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Purpose: Neoadjuvant anti-PD-1 therapy in melanoma may increase tumor-infiltrating lymphocytes (TIL), and more TIL are associated with better treatment response. A major pathologic response (MPR) in melanoma after neoadjuvant anti-PD-1 therapy usually comprises tumor necrosis and fibrosis. The role of TIL in necrotic tumor necrosis (nTIL) has not been explored., Experimental Design: We performed CD3 and CD8 IHC stains on 41 melanomas with geographic necrosis. Of the 41, 14 were immunotherapy-naïve, and 27 had been treated with one dose of neoadjuvant anti-PD-1 in two clinical trials. CD3+ and CD8+ nTIL were graded as absent/minimal or moderate/brisk. The percentage of necrotic areas in the tumor bed before and after treatment was quantified. The endpoints were MPR and 5-year recurrence-free survival (RFS)., Results: In the immunotherapy-naïve cohort, 3/14 (21%) specimens had moderate/brisk CD3+, and 2/14 (14%) had moderate/brisk CD8+ nTIL. In the treated cohort, 16/27 (59%) specimens had moderate/brisk CD3+, and 15/27 (56%) had moderate/brisk CD8+ nTIL, higher than those of the naïve cohort (CD3, P = 0.046; CD8, P = 0.018). Tumor necrosis was significantly increased after anti-PD-1 therapy (P = 0.007). In the treated cohort, moderate/brisk CD3+ and CD8+ nTIL correlated with MPR (P = 0.042; P = 0.019, respectively). Treated patients with moderate/brisk CD3+ nTIL had higher 5-year RFS than those with absent/minimal nTIL (69% vs. 0%; P = 0.006). This persisted on multivariate analysis (HR, 0.16; 95% confidence interval, 0.03-0.84; P = 0.03), adjusted for pathologic response, which was borderline significant (HR, 0.26; 95% confidence interval, 0.07-1.01; P = 0.051)., Conclusions: CD3+ and CD8+ nTIL are associated with pathologic response and 5-year RFS in patients with melanoma after neoadjuvant anti-PD-1 therapy., (©2024 American Association for Cancer Research.)

