139). The 48-month OS for non-CLND patients was 79.8% (95% CI 58.2–91.0) versus 79.2% (95% CI 67.5–87.0) for CLND recipients (p = 0.463). Adjusted Hazard Ratios through inverse probability treatment weighting revealed the impact of CLND to be insignificant on RFS (aHR 0.90, 95% CI 0.37–2.22) and marginal on OS (aHR 0.41, 95% CI 0.13–1.21). Conversely, adjuvant therapy significantly reduced the risk of relapse (aHR 0.46, 95% CI 0.25–0.84), irrespective of CLND. Conclusions: This study corroborates the growing evidence that CLND after positive SLNB does not enhance RFS or OS, while emphasizing the crucial role of adjuvant therapy, be it immunotherapy or targeted therapy, in reducing the risk of relapse in melanoma patients with positive SLNB. [ABSTRACT FROM AUTHOR]

Simple Summary: Melanoma is the deadliest of all skin cancers. Therapy paradigms in cutaneous melanoma have changed significantly over the past 20 years, following both changes in the initial staging work-up of melanoma as well as in the available therapies. Regional recurrences after initial surgery are normally treated with nodal basin resection. However, some regional recurrences may present as bulky masses that can pose significant challenges in the treatment and control of the disease. It is well established that radiation therapy (RT) plays a role in locoregional control of malignancies in general. This review will attempt to discuss evidence for radiation therapy's role in reducing regional recurrence in the adjuvant setting in melanoma, identify adjuvant systemic therapy options, discuss systemic therapy–radiation therapy combinations, and identify paradigms and emerging evidence for the use of radiation therapy after neoadjuvant systemic therapy strategies are employed. In the landscape of Stage III locoregionally advanced cutaneous melanoma treatment, the post-immunotherapy era has sparked a number of questions on the management of the nodal basin. However, much of the available literature is not focused on radiation therapy as an adjuvant therapy. This literature review aims to illuminate the evidence surrounding radiation therapy's potential to mitigate regional recurrences in the adjuvant setting for melanoma. Additionally, it seeks to identify adjunct systemic therapy options and explore the synergy between systemic therapy and radiation. Despite strides in surgical techniques and systemic therapies, controlling regional Stage III melanoma remains a formidable clinical hurdle. While historical data strongly suggest the efficacy of adjuvant radiation therapy in reducing regional recurrence risk, its evaluation predates the advent of MAPK pathway inhibitors and robust immunotherapy options. Notably, clinical trials have yet to definitively demonstrate a survival advantage with adjuvant radiation therapy. Additional research should focus on refining the definition of high risk for regional recurrence through gene expression profiling or tumor immune profiling scores and elucidate the optimal role of adjuvant radiation therapy in patients treated with neoadjuvant systemic therapy. [ABSTRACT FROM AUTHOR]

Abstract Background Neoadjuvant therapy improves recurrence-free survival (RFS) in resectable stage III cutaneous melanoma. However, accurately predicting individual recurrence risk remains a significant challenge. We investigated circulating tumour DNA (ctDNA) as a biomarker for recurrence in measurable stage IIIB/C melanoma patients undergoing neoadjuvant immunotherapy. Methods Plasma samples were collected pre-neoadjuvant treatment, pre-surgery and/or six weeks post-surgery from 40 patients enrolled in the OpACIN-neo and PRADO clinical trials. Patients received two cycles of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) before surgery. Cell free DNA (cfDNA) underwent unbiased pre-amplification followed by tumour-informed mutation detection using droplet digital polymerase chain reaction (ddPCR) with the Bio-Rad QX600 PCR system. Results Pre-treatment ctDNA was detectable in 19/40 (48%) patients. Among these, 17/19 (89%) zero-converted within six weeks of surgery and none recurred. Positive ctDNA post-surgery (N = 4), irrespective of pre-treatment ctDNA status, was 100% predictive of recurrence (sensitivity 44%, specificity 100%). Furthermore, ctDNA cleared prior to surgery in 7/9 (78%) patients who did not recur, warranting further investigation into ctDNA-guided surgical management. Conclusion Post-surgery ctDNA positivity and zero-conversion are highly predictive of recurrence, offering a window for personalised modification of adjuvant therapy.

Background: Neoadjuvant therapy improves recurrence-free survival (RFS) in resectable stage III cutaneous melanoma. However, accurately predicting individual recurrence risk remains a significant challenge. We investigated circulating tumour DNA (ctDNA) as a biomarker for recurrence in measurable stage IIIB/C melanoma patients undergoing neoadjuvant immunotherapy. Methods: Plasma samples were collected pre-neoadjuvant treatment, pre-surgery and/or six weeks post-surgery from 40 patients enrolled in the OpACIN-neo and PRADO clinical trials. Patients received two cycles of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) before surgery. Cell free DNA (cfDNA) underwent unbiased pre-amplification followed by tumour-informed mutation detection using droplet digital polymerase chain reaction (ddPCR) with the Bio-Rad QX600 PCR system. Results: Pre-treatment ctDNA was detectable in 19/40 (48%) patients. Among these, 17/19 (89%) zero-converted within six weeks of surgery and none recurred. Positive ctDNA post-surgery (N = 4), irrespective of pre-treatment ctDNA status, was 100% predictive of recurrence (sensitivity 44%, specificity 100%). Furthermore, ctDNA cleared prior to surgery in 7/9 (78%) patients who did not recur, warranting further investigation into ctDNA-guided surgical management. Conclusion: Post-surgery ctDNA positivity and zero-conversion are highly predictive of recurrence, offering a window for personalised modification of adjuvant therapy. [ABSTRACT FROM AUTHOR]

