Melanoma In Clinical Practice Research Articles

LPCAT1 promotes melanoma cell proliferation via Akt signaling.

Melanoma is the most lethal type of skin cancer with an increasing cutaneous cancer‑related mortality rate worldwide. Despite therapeutic advances in targeted therapy and immunotherapy, the overall survival of patients with melanoma remains unsatisfactory. Thus, a further understanding of the pathogenesis of melanoma may aid towards the development of therapeutic strategies. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is a key enzyme that converts lysophosphatidylcholine into phosphatidylcholine in lipid remodeling. In the present study, LPCAT1 was found to play a pro‑proliferative role in melanoma. Firstly, the expression of LPCAT1 was found to be upregulated in tissues from patients with melanoma compared with that in benign nevi. Subsequently, LPCAT1 knockdown was performed, utilizing short hairpin RNA, which induced melanoma cell cycle arrest at the G1/S transition and promoted cell death. Moreover, LPCAT1 facilitated melanoma cell growth in an Akt‑dependent manner. In summary, the results of the present study indicate that targeting LPCAT1 may impede cell proliferation by inhibiting Akt signaling, thus providing a promising therapeutic strategy for melanoma in clinical practice.

Real-World Effectiveness, Safety, and Health-Related Quality of Life in Patients Receiving Adjuvant Nivolumab for Melanoma in Belgium and Luxembourg: Results of PRESERV MEL.

Nivolumab, an anti-programmed cell death 1 immuno-oncology therapy, is approved as an adjuvant treatment for patients with completely resected stage III or stage IV melanoma. PRESERV MEL (Prospective and REtrospective Study of nivolumab thERapy in adjuVant MELanoma) is a real-world observational study evaluating the effectiveness and safety of adjuvant nivolumab in patients with completely resected stage III or stage IV melanoma in clinical practice in Belgium and Luxembourg. Patients were enrolled prospectively and retrospectively during a 2-year period (January 2019-January 2021), and will be followed for 5 years. The results reported here are for the second interim analysis (cutoff date 31 December 2021). The index date was the date of first administration of adjuvant nivolumab. Patients received nivolumab for up to 12 months per label. Outcomes included relapse-free survival (RFS), adverse events (AEs)/treatment-related AEs (TRAEs), and health-related quality of life (HRQoL; assessed in prospectively enrolled patients using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30), Functional Assessment of Cancer Therapy-Melanoma (FACT-M), and EQ-5D-3L instruments). HRQoL was evaluated at group level (mean change in scores from baseline based on minimally important differences) and individual patient level (percentage of patients with clinically important scores based on threshold of clinical importance). Outcomes were analyzed descriptively. The study enrolled 152 patients (125 prospective, 27 retrospective) at 15 hospitals in Belgium and Luxembourg. Minimum potential follow-up at time of analysis was 11.4 months. Median age was 60 years (range 29-85), and 53% of patients were male. At 12 and 18 months, the RFS rates were 74.7% (95% confidence interval (CI): 66.9-80.9) and 68.4% (95% CI: 60.0-75.5), respectively. Median RFS was not reached. Grade 3 or 4 TRAEs were reported in 14% of patients. AEs led to treatment discontinuation in 23% of patients. Deaths occurred in 3% of patients and were not related to treatment. Questionnaire completion rates for HRQoL were high at baseline (90-94%) and at 24 months (78-81%). In the group-level analysis for HRQoL, mean changes in scores from baseline remained stable and did not exceed prespecified thresholds for minimally important differences during and after treatment, except for a clinically meaningful improvement in FACT-M surgery subscale scores. In the individual patient-level analysis for EORTC QLQ-C30 subscales, the percentages of patients who reported clinically relevant scores for fatigue and cognitive impairment increased during treatment (at 9 months) compared with baseline. After treatment cessation (at 18 months), the percentage of patients who reported clinically relevant scores for fatigue decreased. However, the percentages of patients who reported clinically relevant scores for emotional, cognitive, and social impairment increased at 18 months compared with during treatment. Most patients with emotional impairment at 9 and 18 months did not experience disease recurrence (91% and 89%, respectively). These results confirm the real-world effectiveness and safety of nivolumab as an adjuvant treatment for patients with completely resected stage III or stage IV melanoma. Cancer-specific, disease-specific, and generic HRQoL were maintained during and after treatment. The percentage of patients reporting emotional and cognitive impairment increased after treatment cessation, emphasizing the need for further investigation and tailored supportive care in these patients.

