Treatment Of Cutaneous Melanoma Research Articles

Abstract 5938: Development of HH044, an orally bioavailable nNOS inhibitor, for the treatment of cutaneous melanoma

Abstract Background: Human cutaneous melanoma is one of the few cancers in which the incidence rate continues to increase, and despite recent advances in immune and targeted therapies, the 5-year survival rate of metastatic disease remains low. Neuronal nitric oxide synthase (nNOS) has been identified to contribute to melanoma development, stimulating disease progression, and facilitating escape of melanoma cells from the immune response. We developed a novel small molecule, HH044, which specifically inhibits nNOS activity and reduced nitric oxide production in melanoma cells. We aim to conduct a proof-of-concept study using our nNOS inhibitor administered orally for anti-melanoma treatment. Methods: Human melanoma cell lines (A375, Sk-Mel-28, wm3211) were employed to analyze the anti-cancer activities of HH044 in vitro. An immune-competent syngeneic melanoma mouse model was used to determine the anti-tumor activity of HH044 when administered orally (50 mg/kg/day) or intraperitoneally (10 mg/kg/day) for 21 days. A pharmacokinetic study of drug levels in serum and tumor samples was conducted after a single dose given intraperitoneally or orally using LC-MS/MS analysis at different time points. Results: HH044 has high selectivity of nNOS over iNOS (340-fold) and eNOS (540-fold). The IC50 of HH044 in melanoma cell lines was 5.27 ± 3.3 μM, while iNOS inhibitor 1200W did not exhibit any cytotoxicity up to 100 μM concentration. Of note, nNOS blockade by HH044 did not result in reactivation of iNOS, and expression levels of iNOS were not changed after HH044 treatment. In vivo studies demonstrated that HH044 treatment given intraperitoneally exhibited potent anti-tumor activity and reduced tumor weight to 45% of control. When administered orally, HH044 at 50 mg/kg significantly reduced tumor growth to 61% of control and extended mice median survival from 32 days to 53 days. Pharmacokinetic analysis showed that oral administration achieved sufficient drug levels in xenograft tumors, which were well above the Ki value (0.005 μM) despite a wide range of bioavailability. The drug level peaked at 2 hours after a single dose (2.27 ± 0.666 μM in the tumor and 23.68 ± 17.43 μM in the serum). Intraperitoneal injection achieved much higher levels in serum and tumor samples, which also declined slower compared to oral gavage administration. By 24 hours, the drug levels in serum and xenograft tumors remained at 1.55 ± 0.12 μM and 1.77 ± 0.24 μM concentration, respectively. No significant systemic toxicities were observed with HH044 treatments either given via i.p. injection or orally. Further in vivo studies combining nNOS inhibitors with immune checkpoint blockade are currently underway. Conclusions: HH044, as the first-in-class nNOS inhibitor, exhibits potent anti-melanoma activity by oral administration. Developing selective nNOS inhibitors has shown to be a novel therapeutic strategy to improve melanoma treatment. Citation Format: Anika Patel, Shirley Tong, Richard B. Silverman, Sun Yang. Development of HH044, an orally bioavailable nNOS inhibitor, for the treatment of cutaneous melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5938.

Abstract 4745: A novel combination therapy targeting RAF, MEK and FAK to overcome skin cutaneous melanoma treatment resistance