Background: Both immunotherapy (IO) and targeted therapy (TT) are used as adjuvant (adj) treatment for stage III melanoma, however, data describing real‐world outcomes are limited. In addition, a significant proportion of patients relapse, for whom best management is unclear. The aim of our study was to assess the efficacy, and safety of adj anti‐PD1 IO and TT in a real‐world cohort of patients with resected stage III melanoma, and further delineate patterns of recurrence and treatment strategies. Methods: We retrospectively analyzed 130 patients who received adj therapy (100 anti‐PD1 IO and 30 TT). Results: At a median follow‐up of 30 months, median relapse‐free survival (RFS) was 24.6 (95% CI, 17–not reached [NR]) versus 64 (95% CI, 29.5–NR) months for the TT and IO groups, respectively (p = 0.26). Median overall survival (OS) was NR for either subgroup. At data cutoff, 77% and 82% of patients in TT and IO arms were alive. A higher number of grade ≥3 treatment‐related adverse events (AEs) were noted in the IO group (11% vs. 3%), however, a higher proportion of patients permanently discontinued adj therapy in the TT group (43% vs. 11%) due to toxicity. Strategies at relapse and outcomes were variable based on location and timing of recurrence. A significant number of patients who relapsed after adj IO received a second round of IO. Among them, patients who were off adj IO at relapse had superior second median RFS (mRFS2), compared to those who relapsed while on adj IO; mRFS2 was NR versus 5.1 months (95% CI, 2.5–NR), respectively, p = 0.02. Conclusion: In summary, both TT and IO yielded prolonged RFS in a real‐world setting, however, longer follow‐up is needed to determine any potential OS benefit. Adj therapy, particularly TT, may not be as well tolerated as suggested in clinical trials, with lower completion rates (59% vs. 74%) in a real‐life setting. Overall, patients who relapse during adj therapy have poor outcomes, while patients who relapse after discontinuation of adj IO therapy appear to benefit from IO re‐treatment. [ABSTRACT FROM AUTHOR]

Abstract Background The objective of this study was to describe real-world adjuvant therapy (AT) use by disease substage and assess determinants of treatment choice among patients with stage III melanoma. Methods This non-interventional retrospective study included survey responses and data from patient records provided by US medical oncologists. Survey responses, patient demographic/clinical characteristics, treatment utilization, and reasons for treatment were reported descriptively. The association between patient and disease characteristics and AT selection was assessed using logistic and multinomial regression models, overall and stratified by AJCC8 substage (IIIA vs. IIIB/C/D) and type of AT received (anti-PD1 monotherapy, BRAF/MEK, no AT), respectively. Results In total 152 medical oncologists completed the survey and reviewed the charts of 507 patients (168 stage IIIA; 339 stages IIIB/IIIC/IIID); 405 (79.9%) patients received AT (360/405 (88.9%) received anti-PD1 therapy; 45/405 (11.1%) received BRAF/MEK therapy). Physicians reported clinical guidelines (61.2%), treatment efficacy (37.5%), and ECOG performance status (31.6%) as drivers of AT prescription. Patient-level data confirmed that improving patient outcomes (79%) was the main reason for anti-PD1 prescription; expected limited treatment benefit (37%), patient refusal (36%), and toxicity concerns (30%) were reasons for not prescribing AT. In multivariable analyses stage IIIB/IIIC/IIID disease significantly increased the probability of receiving AT (odds ratio [OR] 1.74) and anti-PD1 therapy (OR 1.82); ECOG 2/3 and Medicaid/no insurance decreased the probability of AT receipt (OR 0.37 and 0.42, respectively) and anti-PD1 therapy (OR 0.41 and 0.42, respectively) among all patients and patients with stage IIIA disease. Conclusion Most patients were given AT with a vast majority treated with an anti-PD1 therapy. Physician- and patient-level evidence confirmed the impact of disease substage on AT use, with stage IIIA patients, patients without adequate insurance coverage, and worse ECOG status having a lower probability of receiving AT.

Background: The objective of this study was to describe real-world adjuvant therapy (AT) use by disease substage and assess determinants of treatment choice among patients with stage III melanoma. Methods: This non-interventional retrospective study included survey responses and data from patient records provided by US medical oncologists. Survey responses, patient demographic/clinical characteristics, treatment utilization, and reasons for treatment were reported descriptively. The association between patient and disease characteristics and AT selection was assessed using logistic and multinomial regression models, overall and stratified by AJCC8 substage (IIIA vs. IIIB/C/D) and type of AT received (anti-PD1 monotherapy, BRAF/MEK, no AT), respectively. Results: In total 152 medical oncologists completed the survey and reviewed the charts of 507 patients (168 stage IIIA; 339 stages IIIB/IIIC/IIID); 405 (79.9%) patients received AT (360/405 (88.9%) received anti-PD1 therapy; 45/405 (11.1%) received BRAF/MEK therapy). Physicians reported clinical guidelines (61.2%), treatment efficacy (37.5%), and ECOG performance status (31.6%) as drivers of AT prescription. Patient-level data confirmed that improving patient outcomes (79%) was the main reason for anti-PD1 prescription; expected limited treatment benefit (37%), patient refusal (36%), and toxicity concerns (30%) were reasons for not prescribing AT. In multivariable analyses stage IIIB/IIIC/IIID disease significantly increased the probability of receiving AT (odds ratio [OR] 1.74) and anti-PD1 therapy (OR 1.82); ECOG 2/3 and Medicaid/no insurance decreased the probability of AT receipt (OR 0.37 and 0.42, respectively) and anti-PD1 therapy (OR 0.41 and 0.42, respectively) among all patients and patients with stage IIIA disease. Conclusion: Most patients were given AT with a vast majority treated with an anti-PD1 therapy. Physician- and patient-level evidence confirmed the impact of disease substage on AT use, with stage IIIA patients, patients without adequate insurance coverage, and worse ECOG status having a lower probability of receiving AT. [ABSTRACT FROM AUTHOR]