Real-world efficacy and safety data of anti-PD-1 plus anti-CTLA-4 combination therapy in Chinese patients with advanced melanoma.

e21530 Background: Combination of anti-PD-1 plus anti-CTLA-4 has shown superior efficacy over monotherapy in advanced melanoma among Caucasian populations. However, it has not been evaluated in Chinese patients, and data on acral and mucosal melanoma are limited. We aimed to assess the efficacy and safety of anti-PD-1 antibody plus ipilimumab therapy in Chinese patients with advanced melanoma in clinical practice. Methods: Advanced melanoma patients treated with anti-PD-1 antibody combined with ipilimumab in Sun-Yat sen University Cancer Center from May 2015 to October 2022 were retrospectively assessed. Patient baseline characteristics, tumor responses (RECIST), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis. Toxicity was assessed to estimate safety. Results: Altogether, 86 patients were included. The primary site was cutaneous, acral, mucosal, uveal and central nervous system (CNS) in 34, 21, 20, six and five patients, respectively. Among them, 21 patients were treatment-naive, 65 patients were previously treated, and 54 patients progressed of front-line ani-PD-1 therapy. 12 patients received ipilimumab 3mg/kg combined with low dose anti-PD-1 (Nivolumab 80mg or Pembrolizumab 1mg/kg) Q3w for four doses, and the other 74 patients received standard dose of anti-PD-1 plus ipilimumab 1mg/kg Q3w therapy. There were 25(29%) patients with liver metastasis and 26(30.2%) patients with CNS metastasis at baseline. The overall response rate (ORR) was 15.1% in the whole cohort, with complete response observed in six (6%) patients, partial response in 7 (8.1%), stable disease in 28 (32.6%). The response rate in the treatment-naive and prior systemic therapy group was 23.8% and 12.3%, respectively. For those treated with anti-PD-1 followed by the anti-PD-1+ ipilimumab as subsequent therapy after disease progression, the ORR was 11.1%. The response rate for cutaneous melanoma was 23.5%, and 37.5% in the naïve group. Response rates for acral, uveal, CNS and mucosal melanoma were 19.0%, 16.7%,0% and 0% respectively. The median progression-free survival (PFS) and overall survival (OS) in all patients was 4.5 (3.6-5.4) months and 22.0 (12.4-31.6) months, respectively. The 3-year OS were 100% in patients who achieved ORR. There were no significant differences in PFS or OS for patients with cutaneous or acral melanoma. mucosal primary tumor type, liver metastasis and elevated LDH were predictive of shorter PFS and OS. CNS metastasis, previous treatment, BRAF/NRAS mutation status and sex were not found to be related to survival. Adverse events occurred in 71% of patients and 13% were grade 3 or worse. Conclusions: The efficacy of anti-PD-1+ ipilimumab combination therapy in Chinese patients tended to be inferior compared to global studies but was well tolerated. OS were good in cases with CR or PR.

Systemic adjuvant therapy for high-risk cutaneous melanoma.

Cutaneous melanoma continues to increase in incidence and poses a significant mortality risk. Surgical excision of melanoma in its early stages is often curative. However, patients with resected stages IIB-IV are considered at high risk for relapse and death from melanoma where systemic adjuvant therapy is indicated. The long-studied high-dose interferon-α was shown to improve relapse-free survival (RFS) and overall survival (OS) but is no longer in use. Adjuvant therapy with ipilimumab at 10 mg/kg (ipi10) demonstrated significant RFS and OS improvements but at a high cost in terms of toxicity, while adjuvant ipilimumab 3 mg/kg was shown to be equally effective and less toxic. More recently, the adjuvant therapy for resected stages III-IV melanoma in clinical practice has changed in favor of nivolumab, pembrolizumab, and BRAF-MEK inhibitors dabrafenib plus trametinib (for BRAF mutant melanoma) based on significant improvements in RFS as compared to ipi10 (nivolumab and pembrolizumab) and placebo (dabrafenib plus trametinib). For resected stages IIB-IIC melanoma, pembrolizumab achieved regulatory approval in the United States based on significant RFS benefits. In this article, we review completed and ongoing phase III adjuvant therapy trials. We also briefly discuss neoadjuvant therapy for locoregionally advanced melanoma. Finally, we explore recent studies on predictive and prognostic melanoma biomarkers in the adjuvant setting.

