Immune therapy has become the fourth approach after surgery, chemotherapy, and radiotherapy in cancer treatment. Many immune checkpoints were identified in the last decade since ipilimumab, which is the first immune checkpoint inhibitor to cytotoxic T-lymphocyte associated protein 4, had been approved by the US Food and Drug Administration (FDA) for the treatment of unresectable or metastatic melanoma in 2011. The use of several antibody drugs that target PD1/PD-L1 for various cancer treatments has been approved by the FDA. However, fewer people are benefitting from immune checkpoint inhibitor treatment in solid cancers. Approximately 80% of patients do not respond appropriately because of primary or acquired therapeutic resistance. Along with the characterization of more immune checkpoints, the combinatory treatment of multiimmune checkpoint inhibitors becomes a new option when monotherapy could not receive a good response. In this work, the author focuses on the combination therapy of multiple immune checkpoints (does not include targeted therapy of oncogenes or chemotherapy), introduces the current progression of multiple immune checkpoints and their related inhibitors, and discusses the advantages of combination therapy, as well as the risk of immune-related adverse events.
Combined Modality Therapy ; Humans ; Immune Checkpoint Inhibitors ; Immunotherapy ; Melanoma/drug therapy* ; Tumor Escape

Catechins have been proven to exert antitumor effects in different kinds of cancers. However, the underlying mechanisms have not been completely clarified yet. This study aimed to assess the effects and mechanisms of (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin-3-gallate (ECG) on human melanoma skin A375 cells. Results showed that EGCG and ECG inhibited the proliferation of A375 cells and ECG showed better inhibitory effect. Flow cytometry analysis had shown that EGCG and ECG induced apoptosis and led to cell cycle arrest. EGCG and ECG decreased Bcl-2 expression and upregulated Caspase-3 protein level, indicating the development of apoptosis. Furthermore, EGCG and ECG could decreased mitochondrial membrane potential of A375 cells. In addition, the expression of Beclin-1, LC3 and Sirt3 were downregulated at protein levels, which known to be associated with autophagy. After autophagy was increased by rapamycin, the apoptotic trend was not change, indicating that apoptosis and autophagy are independent. Mechanistically, EGCG and ECG treatments decreased phosphorylated-AMPK (p-AMPK) and increased the ratios of p-PI3K, p-AKT and p-mTOR in melanoma cells. Conclusively, EGCG and ECG induced apoptosis via mitochondrial signaling pathway, downregulated autophagy through modulating the AMPK/mTOR and PI3K/AKT/mTOR signaling pathway. It indicated that EGCG and ECG may be utilized in human melanoma treatment.
AMP-Activated Protein Kinases/genetics* ; Apoptosis ; Autophagy ; Catechin/analogs & derivatives* ; Electrocardiography ; Humans ; Melanoma/drug therapy* ; Phosphatidylinositol 3-Kinases/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; TOR Serine-Threonine Kinases/metabolism*

Interleukins (ILs) and associated cytokines serve as the means of communication for immune cells and non-immune cells. The use of ILs in harnessing the immune system to cancer treatment has been a promising approach. ILs not only nurture an environment enabling cancer growth but also simultaneously trigger a productive tumor-directed immune response. These properties of ILs are increasingly being explored as a strategy to improve the outcomes of cancer. Here, we describe recently innovative technological approaches that have been developed to improve the pharmacokinetics, safety, and efficacies of IL-2, 15, 10, and 18 in the treatment of melanoma. Furthermore, the combination of ILs and immune checkpoint inhibition may synergize to reshape the tumor environment, thus yielding better clinical benefits in the future.
Cytokines ; Humans ; Interleukins ; Melanoma/drug therapy*

Interleukin-2 (IL-2) is one of the most important regulators in immune system, as it plays an essential part both in immune activation and suppression. However, as the first immunotherapy drug approved for the treatment of cancer, IL-2 is limited in clinical application by the serious adverse reactions. The long-felt needs in clinical practice, including prolonged half-lives, T cell subset specificity, and toxicity reduction can be achieved by polyethylene glycol (PEG) modification, Fc fusing, or protein mutation of IL-2. NKTR-214, the most advanced IL-2 pathway-targeted agent in clinical development for oncology, shows exciting results in treatment of melanoma in combination with nivolumab. At the same time, many more other modified molecules against cancer and autoimmune diseases are being tested in clinical research, an exciting future lying ahead for IL-2 therapeutics.
Drug Development ; Humans ; Immunotherapy/methods* ; Interleukin-2/therapeutic use* ; Melanoma/drug therapy* ; Nivolumab/therapeutic use* ; Polyethylene Glycols