Abstract Background Both immunotherapy (IO) and targeted therapy (TT) are used as adjuvant (adj) treatment for stage III melanoma, however, data describing real‐world outcomes are limited. In addition, a significant proportion of patients relapse, for whom best management is unclear. The aim of our study was to assess the efficacy, and safety of adj anti‐PD1 IO and TT in a real‐world cohort of patients with resected stage III melanoma, and further delineate patterns of recurrence and treatment strategies. Methods We retrospectively analyzed 130 patients who received adj therapy (100 anti‐PD1 IO and 30 TT). Results At a median follow‐up of 30 months, median relapse‐free survival (RFS) was 24.6 (95% CI, 17–not reached [NR]) versus 64 (95% CI, 29.5–NR) months for the TT and IO groups, respectively (p = 0.26). Median overall survival (OS) was NR for either subgroup. At data cutoff, 77% and 82% of patients in TT and IO arms were alive. A higher number of grade ≥3 treatment‐related adverse events (AEs) were noted in the IO group (11% vs. 3%), however, a higher proportion of patients permanently discontinued adj therapy in the TT group (43% vs. 11%) due to toxicity. Strategies at relapse and outcomes were variable based on location and timing of recurrence. A significant number of patients who relapsed after adj IO received a second round of IO. Among them, patients who were off adj IO at relapse had superior second median RFS (mRFS2), compared to those who relapsed while on adj IO; mRFS2 was NR versus 5.1 months (95% CI, 2.5–NR), respectively, p = 0.02. Conclusion In summary, both TT and IO yielded prolonged RFS in a real‐world setting, however, longer follow‐up is needed to determine any potential OS benefit. Adj therapy, particularly TT, may not be as well tolerated as suggested in clinical trials, with lower completion rates (59% vs. 74%) in a real‐life setting. Overall, patients who relapse during adj therapy have poor outcomes, while patients who relapse after discontinuation of adj IO therapy appear to benefit from IO re‐treatment.

Background Adjuvant therapies have been approved for resected melanoma based on improved recurrence-free survival. We present early findings from a real-world study on adjuvant treatments for melanoma. Methods A comprehensive chart review was conducted for patients receiving adjuvant systemic therapy for resected high-risk stages III and IV melanoma. Statistical analysis was performed to assess recurrence-free survival and subgroup differences. Results A total of 149 patients (median age = 58.0 years, 61.1% men, 49.7% with BRAF V600E/K genotypes) were included, with 94.6% having resected stage III melanoma. Anti-PD-1 immunotherapy was received by 86.5% of patients, while 13.4% received BRAF-targeted therapy. At a median follow-up of 22.4 months, the recurrence rate was 31.5%, with 1-year and 2-year recurrence-free survival rates of 79% and 62%, respectively. Similar recurrence rates were observed between anti-PD-1 immunotherapy and BRAF-targeted therapy. Long-term toxicity affected 27.4% of patients, with endocrinopathies and late-emergent immune-related adverse events being common. Conclusions Real-world adjuvant systemic therapy aligns with clinical trial practice. Recurrence rates remain high despite treatment, and long-term toxicities, including endocrinopathies and chronic inflammatory conditions, are not uncommon. [ABSTRACT FROM AUTHOR]

Introduction: Within stage III melanoma prognosis and outcomes significantly vary. Advances in systemic therapy improved prognosis in metastatic melanoma. Adjuvant therapy in stage III significantly lowered relapses, although the effect on survival is less evident. Analysis of treatment results in stage IIIC and IIID before introduction of the modern adjuvant therapy, but after introduction of the effective systemic therapy in metastatic relapse, is needed. Aim: To analyse the clinical outcomes in patients with stage IIIC and IIID melanoma before the introduction of the novel adjuvant therapy. Material and methods: Consecutive stage IIIC and IIID melanoma patients treated in 2015-2018 in 4 reference centres in Poland were enrolled in the analysis of RFS and OS (in-transit metastases excluded). Median follow-up was 26.6 months (1.7-67.2). Results: There were 224 stage IIIC and 49 stage IIID patients. Recurrence was observed in 170 (62.2%); 102 (45.5%) deaths in stage IIIC and 28 (57.1%) in stage IIID were reported. RFS and OS were better in stage IIIC compared to stage IIID. RFS and OS in the IIIC group were 19.7 and 36.2 months, respectively, and in IIID - 8.9 and 27.8 months, respectively. Conclusions: The survival of patients with high-risk melanomas has improved in recent years, however, it is still unsatisfactory. The major changes in melanoma management related to the introduction of the adjuvant therapy require further careful observation. [ABSTRACT FROM AUTHOR]