Abstract Metastatic melanoma is the most aggressive malignancy of the skin and BRAFV600E mutation is the most common genetic alteration in skin cutaneous melanoma (SKCM). Despite the advent of immune checkpoint inhibition (ICI) immunotherapy, only 40% of patients show long-term responses. As such, combined therapy with BRAF and MEK inhibitors (BRAFi + MEKi) remains the standard of care for BRAFV600E+ SKCM. In the present study, transcriptome analysis of BRAFV600E+ SKCM tumors derived from patients revealed that activation of extracellular matrix signaling, including focal adhesion signaling, is highly enriched in patients who experienced disease progression on BRAFi + MEKi therapy. Consistent with these results, we found increased activation of focal adhesion kinase (FAK) in human BRAFV600E+ SKCM A375 cells treated with BRAFi, MEKi or the RAF/MEK clamp avutometinib. Mechanistically, we discovered that avutometinib-mediated inhibition of the RAF/MEK/ERK pathway decreased RhoE/Rnd3 expression, thereby unleashing RhoA/FAK/AKT signaling. Thus, we hypothesized that FAK activation represents a resistance mechanism to BRAFi + MEKi and that FAK inhibition (FAKi) might overcome resistance to BRAFi/MEKi. Indeed, avutometinib demonstrated synergistic antiproliferative and proapoptotic activity when combined with FAKi in human BRAFV600E+ SKCM A375 cells. Importantly, we found that the combination of FAKi + avutometinib overcame resistance to BRAFi + MEKi in SKCM xenografts and patient-derived cells from SKCM-resistant lesions. Finally, we showed that while BRAFV600E+ SKCM YUMM 1.7 syngeneic tumors failed to respond to ICI therapy, avutometinib ± FAKi inhibited tumor growth. We observed that tumors treated with avutometinib as single agent eventually developed resistance and escaped growth inhibition, but those treated with combined avutometinib and FAKi displayed durable treatment responses, often with complete tumor regression. These findings provide a rationale for the clinical development of avutometinib with defactinib (FAKi) in patients with BRAFV600E+ cutaneous melanoma following progression on BRAFi + MEKi and/or ICI therapy. Citation Format: Simone Lubrano, Farhoud Faraji, Rodolfo Daniel Cervantes-Villagrana, Sydney Ramirez, Nadia Arang, Adam Officer, Damiano C. Rigiracciolo, Paola Y. Anguiano Quiroz, Antonieta Bacchiocchi, Ruth Halaban, Silvia Coma, Sheri Holmen, Claudia Martini, Jonathan Pachter, Andrew Aplin, J. Silvio Gutkind. A novel combination therapy targeting RAF, MEK and FAK to overcome skin cutaneous melanoma treatment resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4745.

The Future of Checkpoint Inhibitors in Uveal Melanoma: A Narrative Review.

Immune checkpoint inhibitors have made tremendous progress over the last decade in the treatment of cutaneous melanoma, but their application in uveal melanoma treatment is less successful, owing in part to the immunological privilege of the eye and the liver, the most frequent site of metastasis. Nevertheless, the therapeutic outcomes reported currently are less pessimistic. In this review, we provide an overview of recent studies of immune checkpoint inhibitors in uveal melanoma and its metastasis and classify studies in this field into three groups: monotherapy of immune checkpoint inhibitors, dual-agent immune checkpoint inhibitors, and immune checkpoint inhibitors combined with other systemic or regional therapies. Briefly, monotherapy with immune checkpoint inhibitors performed poorly. Dual-agent immune checkpoint inhibitors had slightly better outcomes than traditional treatments, especially in specific patient populations. As for the combination therapy, the combination with other systemic therapies did not show superiority over dual-agent immune checkpoint inhibitors, but combination with hepatic regional therapies was quite promising. Moreover, research on emerging checkpoints is currently limited to the stage of mechanistic studies. We propose that immune checkpoint inhibitors remain alternative treatments for patients with uveal melanoma, but factors such as cost-effectiveness should also be taken into account. The combination therapy with immune checkpoint inhibitors deserves to be further explored.

Melanoma and sex hormones: Pathogenesis, progressive disease and response to treatments.

Cutaneous melanoma represents the fifth tumor in terms of incidence in young adults, with a major involvement of males than females. Despite the significant changes in available effective treatments for cutaneous melanoma, there is still a proportion of patients that do not benefit long-term disease control with immune checkpoint inhibitors and/or BRAF/MEK inhibitors, and eventually develop progressive disease. In addition to the emerging biomarkers under investigation to understand resistance to treatments, recent studies resumed the role of sex hormones (estrogens, progesterone and androgens) in melanoma patients. In the last decades, the impact of sex hormones has been considered controversial in melanoma patients, but actual growing preclinical and clinical evidence underline the potential influence on melanoma cells' growth, tumor microenvironment, the immune system and consequently on the course of disease.This review will provide available insights on the role of sex hormones in melanoma pathogenesis, disease progression and response/resistance to systemic treatments. We will also offer an overview on the recent studies on the theme, describing the hormonal contribution to disease response and the interaction with targeted therapies and immune-checkpoint inhibitors in cutaneous melanoma patients, illustrating an insight into future research in this field.