Background: While neoadjuvant immunotherapy for melanoma has shown promising results, the data have been limited by a relatively short follow-up time, with most studies reporting 2-year outcomes. The goal of this study was to determine long-term outcomes for stage III/IV melanoma patients treated with neoadjuvant and adjuvant programmed cell death receptor 1 (PD-1) inhibition., Patients and Methods: This is a follow-up study of a previously published phase Ib clinical trial of 30 patients with resectable stage III/IV cutaneous melanoma who received one dose of 200 mg IV neoadjuvant pembrolizumab 3 weeks before surgical resection, followed by 1 year of adjuvant pembrolizumab. The primary outcomes were 5-year overall survival (OS), 5-year recurrence-free survival (RFS), and recurrence patterns., Results: We report updated results at 5 years of follow-up with a median follow-up of 61.9 months. No deaths occurred in patients with a major pathological response (MPR, <10% viable tumor) or complete pathological response (pCR, no viable tumor) (n = 8), compared to a 5-year OS of 72.8% for the remainder of the cohort (P = 0.12). Two of eight patients with a pCR or MPR had a recurrence. Of the patients with >10% viable tumor remaining, 8 of 22 patients (36%) had a recurrence. Additionally, the median time to recurrence was 3.9 years for patients with ≤10% viable tumor and 0.6 years for patients with >10% viable tumor (P = 0.044)., Conclusions: The 5-year results from this trial represent the longest follow-up of a single-agent neoadjuvant PD-1 trial to date. Response to neoadjuvant therapy continues to be an important prognosticator with regard to OS and RFS. Additionally, recurrences in patients with pCR occur later and are salvageable, with a 5-year OS of 100%. These results demonstrate the long-term efficacy of single-agent neoadjuvant/adjuvant PD-1 blockade in patients with a pCR and the importance of long-term follow-up for these patients., Trial Registration: Clinicaltrials.gov, NCT02434354., Competing Interests: Disclosure GCK serves on an advisory board of Merck. All remaining authors have declared no conflicts of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Given the results of the recent KEYNOTE-716 trial, the performance of sentinel lymph node (SLN) biopsy for patients with clinical stage IIB/C melanoma has been questioned., Objective: Determine the utility of SLN status in guiding the recommendations for adjuvant therapy., Methods: Patients with clinical stage IIB/C cutaneous melanoma who underwent wide local excision and SLN biopsy between 2004 and 2011 were identified from the Surveillance, Epidemiology, and End Results database. Two prognostic models, with and without SLN status, were developed predicting risk of melanoma-specific death (MSD). The primary outcome was net benefit at treatment thresholds of 20% to 40% risk of 5-year MSD., Results: For the 4391 patients included, the 5-year MSD rate was 46%. The model estimating 5-year MSD risk that included SLN status provided greater net benefit at treatment thresholds from 30% to 78% compared to the model without SLN status. The added net benefit for the SLN biopsy-containing model persisted in subgroup analysis of patients in different age groups and with various T stages., Limitations: Retrospective study., Conclusions: A prognostic model with SLN status estimating patient risk for 5-year MSD provides superior net benefit compared to a model with primary tumor staging factors alone for threshold mortality rates ≥30%., Competing Interests: Conflicts of interest Bartlett receives institutional research support from SkylineDx and discloses an honorarium from Excite International. Karakousis is a PI of an investigator-initiated trial with institutional support by Merck and serves on the Merck advisory board. The other authors have no conflict to disclose., (Copyright © 2022 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Sentinel lymph node biopsy is not routinely recommended for T1a cutaneous melanoma due to the overall low risk of positivity. Prognostic factors for positive sentinel lymph node (SLN + ) in this population are poorly characterized., Objective: To determine factors associated with SLN + in patients with T1a melanoma., Methods: Patients with pathologic T1a (<0.80 mm, nonulcerated) cutaneous melanoma from 5 high-volume melanoma centers from 2001 to 2020 who underwent wide local excision with sentinel lymph node biopsy were included in the study. Patient and tumor characteristics associated with SLN + were analyzed by univariate and multivariable logistic regression analyses. Age was dichotomized into ≤42 (25% quartile cutoff) and >42 years., Results: Of the 965 patients identified, the overall SLN + was 4.4% (N = 43). Factors associated with SLN + were age ≤42 years (7.5% vs 3.7%; odds ratio [OR], 2.14; P = .03), head/neck primary tumor location (9.2% vs 4%; OR, 2.75; P = .04), lymphovascular invasion (21.4% vs 4.2%; OR, 5.64; P = .01), and ≥2 mitoses/mm 2 (8.2% vs 3.4%; OR, 2.31; P = .03). Patients <42 years with ≥2 mitoses/mm 2 (N = 38) had a SLN +  rate of 18.4%., Limitations: Retrospective study., Conclusion: SLN + is low in patients with T1a melanomas, but younger age, lymphovascular invasion, mitogenicity, and head/neck primary site appear to confer a higher risk of SLN + ., Competing Interests: Conflicts of interest Faries serves on the advisory boards for Novartis, Bristol Myers Squibb, Merck, Sanofi, Array Bioscience, and Nektar Biofarma. Shannon, Sharon, Straker, Carr, Sinnamon, Bogatch, Thaler, Kelly, Vetto, Fowler, DePalo, Miura, Zager, and Karakousis have no conflicts of interest to declare., (Copyright © 2022 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Immediate completion lymph node dissection (CLND) for patients with sentinel lymph node (SLN) metastasis from cutaneous melanoma has been replaced largely by ultrasound nodal surveillance since the publication of two landmark trials in 2016 and 2017. National practice patterns of CLND remain poorly characterized., Methods: Patients with a diagnosis of cutaneous melanoma in 2016 and 2018 without clinical nodal disease who underwent sentinel lymph node biopsy (SLNB) were identified from the National Cancer Database (NCDB). Characteristics associated with CLND were analyzed by uni- and multivariate logistic regression. Overall survival (OS) was estimated using Kaplan-Meier and Cox proportional hazards regression analyses., Results: Of the 3517 patients included in the study, 1405 had disease diagnosed in 2016. The patients with cutaneous melanoma diagnosed in 2016 had a median age of 60 years and a tumor thickness of 2.3 mm compared to 62 years and 2.4 mm, respectively, for the patients with cutaneous melanoma diagnosed in 2018. According to the NCDB, 40 % (n = 559) of the patients underwent CLND in 2016 compared with 6 % (n = 132) in 2018. The factors associated with receipt of CLND in 2018 included younger age (odds ratio [OR], 0.97; 95 % confidence interval [CI], 0.95-0.99; p = 0.001), rural residence (OR, 3.96; 95 % CI, 1.50-10.49; p = 0.006), head/neck tumor location (OR, 1.88; 95 % CI, 1.10-3.23; p = 0.021), and more than one positive SLN (OR, 1.80; 95 % CI, 1.17-2.76; p = 0.007). The 5-year OS did not differ between the patients who received SLNB only and those who underwent CLND (hazard ratio [HR], 0.93; p = 0.54)., Conclusion: The rates of CLND have decreased nationally. However, patients with head/neck primary tumors who live in rural locations are more likely to undergo CLND, highlighting populations for which treatment may be non-uniform with national practice patterns., (© 2022. Society of Surgical Oncology.)