Background and Objectives: The impact of neoadjuvant immunotherapy (NIT) on overall survival (OS) in patients with resectable stage III melanoma remains unknown. We sought to identify factors associated with receipt of NIT and survival outcomes in patients with clinical stage III melanoma undergoing surgery., Methods: The National Cancer Database (2016-2020) was used to identify patients with clinical stage III melanoma who underwent surgery and received either NIT or adjuvant immunotherapy (AIT) only. Multivariable regression, Kaplan-Meier, and Cox proportional hazard methods were used to analyze variables of interest., Results: Patients with clinical N3 disease had 2.5 times the odds of NIT compared to those with N1 disease (95% CI 1.74-3.49). There was no difference in 3-year OS between the two cohorts: 79% (95% CI 73%-85%) for NIT patients and 75% (95% CI 73%-76%) for AIT patients (p = 0.078). Patients with N2/N3 disease had improved 3-year OS of 79% with NIT versus 71% for AIT-only (HR 0.61, 95% CI 0.38-0.97, p = 0.037)., Conclusions: NIT is given more selectively to clinical stage III patients with more advanced N category disease. Despite significant differences in N category between groups, there was no difference in OS observed at 3 years, and NIT was associated with a survival advantage among N2/N3 patients., (© 2024 The Author(s). Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Melanoma is a form of skin cancer that is frequently diagnosed at early stages. In most cases, surgical resection is curative. In case of thicker melanomas (> pT1b) without clinical or instrumental evidence of metastasis, a sentinel lymph node biopsy is recommended for staging purposes. If the lymph nodes are the only site of disease (macroscopic or microscopic> 1mm), configuring stage III, the international guidelines recommend the use of adjuvant therapy with checkpoint inhibitors (nivolumab or pembrolizumab) or targeted therapies (dabrafenib plus trametinib). These drugs have shown a significant increase in recurrence-free survival, although some doubts and open questions remain. Specifically, none of the available treatments has shown a clear benefit in the overall survival rates, the advantages they give in stage IIIA are not well known, and finally there are still no prospective clinical studies identifying the best approach to continue the therapeutic process in case of relapse. Furthermore, there are new opportunities opening up with the upcoming results of the neoadjuvant trials that could revolutionize the treatment of clinically evident stage III melanoma.

Aim: To describe treatment patterns among patients with stage III melanoma who underwent surgical excision in years 2011–2016, and assess outcomes among patients who subsequently received systemic adjuvant therapy versus watch-and-wait. Methods: Chart review of 380 patients from 17 melanoma centers in North America, South America and Europe. Results: Of 129 (34%) patients treated with adjuvant therapy, 85% received interferon α-2b and 56% discontinued treatment (mostly due to adverse events). Relapse-free survival was significantly longer for patients treated with adjuvant therapy versus watch-and-wait (hazard ratio = 0.63; p < 0.05). There was considerable heterogeneity in adjuvant treatment schedules and doses. Similar results were found in patients who received interferon-based adjuvant therapy. Conclusion: Adjuvant therapies with better safety/efficacy profiles will improve clinical outcomes in patients with stage III melanoma.

Abstract Background The variable prognosis in stage III cutaneous melanoma is partially due to unknown prognostic factors. Improved prognostic tools are required to define patients with an increased risk of developing metastatic disease who might benefit from adjuvant therapies. The aim was to examine if cellular immune markers in association with tumor proliferation rate and BRAF mutation status have an impact on prognosis in stage III melanoma. Methods We have used two sets of case series with stage III disease: 23 patients with short survival (≤ 13 months) and 19 patients with long survival (≥ 60 months). Lymph node metastases were analyzed for Ki67, CD8 and FOXP3 protein expression using immunohistochemistry. BRAF mutation status was analyzed in a previous study on the same samples. Results Low tumor proliferation rate was significantly associated with a better prognosis (p = 0.013). Presence of FOXP3+ T cells was not correlated to adverse clinical outcome. A highly significant trend for a longer survival was found in the presence of an increasing number of markers; CD8+ and FOXP3+ T cells, low tumor proliferation and BRAF wildtype status (p = 0.003). Presence of at least three of these four markers was found to be an independent favorable prognostic factor (OR 19.4, 95% CI 1.9-197, p = 0.012), when adjusting for ulceration and number of lymph node metastases. Proliferation alone remained significant in multivariate analyses (OR 26.1, 95% CI 2.0-344, p = 0.013) but with a wider confidence interval. This panel still remained independent when also adjusting for a previously identified prognostic glycolytic-pigment panel. Conclusions We have demonstrated that presence of immune cells in association with tumor proliferation and BRAF mutation status may further contribute to identify stage III melanoma patients with high risk of relapse.

Background: Health-related quality of life (HRQoL) is an important issue in the rapidly evolving field of adjuvant treatment for stage III melanoma. Dendritic cell vaccination is one of the adjuvant forms of therapy currently investigated. Methods: We enrolled adults with stage III melanoma to receive adjuvant dendritic cell vaccination after a complete radical lymph node dissection. HRQoL assessment was one of the secondary endpoints of this trial and investigated with the EORTC-QLQ-C30 questionnaire at baseline and week 26. Results: Fifteen patients with a median age of 50 years were included in the study, with twelve evaluable patients on study at time of the second questionnaire. Global health status and role functioning improved clinically relevant with a mean difference of 15 (p = 0.010) and 26 points (p = 0.005), respectively. Discussion: Despite the small number of patients, we found a clinically relevant improved global health status. Besides, compared to the other investigated therapies, toxicity of dendritic cell vaccination is low, which supports our finding. Conclusion: This is the first description of HRQoL in melanoma patients receiving dendritic cell vaccination. We show the expected improvement in global health status after surgical treatment of stage III melanoma. Thus, adjuvant dendritic cell vaccination does not seem to hamper this improvement, as shown in our small explorative study. [ABSTRACT FROM AUTHOR]

Background: The variable prognosis in stage III cutaneous melanoma is partially due to unknown prognostic factors. Improved prognostic tools are required to define patients with an increased risk of developing metastatic disease who might benefit from adjuvant therapies. The aim was to examine if cellular immune markers in association with tumor proliferation rate and BRAF mutation status have an impact on prognosis in stage III melanoma.Methods: We have used two sets of case series with stage III disease: 23 patients with short survival (≤ 13 months) and 19 patients with long survival (≥ 60 months). Lymph node metastases were analyzed for Ki67, CD8 and FOXP3 protein expression using immunohistochemistry. BRAF mutation status was analyzed in a previous study on the same samples.Results: Low tumor proliferation rate was significantly associated with a better prognosis (p = 0.013). Presence of FOXP3+ T cells was not correlated to adverse clinical outcome. A highly significant trend for a longer survival was found in the presence of an increasing number of markers; CD8+ and FOXP3+ T cells, low tumor proliferation and BRAF wildtype status (p = 0.003). Presence of at least three of these four markers was found to be an independent favorable prognostic factor (OR 19.4, 95% CI 1.9-197, p = 0.012), when adjusting for ulceration and number of lymph node metastases. Proliferation alone remained significant in multivariate analyses (OR 26.1, 95% CI 2.0-344, p = 0.013) but with a wider confidence interval. This panel still remained independent when also adjusting for a previously identified prognostic glycolytic-pigment panel.Conclusions: We have demonstrated that presence of immune cells in association with tumor proliferation and BRAF mutation status may further contribute to identify stage III melanoma patients with high risk of relapse. [ABSTRACT FROM AUTHOR]