Transdermal codelivery system of resveratrol nanocrystals and fluorouracil@ HP-β-CD by dissolving microneedles for cutaneous melanoma treatment

Cutaneous melanoma is a serious malignant tumor. In recent years, the morbidity and mortality rate of this disease have been continuously and rapidly increasing. Codelivery of natural product resveratrol (RES) and chemical synthetic drug fluorouracil (Fu) is beneficial to achieve reduced toxicity and increased efficacy effects for melanoma therapeutic. However, the poor solubility and bioavailability of the two drugs resulted in deficient effective and systemic toxicity due to high dose administration. Furthermore, these shortcomings also lead to drug resistance and unsatisfactory patient compliance. In this study, a codelivery dissolvable microneedle (DMN) patch was designed by carrying RES nanocrystals and Fu@hydroxypropyl-beta-cyclodextrin (HP-β-CD) for a synergistic effect. The RES nanocrystals exhibited satisfied solubility and dissolution properties in vitro, and the Fu inclusion compound with HP-β-CD resulted in satisfactory drug loading. Laser confocal fluorescence microscopy demonstrated uniform distribution of both drugs in the DMN. Mechanical tests and in vitro and in vivo puncture tests of the DMN exhibited great mechanical and insertion properties. The DMN in the Franz diffusion cell test released 84.13 ± 5.19 % of the RES and 90.65 ± 18.23 % of the Fu at 12 h. Additionally, for in vivo release, the DMN released 81.24 ± 5.23 % of the RES and 72.48 ± 7.82 % of the Fu. All excipients of the DMN presented high biosafety. In conclusion, codelivery of RES nanocrystals and Fu@HP-β-CD by the DMN presented an excellent pharmaceutical and biological properties and satisfied potential clinical application prospects for cutaneous melanoma treatment.

Abstract PR010: Cutaneous melanoma treatment outcomes in Texas: A study of the Texas Cancer Registry/Medicare linked database and an analysis of disparities

Abstract Background: Given that Hispanics make up a large portion of the United States, further research has been necessary to analyze the effects of treatment methods on all-cause and skin cancer mortality in Hispanic populations. While Caucasians have the highest incidence of melanoma, Hispanics make up the second most common group in the United States and in Texas. Incidence of melanoma is increasing, including in the Hispanic population. Importantly, mortality from melanoma is higher in the Hispanic than in the Caucasian population. Methods: We conducted an analysis of patients with cutaneous melanoma in the Texas Cancer Registry Medicare database to assess treatment modalities used and outcomes among demographic groups from 2007 to 2018. A bivariate analysis using Chi-square, Fisher’s exact test, and Student’s T-Test was done to compare patient, clinical, cancer and treatment characteristics between Hispanic and Non-Hispanic White (NHW). A Cox Proportional Hazard regression analysis was performed to assess treatment effect on outcome, with race-ethnicity as an effector modifier. Models were adjusted for patient age, sex, cancer stage, primary care provider, and comorbidity. Results: A higher percentage of Hispanic patients (7.6%) presented with a metastatic tumor stage diagnosis and cancer-related mortality (22.11%) compared to NHW patients (p <0 .0001). In both the Hispanic and NHW cohorts, post-diagnosis radiation (Hispanic 95% CI 0.984 – 2.634, NHW 95% CI 2.082-2.648) and post-diagnosis chemotherapy (Hispanic 95% CI 1.085-3.321, NHW 95% CI 1.664-2.489) are each associated with an increased risk in cancer-related mortality. Similar results are seen with post-diagnosis radiation (Hispanic 95% CI 1.121-2.40, NHW 95% CI 1.644-1.971) and chemotherapy (Hispanic 95% CI 0.900-2.368, NHW 95% CI 1.356-1.869) when considering all-cause mortality in both populations. However, post-diagnosis surgery (95% CI 0.571-0.678) and post-diagnosis immunotherapy (95% CI 0.032-1.565) had the opposite effect in cancer-related mortality for NHW. Cancer-related mortality for post-diagnosis surgery in the Hispanic cohort had a similar trend (95% CI 0.395-0.856), yet the effect of post-diagnosis immunotherapy was dismissed due to small sample size. Conclusion: Our results propose differences in all-cause and cancer-only related mortality with separate treatment modalities, particularly with chemotherapy and radiation therapy; this retrospective cohort study validated that health disparities exist in the Hispanic Medicare population of Texas with cutaneous melanoma. Citation Format: Hannah R. Riva, Fabiola Ramirez, Lorena Fernandez, Yae Kye, David Lopez, Biai Digbeu, Jessica Chacon. Cutaneous melanoma treatment outcomes in Texas: A study of the Texas Cancer Registry/Medicare linked database and an analysis of disparities [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr PR010.