Adjuvant treatment for melanoma in clinical practice – Trial versus reality

BackgroundLittle is known about outcomes of adjuvant-treated melanoma patients beyond the clinical trial setting. Since 2019, adjuvant-treated melanoma patients have been registered in the DMTR, a population-based registry to monitor the quality and safety of melanoma care in the Netherlands. This study aims to describe treatment patterns, relapse, and toxicity rates of adjuvant-treated melanoma patients beyond the clinical trial setting. MethodsAnalyses were performed on adjuvant-treated melanoma patients included in the DMTR. Descriptive statistics were used to analyse patient-, and treatment characteristics. A baseline registration completeness analysis was performed, and an analysis on trial eligibility in clinical practice patients. Recurrence-free survival (RFS) at 12-months was estimated with the Kaplan–Meier method. ResultsA total of 641 patients were treated with adjuvant anti-PD-1 therapy. RFS at 12-months was 70.6% (95% CI, 66.9–74.6) with a median follow-up of 12.8 months. Sex, stage of disease and Breslow thickness were associated with a higher hazard for RFS. Eighteen per cent of the anti-PD-1-treated patients developed grade ≥3 toxicity. Sixty-one per cent of patients prematurely discontinued anti-PD-1 therapy. ConclusionAdjuvant anti-PD-1 treatment of resected stage III/IV melanoma in daily practice showed slightly higher toxicity rates and more frequent premature discontinuation but similar RFS rates compared to trials.

Early Cost-effectiveness Analysis of Electrochemotherapy as a Prospect Treatment Modality for Skin Melanoma

PurposeElectrochemotherapy is increasingly entering into national and international guidelines, requiring formal evaluation of treatment costs and cost-effectiveness to ensure that its uptake provides value to budget-constrained health care systems. This study analyzed the early cost-effectiveness of electrochemotherapy in patients with Stage IIIc/IV skin melanoma in clinical practice in Slovenia. The costs of electrochemotherapy were compared to those of the standard of care, consisting of palliative treatment and therapy for symptoms. MethodswThe study enrolled 23 patients treated with electrochemotherapy at the Institute of Oncology (Ljubljana, Slovenia). The mean cost of electrochemotherapy was estimated using patient-specific cost data on electrochemotherapy procedures and subsequent follow-up. Quality-adjusted life-years (QALYs) were estimated by collecting EQ-5D-3L questionnaires at baseline, after complete or partial response following the treatment, and after a relapse of skin lesions. A discrete-time Markov model was built to estimate the lifetime costs and consequences of using electrochemotherapy compared to standard of care, from the perspective of the Slovenian health care system. The analysis was conducted separately in the whole patient sample and in the subset of patients with bleeding lesions. Deterministic and probabilistic sensitivity analyses were conducted to test model assumptions and to characterize the uncertainty around model parameters. FindingsIn the whole patient population, electrochemotherapy for skin melanoma Stage IIIc/IV was expected to increase QALYs by 0.29 (95% credible interval [CrI], 0.10–0.50), at the higher cost of 6568 EUR (95% CrI, 4593–8928) in comparison to the standard of care. At the cost-effectiveness threshold of 20,000 EUR/QALY, the estimated probabilities of electrochemotherapy being cost-effective compared to standard of care were 0.30 and 0.91 in the whole patient sample and in patients with bleeding lesions, respectively. In the whole sample population, a 50% reduction in the price of the electrodes was expected to increase the probability of electrochemotherapy being cost-effective from 0.30 to ~0.64. ImplicationsThe findings from this cost-effectiveness analysis of data from clinical practice were based on a small sample size (ie, 23 patents), which made the subgroup of patients with bleeding lesions very small. Therefore, the findings in this patient population should be carefully interpreted.

Observational study of talimogene laherparepvec use for melanoma in clinical practice in the United States (COSMUS-1).

Aim:Talimogene laherparepvec (T-VEC) is an intralesional treatment for unresectable cutaneous, subcutaneous and nodal melanoma. COSMUS-1 was conducted to examine how T-VEC is used in US clinical practice.Materials & methods:A chart review was conducted at seven centers, with 78 patients screened and 76 eligible.Results:Patients began treatment with T-VEC between October 2015 and December 2016. Median follow-up was 9.4 months. Twenty percent of patients (n = 15) completed T-VEC treatment with no remaining injectable lesions or pathologic complete response. Flu-like symptoms were the most commonly reported adverse events (n = 8; 10.5%), followed by lesion ulceration (n = 4; 5.3%). No herpetic lesions or infections were reported.Conclusion:T-VEC was well tolerated and showed clinical utility.