Background After appropriate initial therapy for patients with stage II-III melanoma, there is no consensus regarding surveillance. Thus, follow-up is highly variable among institutions and individual providers. The National Comprehensive Cancer Network recommends routine clinical examination and consideration of imaging for stage IIB-IIIC every 3-12 mo with no distinction between stages. Detection of recurrence is important as novel systemic therapies and surgical resection of recurrence may provide survival benefits. Methods We retrospectively reviewed 369 patients with stage II and III melanoma treated at Ohio State University from 2009-2015, who underwent surgery as primary therapy. Two hundred forty-seven patients who were followed for a minimum of 6 mo after surgical resection to achieve no evidence of disease status (NED) were included in this analysis. One hundred twenty-two were lost to follow-up after surgery and were excluded. Results The rate of recurrence for stage IIA/IIB patients was 11% (14/125). Eleven of the 14 (79%) recurrences were detected by clinical symptoms or physical examination. Thirty-nine percent (49/125) of stage IIA or IIB patients were followed by clinical examination only, whereas 61% (76/125) were followed with at least two serial chest x-rays. The median time to first chest x-ray after NED status was 4.7 mo ( n = 76), median time to second chest x-ray after NED status was 12.7 mo ( n = 76), and 66% (50/76) continued to have additional serial chest x-rays. At median follow-up of 35 mo for the 125 patients with stage IIA/IIB, there was no difference in survival between those followed clinically (95% [95% CI: 0.88-0.99]) versus those followed with at least two serial x-rays (96% [95% CI: 0.89-0.98]). For stage IIC/IIIA-C patients, recurrence was detected in 23% (28/122) at median follow-up 31.2 mo. Fifty percent of recurrences were detected by imaging in asymptomatic patients, whereas 50% (14/28) had recurrence detected on imaging associated clinical findings. Eighty-seven percent (106/122) of stage IIC/IIIA-C patients were followed with at least two serial whole body positron emission tomography/computed tomography (CT) scans or whole body CT scans plus brain magnetic resonance imaging; median time between NED status and second scan was 10.3 mo. Of stage IIC/IIIA-C patients with recurrence, 57% (16/28) went on to surgical resection of the recurrence, whereas 11 (39%) patients received B-RAF inhibitor therapy, immune blockade therapy, or combination therapy. Conclusions For stage IIA and IIB melanoma, surveillance chest x-rays did not improve survival compared to physical examination alone. However, for stage IIC and IIIA-C melanoma, where the recurrence rates are higher, routine whole body imaging detected 50% of recurrences leading to additional surgery and/or treatment with novel systemic therapies for the majority of patients. Detection of melanoma recurrence is important and specific substage should be used to stratify risk and define appropriate follow-up. [ABSTRACT FROM AUTHOR]

Risk stratification of sentinel lymph node biopsy (SNB)-positive patients with malignant melanoma differs among current classification systems. To improve classification of patients with rapidly progressive disease who may profit from adjuvant therapy with novel immune or targeted treatment modalities, a single-center retrospective analysis was performed including all melanoma patients diagnosed with a positive SN at a university-based skin cancer center over a 10-year period (2002-2012) (96 of 419 patients). Sentinel node metastasis mitotic rate (SN-MMR) and further histologic parameters were determined by blinded histological re-evaluation and correlated with clinical follow-up (overall [OS], melanoma-specific [MSS], and disease-free survival [DFS]). Median follow-up was 53 months. In univariate analyses, SN tumor penetrative depth (TPD), maximum tumor diameter (MTD), number of positive SN, SN-MMR and the S-, Rotterdam, RDC, Hannover I and II classification systems correlated with OS, MSS and DFS. Multivariate Cox regression analyses showed that a binary classification system based only on the SN-MMR (<1 vs. ≥1 mitoses/mm2) was the strongest independent prognostic indicator for all endpoints analyzed. Kaplan-Meier analyses confirmed binary SN-MMR to be superior to stratify patients into high- and low-risk groups (45.45% vs. 87.92% 5-yr MSS). The general prognostic validity of the published SN classification systems was confirmed. The novel SN-MMR classification system may improve discrimination of patients with slowly and rapidly progressive disease. We therefore propose its implementation into clinical practice as the SN-MMR can be easily and reliably determined in routine pathology reports. Its prognostic value for the selection of patients amenable to adjuvant therapies should be studied in clinical trials. [ABSTRACT FROM AUTHOR]