Background and Objectives: Type II diabetes mellitus (T2DM) can lead to an immunosuppressed state, but whether T2DM is associated with worse outcomes for patients with melanoma has not been well studied., Methods: Consecutive patients diagnosed with clinical stage I-II cutaneous melanoma who underwent sentinel lymph node biopsy at a single institution (2007-2016) were identified. Melanoma characteristics and recurrence/survival outcomes were compared between patients with and without T2DM at the time of melanoma diagnosis., Results: Of 1128 patients evaluated, 111 (9.8%) had T2DM (n = 94 [84.7%] non-insulin dependent [NID-T2DM]; n = 17 [15.3%] insulin dependent [ID-T2DM]). T2DM patients were more likely to be older (odds ratio [OR] 1.04, p < 0.001), male (OR 2.15, p = 0.003), have tumors >1.0 mm (OR 1.88, p = 0.023), and have microsatellitosis (OR 2.29, p = 0.030). Five-year cumulative incidence of melanoma recurrence was significantly higher for patients with ID-T2DM (46.7% ID-T2DM vs. 25.7% NID-T2DM vs. 17.1% no T2DM, p < 0.001), and on multivariable analysis, ID-T2DM was independently associated with melanoma recurrence (hazard ratio 2.57, p = 0.015). No difference in 5-year disease-specific survival was observed between groups., Conclusions: ID-T2DM appears to be associated with more advanced melanoma and increased risk for melanoma recurrence. Further study as to whether this reflects differences in tumor biology or host factors is warranted., (© 2022 Wiley Periodicals LLC.)

Background: Approval of adjuvant anti-programmed cell death protein 1 therapy for pathologic stage IIB/C cutaneous melanoma has led some to question the role of sentinel lymph node (SLN) biopsy in the clinical stage IIB/C disease., Objective: To determine the prognostic significance of SLN staging on disease-specific survival (DSS) for clinical stage IIB/C primary cutaneous melanoma in the preimmunotherapy era., Methods: A retrospective cohort study was performed evaluating patients who underwent excision of clinical stage IIB/C cutaneous melanoma using the Surveillance, Epidemiology, and End Results database (2004-2011). Patients who did and did not undergo SLN biopsy were compared using propensity matching, and among those who underwent SLN biopsy, matched patients were further stratified by SLN status (SLN positive [SLN+] or SLN negative [SLN-])., Results: Of the 8562 patients evaluated, 6021 (70.3%) underwent SLN biopsy. SLN positivity was associated with significantly reduced 5-year DSS among matched patients who underwent SLN biopsy (47.1% SLN+ vs 75.5% SLN-; P < .001). Five-year DSS remained significantly different across matched T-stages: T3b (54.2% SLN+ vs 64.8% SLN-; P = .004), T4a (55.5% SLN+ vs 71.6% SLN-; P = .001), and T4b (38.6% SLN+ vs 60.9% SLN-; P < .001)., Limitations: Retrospective study., Conclusion: For patients with clinical stage IIB/C cutaneous melanoma, SLN status provides essential prognostic information., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2022 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The prognostic impact of tumor-infiltrating lymphocytes (TILs) on outcomes and treatment efficacy for patients with melanoma in the contemporary era remains poorly characterized., Methods: Consecutive patients who underwent wide excision and sentinel lymph node biopsy for cutaneous melanoma 1 mm thick or thicker at a single institution were identified (2006-2019). The patients were stratified based on primary tumor TIL status as brisk (bTILs), non-brisk (nbTILs), or absent (aTILs). Associations between patient factors and outcomes were analyzed using multivariable analysis., Results: Of the 1017 patients evaluated, 846 (83.2 %) had primary TILs [nbTILs (n = 759, 89.7 %) and bTILs (n = 87, 10.3 %)]. In the multivariable analysis, the patients with any type of TILs had higher rates of regression [odds ratio (OR), 1.86; p = 0.016], lower rates of acral lentiginous histology (OR, 0.22; p < 0.001), and lower rates of SLN positivity (OR, 0.64; p = 0.042) than those without TILs. The multivariable analysis found no association between disease-specific survival and bTILs [hazard ratio (HR), 1.04; p = 0.927] or nbTILs (HR, 0.89; p = 0.683). An association was found between bTILs and recurrence-free survival (RFS) advantage [bTILs (HR 0.46; p = 0.047), nbTILs (HR 0.71; p = 0.088)], with 5-year RFS rates of 84 % for bTILs, 71.8 % for nbTILs, and 68.4 % for aTILs (p = 0.044). For the 114 immune checkpoint blockade (ICB)-naïve patients who experienced a recurrence treated with ICB therapy, no association was observed between progression-free survival and bTILs (HR, 0.64; p = 0.482) or nbTILs (HR, 0.58; p = 0.176)., Conclusions: The prognostic significance of primary TILs in the contemporary melanoma era appears complex. Further studies characterizing the phenotype of TILs and their association with regional metastasis and responsiveness to ICB therapy are warranted., (© 2022. Society of Surgical Oncology.)

