This study represents the largest, single-institution series describing the characteristics and outcomes of AM. AM tumors exhibit aggressive histopathologic features associated with a poorer survival outcome. AM patients have an inferior survival than extremity NACM when matched for stage, perhaps reflecting inherent alterations in tumor biology. This warrants further investigation into the differences between acral and cutaneous melanoma.

Relatlimab and nivolumab combination immunotherapy improves progression-free survival over nivolumab monotherapy in patients with unresectable advanced melanoma1. We investigated this regimen in patients with resectable clinical stage III or oligometastatic stage IV melanoma (NCT02519322). Patients received two neoadjuvant doses (nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks) followed by surgery, and then ten doses of adjuvant combination therapy. The primary end point was pathologic complete response (pCR) rate2. The combination resulted in 57% pCR rate and 70% overall pathologic response rate among 30 patients treated. The radiographic response rate using Response Evaluation Criteria in Solid Tumors 1.1 was 57%. No grade 3–4 immune-related adverse events were observed in the neoadjuvant setting. The 1- and 2-year recurrence-free survival rate was 100% and 92% for patients with any pathologic response, compared to 88% and 55% for patients who did not have a pathologic response (P = 0.005). Increased immune cell infiltration at baseline, and decrease in M2 macrophages during treatment, were associated with pathologic response. Our results indicate that neoadjuvant relatlimab and nivolumab induces a high pCR rate. Safety during neoadjuvant therapy is favourable compared to other combination immunotherapy regimens. These data, in combination with the results of the RELATIVITY-047 trial1, provide further confirmation of the efficacy and safety of this new immunotherapy regimen.

Clinical responses to immunotherapy have been associated with augmentation of preexisting immune responses, manifested by heightened inflammation in the tumor microenvironment. However, many tumors have a noninflamed microenvironment, and response rates to immunotherapy in melanoma have been <50%. We approached this problem by utilizing immunotherapy (CTLA-4 blockade) combined with chemotherapy to induce local inflammation. In murine models of melanoma and prostate cancer, the combination of chemotherapy and CTLA-4 blockade induced a shift in the cellular composition of the tumor microenvironment, with infiltrating CD8 þ and CD4 þ T cells increasing the CD8/Foxp3 T-cell ratio. These changes were associated with improved survival of the mice. To translate these findings into a clinical setting, 26 patients with advanced melanoma were treated locally by isolated limb infusion with the nitrogen mustard alkylating agent melphalan followed by systemic administration of CTLA-4 blocking antibody (ipilimumab) in a phase II trial. This combination of local chemotherapy with systemic checkpoint blockade inhibitor resulted in a response rate of 85% at 3 months (62% complete and 23% partial response rate) and a 58% progression-free survival at 1 year. The clinical response was associated with increased T-cell infiltration, similar to that seen in the murine models. Together, our findings suggest that local chemotherapy combined with checkpoint blockade-based immunotherapy results in a durable response to cancer therapy.

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Background The effect of lymph node metastasis on local tumor control and distant failure in patients with anorectal melanoma has not been fully studied. Understanding the significance of lymphatic dissemination might assist in stratifying patients for either organ preservation or radical surgery. Methods A retrospective review of all patients with anorectal melanoma who underwent surgery at our institution between 1985 and 2010. Abdominoperineal resection (APR) was performed in 25 patients (39 %), and wide local excision (WLE) in 40 (61%). Extent of primary surgery and locoregional lymphadenectomy (mesorectal vs. inguinal vs. none) and pattern of treatment failure were analyzed. Recurrence-free survival (RFS) and disease-specific survival (DSS) were calculated. Results In patients undergoing APR, DSS was not associated with presence (29 %) or absence (71 %) of metastatic melanoma in mesorectal lymph nodes. There was a trend toward improved DSS in patients with clinically negative inguinal lymph nodes (n = 17) compared with patients with proven inguinal metastasis (n = 6; P = 0.12). Type of surgery (WLE vs. APR) was not associated with subsequent development of distant disease. Twelve patients (18 %) had synchronous local and distant recurrence. Synchronous recurrence was not associated with surgical strategy used to treat primary tumor (P = 0.28). Perineural invasion (PNI) was significantly correlated with RFS (P = 0.002). Conclusions Outcome following resection of anorectal melanoma is independent of locoregional lymph node metastasis; lymphadenectomy should be reserved for gross symptomatic disease. PNI is a powerful prognostic marker warranting further exploration in clinical trials.