Definitive treatment for head and neck mucosal melanoma.

Head and neck mucosal melanoma is a rare clinical subtype of melanoma or head and neck cancer. Mucosal melanoma is aetiologically and molecularly distinct from cutaneous melanoma. The therapeutic efficacy of immune checkpoint inhibitors for head and neck mucosal melanoma remains unclear. Surgery is considered as the mainstay of treatment for locally advanced head and neck mucosal melanoma, and adjuvant radiotherapy has a role in local disease control. New treatment modalities, such as targeted therapy and immunotherapy, have changed the treatment of cutaneous melanoma. However, patients with mucosal melanoma have been excluded from most Phase III clinical trials. Due to its rarity, outcome data for locally advanced head and neck mucosal melanoma are scarce and are mainly based on retrospective studies with limited case numbers. The objective of this review was to provide an update and overview of clinical trials, prospective observational studies and retrospective studies and discuss future directions for multimodal treatment of locally advanced head and neck mucosal melanoma.

Enhanced Transdermal Peptide-Modified Flexible Liposomes for Efficient Percutaneous Delivery of Chrysomycin A to Treat Subcutaneous Melanoma and Intradermal MRSA Infection.

Superficial skin diseases, including skin infections and tumors, are common healthcare burdens. In this study, the in vivo activity of chrysomycin A (CA) is explored, and a transdermal liposomal CA formulation is further constructed for the simultaneous treatment of cutaneous melanoma and cutaneous methicillin-resistant Staphylococcus aureus (MRSA) infection. The prepared liposomes (TD-LP-CA) display a strong antitumor effect with an IC50 value of less than 0.1µm in B16-F10 cells, suppress the proliferation of MRSA with a minimum inhibitory concentration (MIC) of 1µm, and eradicate established MRSA biofilms at 10× MIC in vitro. More importantly, TD-LP-CA shows enhanced stratum corneum (SC) penetration, reaching more than 500µm beneath the skin's surface due to modification with the TD peptide, and demonstrates excellent subcutaneous tumor penetration after skin application in vivo. TD-LP-CA displays an excellent therapeutic effect against intradermal MRSA infection in mice after topical dermal administration, as well as a moderate inhibitory effect on subcutaneous melanoma with a 75% tumor inhibition rate. The liposomes prepared herein can be a promising carrier for transcutaneous CA transfer for the treatment of superficial diseases such as skin tumors and infections due to their ability to overcome the skin barrier.

Camrelizumab combined with anlotinib and nab-paclitaxel in patients with untreated advanced mucosal melanoma: A single-arm, multicenter, exploratory study.

TPS9593 Background: Anti-programed cell death-1 (PD-1) monotherapy is a part of the standard treatment for cutaneous melanoma, but its efficacy in mucosal melanoma is not ideal. In vivo studies have demonstrated that co-inhibition of the VEGF receptor (VEGFR) and PD-1 pathways increased T cell infiltration and suppressed tumor growth synergistically. Early phase trial data confirmed that PD-1 inhibitors combined with anti-angiogenic drugs showed efficacy in the treatment of advanced mucosal melanoma, but still did not meet clinical needs. Previous studies have shown that chemotherapy combined with anti-angiogenic drugs has significantly improved median PFS and median OS compared with chemotherapy alone, and has a certain effect as a salvage treatment for progression after PD-1 inhibitor treatment. In addition, previous retrospective analysis showed that PD-1 inhibitors combined with chemotherapy drugs such as nab-paclitaxel were superior to anti-PD-1 monotherapy in the treatment of advanced mucosal melanoma. In summary, the combination of anti-PD-1, anti-angiogenic drugs and chemotherapy may bring new hope for the treatment of advanced mucosal melanoma. Methods: This is a single-arm, multicenter, exploratory study to evaluate the efficacy and safety of camrelizumab combined with anlotinib and nab-paclitaxel as first-line therapy in patients with advanced mucosal melanoma. The trial is expected to enrol 66 patients. Key Inclusion Criteria are pts with confirmed recurrence, unresectable or metastatic mucosal melanoma after surgery (stage III/IV) and ECOG performance status of ≤1.Pts with previous adjuvant therapy or neoadjuvant therapy (except PD-1/PDL1 monoclonal antibody and VEGFR TKI) at least 4 weeks before the first administration of the study drug are allowed. Patients received intravenous camrelizumab (200 mg) on day 1, intravenous nab-paclitaxel (260mg/m2) on day 1, and oral anlotinib (8mg) on days 1-14 every 3 weeks. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease control rate (DCR),progression-free survival (PFS), and 2-year overall survival (OS). Clinical trial information: NCT04979585 .