Competing Interests: Conflicts of interest None disclosed.

Competing Interests: Conflicts of interest None disclosed.

Abstract: Dual immunohistochemical (IHC) staining with D2-40 and S100 improves detection of lymphatic invasion (LI) in primary cutaneous melanoma. However, limited data exist evaluating this technique using other melanocytic markers, and thus, the optimal marker for detection of LI is unestablished. To address this knowledge gap, a case-control study was performed comparing melanoma specimens from 22 patients with known lymphatic spread (LS) with a control group of 11 patients without LS. Specimens underwent dual IHC staining with D2-40 and MART-1, SOX-10, and S100 to evaluate for LI. Receiver operating characteristic analysis was used to estimate each stain's accuracy for detection of LI. The LS group was more likely to be ≥65 years (P = 0.04), have a tumor thickness of ≥1 mm (P < 0.01), and have ulcerated tumors (P = 0.02). Detection of LI with D2-40/MART-1 significantly correlated with LS (P = 0.03), and the D2-40/MART-1 stain was most accurate for LI based on receiver operating characteristic curve analysis (area under the curve [AUC] 0.705) in comparison with D2-40/SOX-10 (AUC 0.575) and D2-40/S100 (AUC 0.633). These findings suggest that MART-1 may be the optimal melanocytic marker to combine with D2-40 for detection of LI in melanoma. Further studies are needed to determine the utility of routinely performing these stains for histopathologic analysis of melanoma., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Sentinel lymph node biopsy (SLNB) has not been studied for invasive melanomas treated with Mohs micrographic surgery using frozen-section MART-1 immunohistochemical stains (MMS-IHC). The primary objective of this study was to assess the accuracy and compliance with National Comprehensive Cancer Network (NCCN) guidelines for SLNB in a cohort of patients who had invasive melanoma treated with MMS-IHC., Methods: This retrospective cohort study included all patients who had primary, invasive, cutaneous melanomas treated with MMS-IHC at a single academic center between March 2006 and April 2018. The primary outcomes were the rates of documenting discussion and performing SLNB in patients who were eligible based on NCCN guidelines. Secondary outcomes were the rate of identifying the sentinel lymph node and the percentage of positive lymph nodes., Results: In total, 667 primary, invasive, cutaneous melanomas (American Joint Committee on Cancer T1a-T4b) were treated with MMS-IHC. The median patient age was 69 years (range, 25-101 years). Ninety-two percent of tumors were located on specialty sites (head and/or neck, hands and/or feet, pretibial leg). Discussion of SLNB was documented for 162 of 176 (92%) SLNB-eligible patients, including 127 of 127 (100%) who had melanomas with a Breslow depth >1 mm. SLNB was performed in 109 of 176 (62%) SLNB-eligible patients, including 102 of 158 melanomas (65%) that met NCCN criteria to discuss and offer SLNB and 7 of 18 melanomas (39%) that met criteria to discuss and consider SLNB. The sentinel lymph node was successfully identified in 98 of 109 patients (90%) and was positive in 6 of those 98 patients (6%)., Conclusions: Combining SLNB and MMS-IHC allows full pathologic staging and confirmation of clear microscopic margins before reconstruction of specialty site invasive melanomas. SLNB can be performed accurately and in compliance with consensus guidelines in patients with melanoma using MMS-IHC., (© 2021 American Cancer Society.)