Background: Malign melanoma continues to present a severe health problem, and the incidence is still raising. Nodal status and ulceration of the primary melanoma are strong prognostic factors. The main treatment of node-positive melanomas (stage III) is complete lymph node dissection. The aim of this study was to describe the outcome in patients with stage III melanoma who underwent completion lymphadenectomy at a department of plastic surgery. Methods: Retrospectively, we included all patients who underwent complete lymph node dissection in the period from 2008 to 2012 subsequent to a positive sentinel node biopsy or palpable metastasis from a cutaneous malign melanoma. Primary outcomes were disease-free survival and melanoma-specific survival. Results: We included 150 patients with an average age of 57 (16-82) years. Melanoma thickness was 3.1 (0.53-15) mm. Ulceration of primary tumor was present in 35 %. Complete lymph node dissection was performed in the neck, axilla, inguinal region, and aberrant region. There was no difference in occurrence of nodal metastases comparing the regions. Seroma was most frequent in the axilla (23.5 %) and inguinal region (18.9 %). Lymphedema occurred in the inguinal region (15.1 %) and the axilla (4.7 %), and wound infection occurred in the inguinal region (30.2 %), the axilla (15.3 %), and the neck (11.1 %). The 5-year nodal recurrence rate was 16.9 % [95 % CI 8.2-33.1 %] and the 5-year rate of distant metastases was 48.3 % [95 % CI 36.5-61.8 %]. Overall survival was 51.8 % [95 % CI 35.6-65.8 %]. More than two nodal metastases worsened the prognosis (reference: <2 lymph nodes). Level of Evidence: Level IV, risk/prognostic study. [ABSTRACT FROM AUTHOR]

Introduction When sentinel lymph node is positive for metastasis (exclusion for micro-metastasis) and in cases of palpable adenopathy, a lymphadenectomy should be performed. Many incisional surgical approach have been described in literature. We perform two type of incision (vertical with skin excision and transversal) for inguinal lymphadenectomy. The aim of this study was to compare post-operative morbidity between these two approach in cases of Stage III Melanoma. We analysed chronic lymphoedeme, skin necrosis, wound dehiscence, wound infection and seroma rates between the two techniques. Methods From April 2000 to February 2012 fifty-three patients underwent to inguinal lymphadenectomy for Stage III melanoma at CHU of Rennes. Patients were stratified in 2 groups according to the surgical approach, group 1 with a vertical incision with skin excision and group 2 with a transverse incision. Results Chronic lymphoedema rate for group 1 was 37.04% and for group 2 rate was 26.92%, this complication was lower un group 2 but no significant difference was observed ( p = 0.558). Skin necrosis ( p = 0.235), wound dehiscence ( p = 1.000), wound infection ( p = 0.236) and seroma ( p = 0.757) were not significantly different. Two cases of skin necrosis were observed in group 2 (7.69%) and none in group 1. Conclusion We do not found significant difference for chronic lymphoedema between these two approach. However, we had less lymphoedema with the transversal technique which has the advantage to reduce the skin suffering when external iliac lymphadenectomy dissection is necessary in addition to the inguinal lymphadenectomy. [ABSTRACT FROM AUTHOR]

New prognostic markers are needed for malignant melanoma. Inducible nitric oxide synthase (iNOS) and cyclooxygenase type 2 (COX-2) have been described to correlate with progression of melanoma. Moreover, activating mutations in BRAF/NRAS oncogenes are often detected in melanoma. The BRAF/NRAS mutation status and expression of COX-2 and iNOS were examined to compare their prognostic value for overall survival (OS) in stage III malignant cutaneous melanoma. The expression of iNOS and COX-2 in metastatic lymph nodes from 21 rapidly progressing (OS from date of diagnosis of stage III disease ≤14 months) and 17 slowly progressing (OS ≥60 months) stage III cutaneous melanoma patients was examined by immunohistochemistry. The presence of BRAF/NRAS mutations was analyzed using direct DNA sequencing. χ2 exact trend test and logistic regression analysis were used for statistical analysis. Both iNOS ( P = 0.002) and COX-2 ( P = 0.048) alone significantly predicted OS. The BRAF/NRAS mutation status did not significantly differ between patient groups, although iNOS significantly ( P = 0.013) correlated with BRAF mutation frequency. Furthermore, the odds ratio (OR) with respect to OS of iNOS (OR = 10.4) was higher than that of COX-2 (OR = 5.6) and was stable in the multivariate analysis of OS together with disease stage IIIB/C, ulceration, number of metastatic lymph nodes, and Breslow tumor thickness. Our data show that iNOS is an independent and stronger prognostic factor for OS in stage III malignant cutaneous melanoma than COX-2. [ABSTRACT FROM AUTHOR]

Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a patient is found to have American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage III or IV melanoma (i.e., any metastatic spread beyond the primary tumour) and that patient's BRAF mutation status is hitherto unknown, even if BRAF mutation testing has not been specifically requested by the treating clinician (in Australia, Medicare-subsidised BRAF V600 mutation testing does not need to be requested by the treating clinician). When performed in centres with appropriate expertise and experience, immunohistochemistry (IHC) using the anti-BRAF V600E monoclonal antibody (VE1) can be a highly sensitive and specific means of detecting BRAF V600E mutations, and may be used as a rapid and relatively inexpensive initial screening test. However, VE1 immunostaining can be technically challenging and difficult to interpret, particularly in heavily pigmented tumours; melanomas with weak, moderate or focal BRAF V600E immunostaining should be regarded as equivocal. It must also be remembered that other activating BRAF V600 mutations (including BRAF V600K ), which account for ∼10-20% of BRAF V600 mutations, are not detected with currently available IHC antibodies. For these reasons, if available and practicable, we recommend that DNA-based BRAF mutation testing always be performed, regardless of whether IHC-based testing is also conducted. Advice about tissue/specimen selection for BRAF mutation testing of patients diagnosed with stage III or IV melanoma is also offered in this article; and potential pitfalls when interpreting BRAF mutation tests are highlighted., (Copyright © 2021 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Background: This study addresses the yield and clinical impact of computed tomography (CT) imaging in otherwise asymptomatic patients with stage III melanoma metastatic to the regional nodes. Methods: The database from the University of Michigan Mutlidisciplinary Melanoma Clinic was reviewed and identified 127 asymptomatic patients with stage III melanoma (regional nodal disease) who received CT scans of the head, chest, abdomen, and/or pelvis. Scans were confirmed as true positive, false positive, and normal. Results: Four hundred twenty-six head and body CT scans were performed at the time of presentation of stage III disease. Twenty patients had a true-positive CT scan revealing unsuspected metastases. Fifteen patients had abnormal CT scans subsequently shown to be a benign process or second malignancy. The incidence of true-positive CT scans was not different between the groups of patients who had clinically apparent versus occult nodal disease. There was a significantly higher incidence of abdominal and pelvic metastatic sites identified by CT scan in patients with inguinal nodal disease compared with axillary or head and neck node-positive patients. Conclusions: The yield of detection of unsuspected metastases by CT scans in asymptomatic patients with stage III melanoma was not insignificant. Because patients with resected stage III disease are recommended to have adjuvant interferon-α for 1 year, CT staging plays an important role in identifying appropriate candidates for treatment. The toxicity of interferon-α therapy is not insignificant. The value of routine CT in asymptomatic patients with nodal metastasis deserves further prospective study. [ABSTRACT FROM AUTHOR]