Moxifloxacin as an inducer of apoptosis in melanoma cells: A study at the cellular and molecular level

Fluoroquinolones were shown to be cytotoxic towards various cancer cell lines, thus representing a potentially important source of new anticancer agents. The aim of the present study was to examine the effect of moxifloxacin on cell viability, redox balance and apoptosis in both amelanotic – C32 and melanotic – COLO829 melanoma cells. Herein, we found that moxifloxacin decreases the viability of C32 and COLO829 cells in concentration- and time-dependent manner. The EC50 values were found to be as 0.16 mM, 0.12 mM and 0.11 mM for amelanotic C32 cells as well as 0.40 mM, 0.22 mM and 0.15 mM for COLO829 cells and 24, 48, 72 h incubation time, respectively. Moxifloxacin have also induced the intracellular disulphide imbalance and apoptosis as shown by externalization of phosphatidylserine, caspase-3/7 activation, G2/M cell cycle arrest and DNA fragmentation. The mechanism of apoptosis was related to the loss of mitochondrial membrane potential. This is the first study that characterized cellular and molecular mechanism underlying moxifloxacin cytotoxic and pro-apoptotic effect towards melanoma cells. Although further studies are required to establish efficacy of moxifloxacin against melanoma in clinical practice, the results of current study strongly suggest, that moxifloxacin is promising candidate as a repositioned drug for anti-melanoma treatment.

PCN60 - Newest Target Therapy And Immunotherapy for the Treatment of Advanced Melanoma: Patterns of Adoption By the Private Health Care Sector in Brazil

We aimed to assess which new treatments for advanced melanoma (AM) are adopted by the Brazilian Private Health Care Sector (PHCS) and describe the profile of patients receiving those therapies. Anonymized, clinical data were retrieved on patients treated for AM during 2016, from a proprietary database of claims (Auditron® - Evidências-Kantar Health) encompassing 20% of people covered by PHCS in Brazil. Evaluated drugs had at least ten months of registry in the National Agency of Sanitary Vigilance (ANVISA): vemurafenib, nivolumab, ipilimumab, dabrafenib, trametinib and cobimetinib. Volume of disease was defined as high (visceral or bone lesions, > one site) or low (single visceral lesion or soft tissue lesions only). Eighty-four patients were included for analysis. Ipilimumab was prescribed for 62% of cases (35% in 1st line; 54% 2nd line and 11% 3rd plus lines). Half these patients had high volume of disease (HVD) and 9.5% had controlled lesions in central nervous system (CNS). Ipilimumab was preceded by 1st line chemotherapy in 92% of cases. Vemurafenib was the second most prescribed new drug (24%) with 50% in 1st line; 35% in 2nd line and 15% in 3rd plus lines. Among these patients, 65% had HVD and 10% had controlled CNS lesions. BRAF status was informed for only 50% of cases. Finally, 13% of patients received nivolumab (73% in 1st line and 27% 2nd line); all had HVD. We retrieved one prescription of cobimetinib for 2nd line in a BRAF+ patient progressing after vemurafenib. No prescriptions for dabrafenib or trametinib were retrieved. Older therapies, like ipilimumab and vemurafenib are already adopted to treat advanced melanoma in clinical practice in Brazil. Prescriptions for more recently approved therapies remain scarce maybe because some are oral medications still unlisted in the regulatory organs’ directory or because they have very specific indications.

Talimogene Laherparepvec for Treating Metastatic Melanoma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Amgen) of talimogene laherparepvec (T-VEC) to submit clinical and cost-effectiveness evidence for previously untreated advanced (unresectable or metastatic) melanoma as part of the Institute's Single Technology Appraisal process. The Liverpool Reviews and Implementation Group (LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article presents a summary of the company's submission of T-VEC, the ERG review and the resulting NICE guidance (TA410), issued in September 2016. T-VEC is an oncolytic virus therapy granted a marketing authorisation by the European Commission for the treatment of adults with unresectable melanoma that is regionally or distantly metastatic (stage IIIB, IIIC and IVM1a) with no bone, brain, lung or other visceral disease. Clinical evidence for T-VEC versus granulocyte-macrophage colony-stimulating factor (GM-CSF) was derived from the multinational, open-label randomised controlled OPTiM trial [Oncovex (GM-CSF) Pivotal Trial in Melanoma]. In accordance with T-VEC's marketing authorisation, the company's submission focused primarily on 249 patients with stage IIIB to stage IV/M1a disease who constituted 57% of the overall trial population (T-VEC, n=163 and GM-CSF, n=86). Results from analyses of durable response rate, objective response rate, time to treatment failure and overall survival all showed marked and statistically significant improvements for patients treated with T-VEC compared with those treated with GM-CSF. However, GM-CSF is not used to treat melanoma in clinical practice. It was not possible to compare treatment with T-VEC with an appropriate comparator using conventionally accepted methods due to the absence of comparative head-to-head data or trials with sufficient common comparators. Therefore, the company compared T-VEC with ipilimumab using what it described as modified Korn and two-step Korn methods. Results from these analyses suggested that treatment with T-VEC was at least as effective as treatment with ipilimumab. Using the discounted patient access scheme (PAS) price for T-VEC and list price for ipilimumab, the company reported incremental cost-effectiveness ratios (ICERs) per quality-adjusted life-year (QALY) gained. For the comparison of treatment with T-VEC versus ipilimumab, the ICER per QALY gained was -£16,367 using the modified Korn method and -£60,271 using the two-step Korn method. The NICE Appraisal Committee (AC) agreed with the ERG that the company's methods for estimating clinical effectiveness of T-VEC versus ipilimumab were flawed and therefore produced unreliable results for modelling progression in stage IIIB to stage IVM1a melanoma. The AC concluded that the clinical and cost effectiveness of treatment with T-VEC compared with ipilimumab is unknown in patients with stage IIIB to stage IV/M1a disease. However, the AC considered that T-VEC may be a reasonable option for treating patients who are unsuitable for treatment with systemically administered immunotherapies (such as ipilimumab). T-VEC was therefore recommended by NICE as a treatment option for adults with unresectable, regionally or distantly metastatic (stage IIIB to stage IVM1a) melanoma that has not spread to bone, brain, lung or other internal organs, only if treatment with systemically administered immunotherapies is not suitable and the company provides T-VEC at the agreed discounted PAS price.