Background: The Affordable Care Act's Medicaid expansion is associated with earlier diagnosis and improved care among lower socioeconomic status populations with cancer, but its impact on melanoma is undefined., Objective: To determine the association of Medicaid expansion with stage of diagnosis and use of sentinel lymph node biopsy in nonelderly adult patients with newly diagnosed clinically localized melanoma., Methods: Quasi-experimental, difference-in-differences retrospective cohort analysis using data from the National Cancer Database from 2010 to 2017. Patients from expansion versus nonexpansion states and diagnosed before (2010-2013) versus after (2014-2017) expansion were identified., Results: Of 83,322 patients, 46.6% were female, and the median age was 55 years (interquartile range, 49-60). After risk adjustment, Medicaid expansion was associated with a decrease in the diagnosis of T1b stage or higher melanoma (odds ratio [OR], 0.93; 95% confidence interval [CI], 0.88-0.98; P = .011) and decrease in uninsured status (OR, 0.61; 95% CI, 0.52-0.72; P < .001) but was not associated with a difference in sentinel lymph node biopsy performance when indicated (OR, 1.06; 95% CI, 0.95-1.20; P = .29)., Limitations: Retrospective study using a national database., Conclusion: In this study of patients with clinically localized melanoma, Medicaid expansion was associated with a decrease in the diagnosis of later T-stage tumors., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2021 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Isolated limb infusion (ILI) is a minimally invasive procedure for delivering high-dose chemotherapy to extremities affected by locally advanced or in-transit melanoma. This study compared the outcomes of melanoma patients treated with ILI in the United States of America (USA) and Australia (AUS)., Methods: Patients with locally recurrent in-transit melanoma treated with ILI at USA or AUS centers between 1992 and 2018 were identified. Demographic and clinicopathologic characteristics were collected. Primary outcomes of treatment response, in-field progression-free survival (IPFS), distant progression-free survival (DPFS), and overall survival (OS) were evaluated by the Kaplan-Meier method. Multivariable analysis evaluated whether availability of new systemic therapies affected outcomes., Results: More ILIs were performed in AUS (n = 411, 60 %) than in the USA (n = 276, 40 %). In AUS, more ILIs were performed for stage 3B disease than in the USA (62 % vs 46 %; p < 0.001). The reported complete response rates were similar (AUS 30 % vs USA 29 %). Among the stage 3B patients, AUS patients had better IPFS (p = 0.001), whereas DPFS and OS were similar between the two countries. Among the stage 3C patients, the USA patients had better OS (p < 0.001), whereas IPFS and DPFS were similar. Availability of new systemic therapies did not affect IPFS or DPFS in either country. However, the USA patients who received ILI after ipilimumab approval in 2011 had significantly improved OS (hazard ratio, 0.62; p = 0.013)., Conclusions: AUS patients were treated at an earlier disease stage than the USA patients with better IPFS for stage 3B disease. The USA patients treated after the availability of new systemic therapies had a better OS.