Melanoma is a form of skin cancer that is frequently diagnosed at early stages. In most cases, surgical resection is curative. In case of thicker melanomas (> pT1b) without clinical or instrumental evidence of metastasis, a sentinel lymph node biopsy is recommended for staging purposes. If the lymph nodes are the only site of disease (macroscopic or microscopic> 1mm), configuring stage III, the international guidelines recommend the use of adjuvant therapy with checkpoint inhibitors (nivolumab or pembrolizumab) or targeted therapies (dabrafenib plus trametinib). These drugs have shown a significant increase in recurrence-free survival, although some doubts and open questions remain. Specifically, none of the available treatments has shown a clear benefit in the overall survival rates, the advantages they give in stage IIIA are not well known, and finally there are still no prospective clinical studies identifying the best approach to continue the therapeutic process in case of relapse. Furthermore, there are new opportunities opening up with the upcoming results of the neoadjuvant trials that could revolutionize the treatment of clinically evident stage III melanoma., Competing Interests: Competing interests: The authors have no conflicts of interest to disclose., (©2021 De Falco et al.)

Aim: To describe treatment patterns among patients with stage III melanoma who underwent surgical excision in years 2011-2016, and assess outcomes among patients who subsequently received systemic adjuvant therapy versus watch-and-wait., Methods: Chart review of 380 patients from 17 melanoma centers in North America, South America and Europe., Results: Of 129 (34%) patients treated with adjuvant therapy, 85% received interferon α-2b and 56% discontinued treatment (mostly due to adverse events). Relapse-free survival was significantly longer for patients treated with adjuvant therapy versus watch-and-wait (hazard ratio = 0.63; p < 0.05). There was considerable heterogeneity in adjuvant treatment schedules and doses. Similar results were found in patients who received interferon-based adjuvant therapy., Conclusion: Adjuvant therapies with better safety/efficacy profiles will improve clinical outcomes in patients with stage III melanoma., Competing Interests: Financial & competing interests disclosure This study was funded by Novartis Pharmaceuticals Corporation. P Mohr: honoraria: Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Pierre Fabre, Novartis, Sanofi and Roche. F Kiecker: advisory boards: Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi and Roche; honoraria: Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre and Roche; clinical trial participation (principal investigator): Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi and Roche. R Koneru: research funding from Novartis; advisory boards: Novartis, Bristol-Myers Squibb, Merck. O Dereure: advisory board or honoraria and travel support: Bristol-Myers Squibb, Merck Sharp and Dohme, Roche, Novartis, Pierre Fabre, Sanofi. P Saiag: personal fees: Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Merck-Serono, Pfizer, Roche-Genentech, Pierre Fabre and Novartis; nonfinancial support from Bristol-Myers Squibb, Merck Sharp & Dohme, Roche-Genentech and Novartis. J Utikal: advisory board or honoraria and travel support: Amgen, Bristol-Myers Squibb, GlaxoSmithKline, LeoPharma, Merck Sharp & Dohme, Novartis, Pierre Fabre and Roche. C Robert: honoraria: Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Pierre Fabre, Novartis, Sanofi and Roche. F Cuadros received research funding from Novartis; advisory boards: Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme; speakers bureau: Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme. RU Villarroel: Advisory Board: Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb; honoraria: Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb; clinical trial participation principal investigator: Novartis, Merck Sharp & Dohme. YG Najjar: research funding: Merck; advisory board: Array Biopharma; clinical trial participation: Novartis, Genentech, Merck and Array Biopharma. L Kottschade: advisory board: Array BioPharma; research funding: Bristol-Myers Squibb. EM Couselo: advisory board: Amgen, Bristol-Myers Squibb, Merck, Sharp & Dohme, Novartis, Pierre Fabre, Sanofi and Roche; honoraria: Amgen, Bristol-Myers Squibb, Merck, Sharp & Dohme, Novartis, Pierre Fabre and Roche; clinical trial participation (principal investigator): Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Sharp & Dohme, Novartis, Pierre Fabre, Sanofi and Roche. R Koruth is an employee of Novartis Pharmaceutical Corporation. A Guérin, R Burne and R Ionescu-Ittu are employees of Analysis Group, Inc., which has received consulting fees from Novartis. M Perrinjaquet is an employee of Navigant Germany GmbH, whose parent company has received consulting fees from Novartis. JS Zager: research funding: Novartis, Amgen, Philogen, Provectus, Delcath Systems, Castle Biosciences; advisory boards: Merck and Array Biopharma; medical advisory board: Delcath Systems; consulting: Philogen; speakers bureau: Sun Pharma and Array Biopharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Medical writing assistance was provided by S Rochette and G DeWalt, employees of Analysis Group, Inc.; support for this assistance was provided by Novartis Pharmaceuticals Corporation. Data collection was coordinated by M Perrinjaquet and E Chater, employees of Navigant, while support for this assistance was provided by Novartis Pharmaceuticals Corporation., (© 2019 The authors.)