Curcumin: A new candidate for melanoma therapy?

Melanoma remains among the most lethal cancers and, in spite of great attempts that have been made to increase the life span of patients with metastatic disease, durable and complete remissions are rare. Plants and plant extracts have long been used to treat a variety of human conditions; however, in many cases, effective doses of herbal remedies are associated with serious adverse effects. Curcumin is a natural polyphenol that shows a variety of pharmacological activities including anti-cancer effects, and only minimal adverse effects have been reported for this phytochemical. The anti-cancer effects of curcumin are the result of its anti-angiogenic, pro-apoptotic and immunomodulatory properties. At the molecular and cellular level, curcumin can blunt epithelial-to-mesenchymal transition and affect many targets that are involved in melanoma initiation and progression (e.g., BCl2, MAPKS, p21 and some microRNAs). However, curcumin has a low oral bioavailability that may limit its maximal benefits. The emergence of tailored formulations of curcumin and new delivery systems such as nanoparticles, liposomes, micelles and phospholipid complexes has led to the enhancement of curcumin bioavailability. Although in vitro and in vivo studies have demonstrated that curcumin and its analogues can be used as novel therapeutic agents in melanoma, curcumin has not yet been tested against melanoma in clinical practice. In this review, we summarized reported anti-melanoma effects of curcumin as well as studies on new curcumin formulations and delivery systems that show increased bioavailability. Such tailored delivery systems could pave the way for enhancement of the anti-melanoma effects of curcumin.

Evidence-Based Dermoscopy

Dermoscopy has been shown in meta-analyses to improve the diagnostic accuracy of melanoma unequivocally compared with naked eye examination and to reduce excision rates of benign melanocytic lesions in clinical trials. Sequential digital dermoscopy imaging (SDDI) allows the detection of dermoscopic featureless melanoma. When used in high-risk individuals or on individual suspicious melanocytic lesions, it has a gross impact for detecting melanoma in clinical practice, with a range of 34% to 61% of melanomas detected exclusively using SDDI in these patients. Furthermore, SDDI has been shown to reduce the excision of benign lesions when used in combination with dermoscopy.

Diagnosis and Management of Melanoma in Clinical Practice

In the last decade there has been no major clinical mono- graph on this increasingly common and difficult malignancy which is a killer of young people. The gap in the literature is now filled by this authoritative volumewhich will be essential reading for any body involved in the study or management of melanoma.

Radioimmunodetection of melanoma: preliminary results of a prospective study.

A prospective study to evaluate the clinical usefulness of radioimmunodetection of melanoma in clinical practice is ongoing at the National Cancer Institute of Milan, Italy. Technical conditions for the application of the method were previously reported. In this trial, 99mTc-labelled F(ab')2 fragments of the 225.28S monoclonal antibody were used against a high molecular weight melanoma associated antigen (HMW-MAA). Retrospective studies on radioimmunodetection of melanoma have already been made by our group and by other Centers in about 300 patients. This study concerns the evaluation of the regional extension of primary melanoma. 23 patients with 32 suspected lymphatic involvements of melanoma on the trunk and arms underwent immunoscintigraphy. No false positive results were observed; 3 false negatives, one corresponding to a micrometastasis, were noticed. Specificity corresponds to 100% and sensitivity to 78.6%.