Introduction: Isolated limb infusion (ILI) is a minimally-invasive procedure for delivering high-dose regional chemotherapy to treat melanoma in-transit metastases confined to a limb. The aim of this international multi-centre study was to identify predictive factors for toxicity and response., Methods: Data of 687 patients who underwent a first ILI for melanoma in-transit metastases confined to the limb between 1992 and 2018 were collected at five Australian and four US tertiary referral centres., Results: After ILI, predictive factors for increased limb toxicity (Wieberdink grade III/IV limb toxicity, n = 192, 27.9%) were: female gender, younger age, procedures performed before 2005, lower limb procedures, higher melphalan dose, longer drug circulation and ischemia times, and increased tissue hypoxia. No patient experienced grade V toxicity (necessitating amputation). A complete response (n = 199, 28.9%) was associated with a lower stage of disease, lower burden of disease (BOD) and thinner Breslow thickness of the primary melanoma. Additionally, an overall response (combined complete and partial response, n = 441, 64.1%) was associated with female gender, Australian centres, procedures performed before 2005, lower limb procedures and lower actinomycin-D doses. On multivariate analysis, higher melphalan dose remained a predictive factor for toxicity, while lower stage of disease and lower BOD remained predictive factors for overall response., Conclusion: ILI is safe and effective to treat melanoma in-transit metastases. Predictive factors for toxicity and response identified in this study will allow improved patient selection and optimization of intra-operative parameters to increase response rates, while keeping toxicity low., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Isolated limb infusion (ILI) is used to treat in-transit melanoma metastases confined to an extremity. However, little is known about its safety and efficacy in octogenarians and nonagenarians (ON)., Patients and Methods: ON patients (≥ 80 years) who underwent a first ILI for American Joint Committee on Cancer seventh edition stage IIIB/IIIC melanoma between 1992 and 2018 at nine international centers were included and compared with younger patients (< 80 years). A cytotoxic drug combination of melphalan and actinomycin-D was used., Results: Of the 687 patients undergoing a first ILI, 160 were ON patients (median age 84 years; range 80-100 years). Compared with the younger cohort (n = 527; median age 67 years; range 29-79 years), ON patients were more frequently female (70.0% vs. 56.9%; p = 0.003), had more stage IIIB disease (63.8 vs. 53.3%; p = 0.02), and underwent more upper limb ILIs (16.9% vs. 9.5%; p = 0.009). ON patients experienced similar Wieberdink limb toxicity grades III/IV (25.0% vs. 29.2%; p = 0.45). No toxicity-related limb amputations were performed. Overall response for ON patients was 67.3%, versus 64.6% for younger patients (p = 0.53). Median in-field progression-free survival was 9 months for both groups (p = 0.88). Median distant progression-free survival was 36 versus 23 months (p = 0.16), overall survival was 29 versus 40 months (p < 0.0001), and melanoma-specific survival was 46 versus 78 months (p = 0.0007) for ON patients compared with younger patients, respectively., Conclusions: ILI in ON patients is safe and effective with similar response and regional control rates compared with younger patients. However, overall and melanoma-specific survival are shorter.

Background: Robotic pelvic lymphadenectomy (rPLND) has been demonstrated to be a safe and effective minimally invasive approach for patients with metastatic melanoma to the iliac nodes. However, the long-term oncologic benefit of this procedure remains poorly defined., Methods: A single-institutional study comparing perioperative outcomes and survival [recurrence-free (RFS) and overall survival (OS)] between rPLND and open PLND (oPLND) for metastatic melanoma was conducted., Results: From 2006 to 2018, a total of 63 PLND cases were identified: 22 rPLND and 41 oPLND. Evidence of isolated pelvic metastasis was the most common indication for PLND in both groups (rPLND: 64%, oPLND: 85%). There was no difference in median pelvic lymph node yield (11 vs. 9 nodes, p = 0.65). Neither treatment group experienced a Clavien-Dindo complication ≥ 3. rPLND was associated with a shorter length of stay compared with oPLND (2 vs. 4 days, p < 0.001). With a median follow-up of 37 months, there was no difference in RFS (14.4 vs. 9.6 months, p = 0.47) and OS (43 vs. 50 months, p = 0.58) between rPLND and oPLND, respectively. In basin recurrence was low with 1 (4.5%) and 3 (7.3%) patients in the rPLND and oPLND cohorts, respectively, experiencing an event (p = 0.9)., Conclusions: rPLND for metastatic melanoma is a safe, minimally invasive treatment strategy that appears to result in similar intermediate term recurrence and survival rates as oPLND but shorter hospital stays.

High-risk resectable melanoma poses therapeutic challenges as this subgroup remains most vulnerable for disease recurrence. Immunotherapy has established its efficacy in cases of advanced melanoma, and now is actively being investigated in the multimodal management of resectable disease. Daromun, an intralesional immunocytokine, has emerged as a unique immunotherapy in its ability to preferentially target tumor cells, resulting in direct destruction, while generating a bystander effect that leads to a distant treatment effect. On the basis of its mechanism of action, there is growing interest in delivering immune-based therapies in a neoadjuvant setting. In this review, the neo-DREAM study, a Phase III trial comparing the safety and efficacy of neoadjuvant Daromun for resectable stage IIIB/C melanoma will be described. Clinical Trial Registration Number: NCT03567889.