The publication of recent randomized trials has prompted a significant shift in both our understanding and the management of patients with melanoma. Here, the current management of the regional lymph nodes in patients with melanoma is discussed. This review focuses on selection for sentinel lymph node biopsy, management of the positive sentinel node, management of the clinically positive node, and the controversy over the therapeutic value of early nodal intervention., (© 2018 Wiley Periodicals, Inc.)

Background and Objectives: Stage III malignant melanoma is a heterogeneous disease where those cases deemed marginally resectable or irresecatble are frequently incurable by surgery alone. Targeted therapy takes advantage of the high incidence of BRAF mutations in melanomas, most notably the V600E mutation. These agents have rarely been used in a neoadjuvant setting prior to surgery., Methods: Thirteen consecutive patients with confirmed BRAF V600E regionally advanced melanoma deemed marginally resectable or irrresectable, were treated with BRAF inhibiting agents, prior to undergoing surgery. The primary outcome measures were a successful resection and pathological response. Disease-free survival was a secondary outcome measure., Results: Overall, 12/13 patients showed a marked clinical responsiveness to medical treatment, enabling a macroscopically successful resection in all cases. Four patients had a complete pathological response with no viable tumor evident in the resected specimens and eight patients showed evidence of minimally residual tumor with extensive tumoral necrosis and fibrosis. One patient progressed and died before surgery. At a median follow up of 20 months, 10 patients remain free of disease., Conclusions: Perioperative treatment with BRAF inhibiting agents in BRAFV600E mutated Stage III melanoma patients facilitates surgical resection and affords satisfactory disease free survival., (© 2017 Wiley Periodicals, Inc.)

Purpose: To determine the effectiveness of adjuvant dendritic cell (DC) vaccination to induce tumor-specific immunological responses in stage III melanoma patients. Experimental design: Retrospective analysis of stage III melanoma patients, vaccinated with autologous monocyte-derived DC loaded with tumor-associated antigens (TAA) gp100 and tyrosinase after radical lymph node dissection. Skin-test infiltrating lymphocytes (SKILs) obtained from delayed-type hypersensitivity skin-test biopsies were analyzed for the presence of TAA-specific CD8+T cells by tetrameric MHC-peptide complexes and by functional TAA-specific T cell assays, defined by peptide-recognition (T2 cells) and/or tumor-recognition (BLM and/or MEL624) with specific production of Th1 cytokines and no Th2 cytokines. Results: Ninety-seven patients were analyzed: 21 with stage IIIA, 34 with stage IIIB, and 42 had stage IIIC disease. Tetramer-positive CD8+T cells were present in 68 patients (70%), and 24 of them showed a response against all 3 epitopes tested (gp100:154–162, gp100:280–288, and tyrosinase:369–377) at any point during vaccinations. A functional T cell response was found in 62 patients (64%). Rates of peptide-recognition of gp100:154–162, gp100:280–288, and tyrosinase:369–377 were 40%, 29%, and 45%, respectively. Median recurrence-free survival and distant metastasis-free survival of the whole study population were 23.0 mo and 36.8 mo, respectively. Conclusions: DC vaccination induces a functional TAA-specific T cell response in the majority of stage III melanoma patients, indicating it is more effective in stage III than in stage IV melanoma patients. Furthermore, performing multiple cycles of vaccinations enhances the chance of a broader immune response. [ABSTRACT FROM AUTHOR]

Locoregional spread of melanoma to its draining lymph node basin is the strongest negative prognostic factor for patients. Exclusive of clinical trials, patients with sentinel lymph node-positive (microscopic) or clinically palpable (macroscopic) nodal disease should undergo lymphadenectomy. This article reviews the management and technical aspects of surgical care for regional metastases. Adjunct therapies (immunotherapy, targeted therapy, and radiation) may supplement lymphadenectomy in certain patient populations. Surgical morbidity after lymphadenectomy can be substantial, creating opportunities for improvement via minimally invasive techniques or refined patient selection., (Copyright © 2015 Elsevier Inc. All rights reserved.)

30-44% of patients with clinical groin node melanoma have involved pelvic nodes. Clinical guidelines selectively target pelvic lymph node dissection (PLND) to those meeting radiological and clinico-pathological criteria, but we lack satisfactory diagnostic tools to preoperatively identify patients with pelvic node disease. We evaluate routine PLND for all patients undergoing superficial node dissection (SLND), performed as a combined single-stage ilioinguinal lymph node dissection (ILND). Retrospective analysis of 67 ILNDs in consecutive patients presenting with palpable, cytologically melanocytic groin nodes. We examine predictors of pelvic node status and determine efficacy of 2010 UK guidelines in patient selection for PLND. 28 patients (42%) had histologically positive pelvic nodes; half had just one involved node (53.6%). 43% of pelvic metastases were radiologically occult. Significant predictors of pelvic melanoma were stage N3 groin nodes (p = 0.049), one third of groin nodes involved (p = 0.0009), positive Cloquet's node (p = 0.005), previous in transit disease (p = 0.001), and staging CT (p = 0.007). UK guidelines, primarily reliant upon staging CT, were effective selection criteria (p = 0.04), identifying 57% of pelvic metastases. CT and in-transit disease status in combination was the strongest predictor of pelvic disease (p = 0.006, RR 4.5, PPV 0.75, NPV 0.83). A combined CT and in-transit disease status provides a potentially clinically useful preoperative selection tool for ILND. With a high prevalence of occult pelvic node involvement, potential to avoid the morbidity of untreated pelvic nodes, and 5 year survival figures of 24-35% following surgery, we advocate ILND in all patients with clinically evident melanoma in a single groin node., (Copyright © 2014 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)