Role of Single Nucleotide Polymorphism-Related Genes in Tumour Immune Cell Infiltration and Prognosis of Cutaneous Melanoma.

Advances in cancer research have allowed for early diagnosis and improved treatment of cutaneous melanoma (CM). However, its invasiveness and recurrent metastasis, along with rising resistance to newer therapies, have lent urgency to the search for novel biomarkers and the underlying molecular mechanisms of CM. Single nucleotide polymorphism- (SNP-) related genes were obtained from the sequencing data of 428 CM samples in The Cancer Genome Atlas. Functional enrichment of these genes was analysed in clusterProfiler. Additionally, a protein-protein interaction (PPI) network was constructed with the Search Tool for the Retrieval of Interacting Gene (STRING) database. Gene Expression Profiling Interactive Analysis (GEPIA) was used to identify the expression and prognostic value of mutated genes. Finally, the Tumour Immune Estimation Resource (TIMER) analysed the relationship between gene expression and immune cell infiltration. We constructed a PPI network from the top 60 SNP-related genes. Mutated genes were mainly involved in calcium and oxytocin signalling pathways, as well as circadian entrainment. In addition, three SNP-related genes, BRAF, FLG, and SORL1, were significantly associated with patient prognosis. BRAF and SORL1 were positively associated with infiltration abundance of B cells, CD8+ T cells, CD4+ T cells, neutrophils, and dendritic cells, whereas FLG expression was negatively associated. Furthermore, higher immune cell infiltration was positively correlated with good prognosis. Our study provides vital bioinformatic data and a relevant theoretical basis to further explore the molecular pathogenesis of CM and improve patient prognosis.

Construction of Imatinib Controlled Release Film-Forming System Based on Drug Ion-Pair and Oligomeric Ionic Liquids for the Long Local Therapy of Cutaneous Melanoma.

An imatinib controlled release film-forming system (FFS) was developed based on the drug ion-pair and newly designed oligomeric ionic liquids (OILs) for the topical therapy of cutaneous melanoma, which avoided the systemic side-effect of oral administration and maintained a long local therapy effect. The OILs significantly improved the drug release capacity about 1.5-fold, and the formability and stability of FFSs (verified by AFM/PLM). The in vivo anti-tumor efficacy studies in melanoma tumor bearing mice showed that compared with the oral capsules, the topical application of the optimized imatinib FFS significantly (p < 0.01) increased tumor inhibition rate (67.54 ± 2.72%) and the amount of apoptotic cells. As confirmed by FT-IR and NMR, the partial protonation of OILs were demonstrated to have high hydrogen bond forming capacity, thus showing low polarity and good biocompatibility. More importantly, based on 13C-NMR study, OILs demonstrated higher hydrogen bond forming capacity, and formed bridge between drug ion-pair (O-H of counter-ion) and PVA (O-H), increased the molecular mobility of PVA, thus maintaining a long drug release capacity. Therefore, an imatinib FFS was developed with good therapeutic effect and the effect of drug ion-pair and OILs on increasing the drug skin retention and controlled release of imatinib FFS for topical therapy was clarified at the molecular level, which provided a safe and effective way for the treatment of cutaneous melanoma.

Nail Apparatus Melanoma: Current Management and Future Perspectives.

Nail apparatus melanoma (NAM) is a rare type of cutaneous melanoma that belongs to the acral melanoma subtype. NAM is managed principally in accordance with the general treatment for cutaneous melanoma, but there is scarce evidence in support of this in the literature. Acral melanoma is genetically different from non-acral cutaneous melanoma, while recently accumulated data suggest that NAM also has a different genetic background from acral melanoma. In this review, we focus on recent advances in the management of NAM. Localized NAM should be surgically removed; amputation of the digit and digit-preserving surgery have been reported. Sentinel lymph node biopsy can be considered for invasive NAM for the purpose of accurate staging. However, it is yet to be clarified whether patients with metastatic sentinel lymph nodes can be safely spared completion lymph node dissection. Similar to cutaneous melanoma, immune checkpoint inhibitors and BRAF/MEK inhibitors are used as the first-line treatment for metastatic NAM, but data on the efficacy of these therapies remain scarce. The therapeutic effects of immune checkpoint inhibitors could be lower for NAM than for cutaneous melanoma. This review highlights the urgent need to accumulate data to better define the optimal management of this rare melanoma.