OBJECTIVE: To investigate the inhibitory effect of aumolertinib on proliferation of human choroidal melanoma MUM-2B cells and explore the possible molecular mechanism. METHODS: CCK-8 assay and colony formation assay were used to evaluate the inhibitory effect of different concentrations of aumolertinib on viability and proliferation of MUM-2B cells. Flow cytometry was performed to analyze the apoptosis, necrosis, cellular ROS production and cell cycle changes in aumolertinib- treated MUM-2B cells. The antitumor effect of aumolertinib against human choroidal melanoma was observed in nude mouse models bearing MUM-2B tumor cell xenografts. RESULTS: The results of CCK-8 and colony formation assay showed that aumolertinib strongly inhibited the proliferation MUM-2B cells in a dose-dependent manner. Flow cytometry showed that aumolertinib dose-dependently increased the total apoptosis rate of MUM-2B cells to as high as 76.65% at the concentration of 8 μmol/L and induced obvious cell cycle arrest at G1 phase. Aumolertinib treatment also caused a dose-dependent increase of ROS production and reduction of mitochondrial membrane potential in MUM-2B cells. In the tumor-bearing nude mice, treatment with aumolertinib significantly inhibited tumor growth without causing obvious body weight loss. CONCLUSION Aumolertinib can effectively inhibit the growth of human choroidal melanoma MUM-2B cells both in vivo and in vitro, suggesting its potential clinical value in the therapy of choroidal melanomas.
Animals ; Mice ; Humans ; Mice, Nude ; Sincalide ; Indoles ; Melanoma/drug therapy*

OBJECTIVES: To study the antitumor effect of piceatannol (PIC) on malignant melanoma METHODS: B16F10 cells were cultured RESULTS: The cell viability of B16F10 decreased with increasing PIC concentration. The results of the Transwell assay showed that invasion ability decreased with increasing PIC concentration, and healing time was prolonged at increased PIC concentration in the wound healing assay. Western blot results showed that PIC mainly inhibited the phosphorylation of Syk and inhibited the expression of MMP-2, MMP-9, and VEGF. RNA interference pointed out that blocking the expression of Syk can reveal the same inhibition effect on B16F10 cells as PIC. CONCLUSIONS PIC might block the progression of malignant melanoma by inhibiting spleen tyrosine kinase.
Animals ; Cell Line, Tumor ; Cell Movement ; Matrix Metalloproteinase 2 ; Matrix Metalloproteinase 9 ; Melanoma/drug therapy* ; Mice ; Neoplasm Invasiveness ; Stilbenes/pharmacology* ; Syk Kinase ; Vascular Endothelial Growth Factor A

Primary ovarian melanoma arising on a mature ovarian cystic teratoma is extremely rare. As best of our knowledge, to date, 49 cases have been reported in literature. Few information was reported about best management and therapy. We present a case occurred in a 69-year-old woman, without symptoms, who come to our unit for stress incontinence. A pelvic mass was detected and, after imaging evaluation, surgery was performed. The diagnosis was ovarian melanoma arose on a mature teratoma. No other adjuvant treatment was proposed after surgery. She died 9 months after the first diagnosis. Primary ovarian melanoma is a definite entity associated with a variable natural history and poor prognosis. Differential diagnosis is a challenge for the pathologist, because it must be differentiated by metastatic melanoma. The corner stone treatment of this disease is surgery; however, chemotherapy, immunotherapy, and target therapy seem to have a role.
Aged ; Diagnosis ; Diagnosis, Differential ; Drug Therapy ; Female ; Humans ; Immunotherapy ; Melanoma* ; Natural History ; Ovarian Cysts ; Ovarian Neoplasms ; Prognosis ; Teratoma