Background: Isolated limb infusion (ILI) is a minimally invasive procedure for delivering high-dose regional chemotherapy to patients with locally advanced or in-transit melanoma located on a limb. The current international multicenter study evaluated the perioperative and long-term oncologic outcomes for patients who underwent ILI for stage 3B or 3C melanoma., Methods: Patients undergoing a first-time ILI for stage 3B or 3C melanoma (American Joint Committee on Cancer [AJCC] 7th ed) between 1992 and 2018 at five Australian and four United States of America (USA) tertiary referral centers were identified. The primary outcome measures included treatment response, in-field (IPFS) and distant progression-free survival (DPFS), and overall survival (OS)., Results: A total of 687 first-time ILIs were performed (stage 3B: n = 383, 56%; stage 3C; n = 304, 44%). Significant limb toxicity (Wieberdink grade 4) developed in 27 patients (3.9%). No amputations (grade 5) were performed. The overall response rate was 64.1% (complete response [CR], 28.9%; partial response [PR], 35.2%). Stable disease (SD) occurred in 14.5% and progressive disease (PD) in 19.8% of the patients. The median follow-up period was 47 months, with a median OS of 38.2 months. When stratified by response, the patients with a CR or PR had a significantly longer median IPFS (21.9 vs 3.0 months; p < 0.0001), DPFS (53.6 vs 12.7 months; p < 0.0001), and OS (46.5 vs 24.4 months; p < 0.0001) than the nonresponders (SD + PD)., Conclusion: This study is the largest to date reporting long-term outcomes of ILI for locoregionally metastatic melanoma. The findings demonstrate that ILI is effective and safe for patients with stage 3B or 3C melanoma confined to a limb. A favorable response to ILI is associated with significantly longer IFPS, DPFS, and OS.

Background: Talimogene laherparepvec (TVEC) is an oncolytic herpes virus used as intralesional therapy for patients with unresectable stage IIIB through IV melanoma. We reviewed the standard of care treatment of TVEC at a single institution., Methods: All patients treated with TVEC for advanced melanoma were retrospectively evaluated from 2015 to 2018. Patient demographics, clinicopathologic characteristics, treatment response, and toxicity were reviewed., Results: Twenty-seven patients underwent therapy with TVEC. Median age was 75 years, and 63% of patients were female. Seventeen (63.0%) patients underwent injections on the lower extremity, four (14.8%) on the upper extremity, four (14.8%) on the head and neck, and two (7.4%) on the trunk. Median number of injections was five. Median follow-up was 8.6 months. Of the 27 patients, 23 patients met the criteria for response analysis with at least 8 weeks follow-up. Ten (43.5%) patients experienced a complete response (CR), three (13.1%) experienced a partial response (PR), and five (21.7%) had stable disease (SD) for an overall response rate of 56.5% (CR + PR) and a disease control rate of 78.3% (CR + PR + SD). Adverse events were mostly limited to mild constitutional symptoms within 48 h of injection. Two patients developed cellulitis treated with oral antibiotics, and one patient underwent excision of a lesion for ulceration and bleeding during therapy., Discussion: TVEC is an effective and well-tolerated intralesional therapy for patients with unresectable stage IIIB through IV melanoma. A CR was achieved in almost half of patients treated. Disease control is seen in the vast majority.

Introduction: The emergence of novel intralesional therapies have dramatically changed the treatment landscape for melanoma. The heterogeneous presentation of melanoma continues to pose challenges for clinicians, especially when dealing with advanced locoregional disease. Intralesional therapies have the benefit of causing local tumor destruction, while minimizing systemic toxicity. Moreover, the integration of immunotherapeutic agents into intralesional compounds has resulted in the additional benefit of a bystander effect, whereby untreated distant lesions also derive a benefit from treatment. Intralesional therapy has assumed an important role in the management of unresectable, locoregional disease for melanoma. Areas covered: Multiple intralesional agents have been studied over the years, with only a few demonstrating promising results. This review will provide an overview of the different intralesional agents for melanoma. Mechanisms of action, clinical efficacy, and side effects will be the primary focus. Expert commentary: Treatment options for advanced melanoma continue to evolve. Attractive new therapies delivered by an intralesional route has demonstrated promising results, with minimal side effects. The ideal treatment strategy for melanoma will remain a multimodal approach; intralesional therapy provides an additional tool in the treatment armamentarium for melanoma.