MicroRNA as a Diagnostic Tool, Therapeutic Target and Potential Biomarker in Cutaneous Malignant Melanoma Detection-Narrative Review.

Melanoma is the most serious type of skin cancer, causing a large majority of deaths but accounting for only ~1% of all skin cancer cases. The worldwide incidence of malignant melanoma is increasing, causing a serious socio-economic problem. Melanoma is diagnosed mainly in young and middle-aged people, which distinguishes it from other solid tumors detected mainly in mature people. The early detection of cutaneous malignant melanoma (CMM) remains a priority and it is a key factor limiting mortality. Doctors and scientists around the world want to improve the quality of diagnosis and treatment, and are constantly looking for new, promising opportunities, including the use of microRNAs (miRNAs), to fight melanoma cancer. This article reviews miRNA as a potential biomarker and diagnostics tool as a therapeutic drugs in CMM treatment. We also present a review of the current clinical trials being carried out worldwide, in which miRNAs are a target for melanoma treatment.

Timeliness of diagnosis and treatment of cutaneous melanoma with dermatology, general practice, plastics surgery collaboration - are we meeting standards?

Introduction Melanoma is a serious type of skin cancer with a high burden in New Zealand. MelNet Quality Statements (2021) guide the timeliness of investigations and management for melanoma patients, who might experience long delays waiting for treatment. Aim To assess compliance of melanoma diagnosis and treatment timeliness with the MelNet Quality Statements at Waikato Hospital and in primary care for melanoma and melanoma in situ (MIS). Methods This is a retrospective clinical audit of patients referred via the Suspected Skin Cancer (SSC) teledermatology pathway between June 2020 and June 2022, and histologically confirmed as having melanoma or MIS. Time intervals between elements of service were analysed. Results For 43 melanomas and 105 MIS, compliance with MelNet Quality Statements across all melanoma services was poor, except for teledermatology response rates (100% compliance). From referral to first cancer treatment (Statement 2.1.1), compliance was 50% in general practice and 7.7% in Waikato Hospital. From teledermatologist response to biopsy (Statement 2.1.3), compliance was 65.2% in general practice and 7.7% in hospital plastics department. Histopathological reporting delays were also identified. Discussion Long delays for melanoma care in hospital likely reflect system failures (such as inadequate funding and human resources) and the increasing burden of skin cancer. In contrast, primary care provided quicker diagnostic biopsies and surgical treatments for melanoma.

PRAME Staining in Sinonasal Mucosal Melanoma: A Single-Center Experience.

Sinonasal mucosal melanoma (MM) is a rare, aggressive melanoma subtype. Complete surgical excision, with or without adjuvant radiotherapy, remains the cornerstone of treatment and yields adequate locoregional control. Metastatic MM is managed similarly to metastatic cutaneous melanoma but with poorer survival. PReferentially expressed Antigen in MElanoma (PRAME) has been identified as a potential diagnostic marker and therapeutic target in the treatment of cutaneous melanoma. Retrospective analysis of the clinical characteristics and immunohistochemical features of all sinonasal MM patients referred to the department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, between 2011 and 2021 was performed. Single nucleotide polymorphism (SNP) array and next-generation sequencing (NGS) were performed in selected cases. A total of 26 patients with an MM were included. The median follow-up duration was 15 months. At the end of follow-up, 13 patients had died due to progression of their disease, and one patient died of intercurrent disease. PRAME immunohistochemistry was performed in 23 out of 26 cases, all displaying PRAME expression. In two cases PRAME expression was present both within the melanoma cells and in melanocytes in adjacent mucosa. SNP array showed ≥ 5 copy number variants (CNV) in all tested cases, with a median of 29.5 CNVs (IQR 23.25-40). The three most common mutations identified by NGS were NRAS (7 cases) and NF1 (2 cases). We show that expression of PRAME is common in sinonasal MM, making PRAME a useful ancillary diagnostic tool and a potential therapeutic target in sinonasal MM. The demonstrated occurrence of extensive presence of PRAME-positive melanocytes in the surrounding mucosa of sinonasal MM might explain the multifocal nature of melanoma in the (sinonasal) mucosa, and would be an extra argument for a PRAME targeting treatment in preventing local disease recurrence.

