Matthew J. Hadfield

Adjuvant management of resectable stage III/IV melanoma

Purpose of Review Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine carcinoma that is primarily driven by Merkel cell polyomavirus (MCPyV) and ultraviolet radiation. Due to its rarity and innocuous appearance on clinical exam, MCC diagnosis is often delayed and therefore diagnosed at advanced stages. Overall survival outcomes are poor and notably worse than melanoma, with an estimated five-year survival ranging from 35 to 60% for stage I or II disease to < 15% for metastatic disease. Our review examines the diagnostic workup, prognostic markers, and current and emerging treatments of MCC. Recent Findings For local disease in which surgical resection is feasible, tumor removal with potential adjuvant radiation therapy is the primary treatment modality. Immunotherapy with PD-1 / PD-L1 inhibitors is now standard for advanced disease where complete resection is not feasible. Additionally, there are many ongoing clinical trials examining novel immune checkpoint inhibitors, immunomodulators, targeted therapies, cellular therapies, vaccines, and oncolytic virus therapies with the goal of improving outcomes for patients with advanced disease or those who experience recurrence after first-line immunotherapy. Summary MCC is an aggressive disease with a rapidly evolving treatment landscape, and emerging therapies hold the potential to improve prognosis in advanced disease.

Responses to immune checkpoint inhibitors (ICIs) differ significantly between uveal melanoma (UM) and cutaneous melanoma (CM) patients. We investigated the immune profile of metastatic UM(mUM) patients and identified markers that are predictive of improved survival. Metastatic liver samples from 189 UM patients and 48 CM patients were analyzed at genomic and transcriptional levels, and survival analysis was performed on a subgroup of 76 ICI-treated mUM patients. UM liver metastases seem to preserve the genomic and immune characteristics of primary UM (pUM), with a low prevalence of ICI markers and high mutation rates of GNA11, GNAQ, BAP1, and SF3B. Compared with mCM, UM liver metastasis showed lower infiltration of several immune cells, but a greater proportion of M2 macrophages. Compared with UM liver metastases, CM liver metastases showed higher expression of G2M checkpoint and EF2 target genes. Among the mUM and mCM samples, expression of G2M and E2F pathway genes was highest in tumors with high TMB values and T-cell inflamed scores. A longer median overall survival (OS) was observed in mUM patients with higher expression of LAG3, HLA class I, or HLA class II; which may represent a small proportion of immune hot tumors. Expression patterns of G2M checkpoint and E2F targets suggest a possible contribution to immunotherapy response.

The last two decades have ushered in unprecedented advancements in the treatment of cancer

Cholangiocarcinoma is a malignancy of the bile ducts that is often associated with late diagnosis, poor overall survival, and limited treatment options. The standard of care therapy for cholangiocarcinoma has been cytotoxic chemotherapy with modest improvements in overall survival with the addition of immune checkpoint inhibitors. The discovery of actionable mutations has led to the advent of targeted therapies against FGFR and IDH-1, which has expanded the treatment landscape for this patient population. Significant efforts have been made in the pre-clinical space to explore novel immunotherapeutic approaches, as well as antibody–drug conjugates. This review provides an overview of the current landscape of treatment options, as well as promising future therapeutic targets.