The cutaneous melanoma has been regarded as rare disease entity in Korea for long time but it shows a silent growth recently. Furthermore the management of cutaneous melanoma including staging system, surgical principle, sentinel lymph node biopsy and subsequent complete node dissection and, most importantly, immunotherapy and target therapy against cutaneous melanoma recently. The incidence of cutaneous melanoma is steadily increasing in Korea but its increase is rapid recent 2 decades to 4.3 times and should be greater soon according to the steeper increase of life expectancy. New staging system proposed by American Joint Committee on Cancer (2017) includes changes in individual TNM category and stage groups, particularly from a prognostic viewpoint. Dermoscopy has been successfully introduced in the differential diagnosis of pigmented skin lesion focusing on cutaneous melanoma by non-invasive simple diagnostic tool. Sentinel lymph node biopsy was a issue of long debate whether survival benefit is real or not. Temporary conclusion about this question is reached after two large scale studies and immediate complete node dissection should be performed in a certain situations. Most important change is drug therapy focusing on immunotherapy and target therapy. Braf- and MEK-inhibitor, immune checkpoint inhibitor and PD-1 blocker has been proved to be effective as a sole or combination regimen against advanced and/or high-risk adjuvant setting of cutaneous melanoma. In conclusion, these remarkable changes will be reviewed shortly here.
Dermoscopy ; Diagnosis, Differential ; Drug Therapy ; Immunotherapy ; Incidence ; Joints ; Korea ; Life Expectancy ; Melanoma ; Rare Diseases ; Sentinel Lymph Node Biopsy ; Skin

Tumor suppressor gene O⁶-methylguanine-DNA methyltransferase (MGMT) promoter methylation has been reported in melanoma. However, the clinical and prognostic significance of MGMT promoter methylation in patients with melanoma remained to be determined. A systematic search was performed to identify eligible papers published. The overall odds ratios (ORs) or hazard ratios and their 95% confidence intervals were calculated. Final 12 eligible publications involving Caucasian population were performed in this study, including 1,071 metastatic melanoma patients, 154 primary melanoma patients, and 211 normal controls. MGMT promoter methylation was significantly higher in primary or metastatic melanoma than in normal controls (p < 0.05). No difference of MGMT promoter methylation was found in primary and metastatic melanoma (p=0.432). When metastatic melanoma was compared to normal controls, subgroup analysis showed the correlation between MGMT promoter methylation and different sample materials (tissue: OR=7.01, p < 0.001 and blood: OR=12.04, p=0.005). MGMT promoter methylation was not associated with response to drug therapy and the prognosis in overall survival and progression-free survival for multivariate analysis. Our results show that MGMT promoter methylation may be correlated with the increased risk of primary or metastatic melanoma. Based on blood samples, MGMT promoter methylation may become a noninvasive biomarker for the detection of metastatic melanoma. Further additional clinical studies are necessary.
Disease-Free Survival ; Drug Therapy ; Genes, Tumor Suppressor ; Humans ; Melanoma* ; Methylation* ; Multivariate Analysis ; Odds Ratio ; Prognosis

Primary or metastatic malignant melanoma can mimic benign blue nevus in rare cases, making the diagnosis challenging. Herein, we report an exceptionally rare case of blue nevus-like melanoma and its blue nevus-like metastasis which was detected by catheterized urine cytology. The patient presented with blue-colored papuloplaques on his temple which were diagnosed as blue nevus-like melanoma on punch biopsies. While he was admitted for administration of chemotherapy, hematuria was detected. Catheterized urine cytology revealed singly scattered oval to spindle-shaped pigmented cells with a moderate degree of variation in shape and size. Many of them had small nuclei with indiscernible to inconspicuous nucleoli while only a few cells showed nuclear enlargement and nuclear hyperchromasia, which could be diagnostic pitfalls. Most of the cells on the smear were positive for HMB45 immunostaining, which confirmed the diagnosis of metastatic blue nevus-like melanoma. To the best of our knowledge, the present case is the first report describing cytomorphologic findings of blue nevus-like metastasis of melanoma in the urine specimen.
Biopsy ; Catheters* ; Diagnosis ; Drug Therapy ; Hematuria ; Humans ; Melanoma* ; Neoplasm Metastasis ; Nevus, Blue