LINC01296 promotes proliferation of cutaneous malignant melanoma by regulating miR-324-3p/MAPK1 axis.

To investigate the functions and potential molecular mechanism of LINC01296 regarding the progression of cutaneous malignant melanoma (CMM) by the regulation of miR-324-3p/MAPK1 axis. The candidate differential lncRNAs of CMM were selected from GEPIA database, and quantitative real-time PCR (qRT-PCR) was utilized to assess the expression level of LINC01296 in human CMM tissues and cell lines. Cell proliferation assay, Colony formation assay, Ethynyl-2'-deoxyuridine (EDU) assay in vitro and tumorigenicity assays in nude mice in vivo were performed to examine the functions of LINC01296. Bioinformatics analysis, luciferase reporter assay and rescue experiments were also gained an insight into the underlying mechanisms of LINC01296 in CMM cell lines by miR-324-3p/MAPK1 axis. In this study, the up-regulation of LINC01296 was found in CMM tissues and cell lines. Functionally, the over-expression of LINC01296 promoted the proliferation in CMM cell lines. In addition, immunochemistry analysis confirmed that the levels of MAPK1 and Ki-67 in sh-LINC01296-xenografted tumors was weaker than that in sh-NC-xenografted tumors. Then, bioinformatics analysis confirmed that LINC01296 interacted with miR-324-3p. Further investigations showed that MAPK1, which collected from the potential related genes of LINC01296, was the conjugated mRNA of miR-324-3p by luciferase reporter assay. Finally, the rescue experiments suggested the positive regulatory association among LINC01296 and MAPK1, which showed that MAPK1 could reverse the promoting-effect of LINC01296 in CMM cells in vitro. Therefore, our findings provided insight into the mechanisms of LINC01296 via miR-324-3p/MAPK1 axis in CMM, and revealed an alternative target for the diagnosis and treatment of CMM.

Interventions for treatment of cutaneous melanoma in horses: a structured literature review.

Several therapies have been developed to treat equine cutaneous melanoma, but formal comparisons among different treatment options are currently unavailable. It was our intent to assess the efficacy of different treatment protocols and the quality of the studies based on the original published data, and summarize the knowledge concerning the outcome after equine cutaneous melanoma management. This structured review followed PRISMA procedure to search for treatment protocols on equine cutaneous melanoma published from 1960 until June 2021. Studies were assessed for the risk of bias. A descriptive analysis was performed, considering the disease control rate, the recurrence rate of the tumor, comorbidities, need for anesthesia, and horses' welfare. Twenty-three studies were included, from which the treatment outcomes of 173 horses were assessed. The homogeneity of the included trials was low. The percentages of each treatment arm achieving a partial response and curative effects accounted for 93.1% (surgical intervention), 90% (medication), and 39.4% (immunotherapies), respectively. A variable efficacy of different therapies of equine cutaneous melanoma was observed. Surgical intervention performed the best from the perspective of local antitumor effects alone. This literature review and descriptive analysis can serve as a source to assist in designing quality therapy research and can potentially aid in providing a clinical treatment reference for equine cutaneous melanoma.

872P Ipilimumab-induced gastrointestinal and hepatic immune-related adverse events: A national cohort

There is a paucity of population-based data regarding ipilimumab-induced gastrointestinal and hepatic immune-related adverse events (irAE) during cutaneous melanoma treatment. We examined the risk and predictors of gastrointestinal and hepatic irAE in a national cohort of patients diagnosed with cutaneous melanoma. This retrospective study used Surveillance, Epidemiology and End Results - Medicare linked data of patients diagnosed with cutaneous melanoma between the years 2010 and 2015 treated with ipilimumab or other therapies. We excluded patients with preexisting gastrointestinal and hepatic conditions. Our endpoint was time to gastrointestinal and hepatic irAE after treatment. We used multivariable competing-risk analysis adjusted for death of any cause within one year of treatment as a competing event to estimate the risk of gastrointestinal and hepatic irAE. Then, we used a stepwise competing-risk model to assess the predictors of having at least one gastrointestinal and hepatic irAE among patients treated with ipilimumab. The covariates included were patient demographics, disease stage, prevalent autoimmune disease, history of hypertension, anticoagulant use, end-stage renal disease, steroid use, and Charlson Comorbidity Index. Overall, 620 out of 31,234 (2%) patients were treated with ipilimumab. Incidence rates of gastrointestinal and hepatic irAE among patients who received ipilimumab and controls were 32.3 and 4.0 per 1,000 person-years, respectively. Receiving ipilimumab was associated with an increased risk of gastrointestinal and hepatic irAE compared to controls (HR: 10.18, 95% CI: 8.11-12.78, p<.001). Other predictors of gastrointestinal and hepatic irAE are found in the table.Table: 872PSignificant predictors of gastrointestinal and hepatic immune-related adverse eventsCovariantEntire Cohort (n=31,234)Ipilimumab Cohort (n=620)Hazard Ratio †95 % Confidence Intervalp-valueHazard Ratio ‡95 % Confidence Intervalp-valueIpilimumab10.188.11 – 12.78<.001NANANAYear of Diagnosis0.880.84 – 0.91<.001---Gender1.201.04 – 1.38=.011---Charlson Comorbidity Index1.481.09 – 2.01=.011---Autoimmune Disease1.531.25 – 1.88<.0010.260.09 – 0.83=.023Hypertension1.531.28 – 1.83<.001---Anticoagulant1.341.11 – 1.60=.002---- Not significant at 0.05 threshold † Competing risk model (Fine & Gray method) ‡ Stepwise competing risk model. Open table in a new tab - Not significant at 0.05 threshold † Competing risk model (Fine & Gray method) ‡ Stepwise competing risk model. Patients treated with ipilimumab had higher risk of gastrointestinal and hepatic irAE than controls.Among patients who received ipilimumab, history of autoimmune disease was associated with lower risk of irAE.

Ocular Inflammatory Complications of Treatment for Metastatic Melanoma

ABSTRACT Purpose To characterize various ocular inflammatory complications arising from metastatic cutaneous melanoma therapies and their management. Methods Retrospective case series of patients who were referred to a tertiary uveitis practice for ophthalmic exam All patients received targeted metastatic cutaneous melanoma treatment, including BRAF/MEK inhibitors and various immunotherapies. Results 109 patients were identified, with 43 (39.4%) having 65 definitive instances of OIAE. Sixteen different OIAE were identified. Ipilimumab monotherapy and ipilimumab/nivolumab combination therapy were most commonly associated. Anterior uveitis was the most common OIAE (18/65, 27.7%). Thirty patients (69.8%) were managed with observation or topical steroid therapy. Only 4 patients required further therapies for OIAE, with one patient not attaining resolution. Conclusions and Relevance While a broad range of OIAE was identified, most were not vision-threatening and did not require discontinuation of the associated therapy.

AURKA is a prognostic potential therapeutic target in skin cutaneous melanoma modulating the tumor microenvironment, apoptosis, and hypoxia.

AURKA, Aurora kinase A encoding gene, is an important signaling hub gene for mitosis. In recent years, AURKA has been implicated in the occurrence and development of several cancers. However, its relationship with the tumor microenvironment in skin cutaneous melanoma (SKCM) and the molecular mechanisms underlying its effects are still unclear. We adopted a variety of bioinformatics methods to comprehensively analyze the potential carcinogenesis of AURKA in SKCM, and constructed a prognostic nomogram model. We also dentified an inhibitor targeting AURKA and verified its therapeutic effects against SKCM using the molecular docking technology. We found that abnormally high expression of AURKA was responsible for driving the occurrence and development of SKCM, and affected various pathological factors in SKCM. In addition, AURKA was established as an independent marker of poor SKCM prognosis. We also characterized the potential mechanisms by which AURKA manifests its effects in SKCM and found that AURKA inhibits the infiltration of CD8+ T cells and promotes hypoxia by activating the TGF-β signaling pathway. At the same time, the high AURKA expression group had higher tumor stemness index and promoted cell proliferation and metastasis. Finally, the small-molecule compound ZNC97018978 targeting AURKA screened by molecular docking technology can inhibit the proliferation, invasion and metastasis of SKCM. The possible mechanism is that ZNC97018978 induces apoptosis by arresting the cell cycle, thereby inhibiting cell proliferation. AURKA is the core hub gene driving the occurrence and development of SKCM, and its expression is regulated by epigenetic modifications. AURKA can regulate the infiltration level of various immune cells in the tumor microenvironment, reshape the immunosuppressive tumor microenvironment, and apoptosis, and hypoxia. Thus, it is a prognostic biomarker and potential therapeutic target in SKCM. ZNC97018978 is an effective and safe inhibitor of AURKA in vitro; its safety and effectiveness in vivo as a potential treatment for cutaneous melanoma should be further determined.