Course Of Melanoma Research Articles

Review of pharmacoeconomic studies of melanoma treatment for the period 2018–2023

When analyzing pharmacoeconomic studies of the skin melanoma treatment conducted in various countries, the combinations of vemurafenib + cobimetinib and encorafenib + binimetinib are the most acceptable therapy options in terms of increasing life expectancy with adjustments for quality, but, according to the clinical guidelines of the National Joint Oncology Network (NCCN), USA, version 2.2023 – “Melanoma: Cutaneous”, not for adjuvant therapy. At the same time, social networks can be a valuable asset of information about patient’s quality of the life. For the patients with advanced melanoma with a BRAF mutation, the combination of atezolizumab + vemurafenib + cobimetinib indicated the highest clinical effectiveness and can be recommended for pharmacotherapy under condition of drug price reduction.Comparison various drugs combinations with monotherapy for patients with unresectable or metastatic melanoma with a positive BRAF V600 mutation indicated that nivolumab + ipilimumab therapy is not cost-effective in comparison with nivolumab monotherapy, but combination of dabrafenib + trametinib, on the contrary, increases the patient's life expectancy compared to vemurafenib and it’s more cost-effective. It was shown that Pembrolizumab to increase life expectancy but it’s associated with increased costs compared to ipilimumab when comparing different monotherapy options. The assumed additional cost-effectiveness factor is acceptable for most European countries, because it does not exceed the “willingness to pay” threshold. It is necessary to conduct large-scale pharma-economic studies in order to identify the most cost-effective treatment for Russia for various variants of the course of melanoma, both of various combined regimens with each other, and their comparison with monotherapy. It is important to take into account also the costs of correcting undesirable adverse drug reactions, since they have a significant impact to the structure of direct costs. The development of innovative drugs for the treatment of melanoma is proceeding rapidly, however, access to these drugs is limited due to their high cost. Patient-centred drug development and reimbursement options need to be found.

Features of the course of melanoma during pregnancy

В статье представлен клинический случай меланомы, ассоциированной с беременностью, показано крайне агрессивное течение заболевания, приведшее к летальному исходу беременной пациентки. Представленный клинический случай наглядно продемонстрировал негативное влияние беременности на клиническое течение меланомы: от момента появления первых клинических признаков до смерти пациентки прошло меньше месяца. Современный анализ литературы по частоте встречаемости и особенностях клинического течения меланомы на фоне беременности показал, что беременные женщины на момент диагностики злокачественного заболевания имеют менее благоприятный прогноз развития меланомы, чем не беременные.

Baseline gene expression profiling determines long-term benefit to programmed cell death protein 1 axis blockade

Treatment with immune checkpoint inhibitors has altered the course of malignant melanoma, with approximately half of the patients with advanced disease surviving for more than 5 years after diagnosis. Currently, there are no biomarker methods for predicting outcome from immunotherapy. Here, we obtained transcriptomic information from a total of 105 baseline tumor samples comprising two cohorts of patients with advanced melanoma treated with programmed cell death protein 1 (PD-1)-based immunotherapies. Gene expression profiles were correlated with progression-free survival (PFS) within consecutive clinical benefit intervals (i.e., 6, 12, 18, and 24 months). Elastic net binomial regression models with cross validation were utilized to compare the predictive value of distinct genes across time. Lasso regression was used to generate a signature predicting long-term benefit (LTB), defined as patients who remain alive and free of disease progression at 24 months post treatment initiation. We show that baseline gene expression profiles were consistently able to predict long-term immunotherapy outcomes with high accuracy. The predictive value of different genes fluctuated across consecutive clinical benefit intervals, with a distinct set of genes defining benefit at 24 months compared to earlier outcomes. A 12-gene signature was able to predict LTB following anti-PD-1 therapy with an area under the curve (AUC) equal to 0.92 and 0.74 in the training and validation set, respectively. Evaluation of LTB, via a unique signature may complement objective response classification and characterize the logistics of sustained antitumor immune responses.

Protease Profile of Tumor-Associated Mast Cells in Melanoma.

Mast cells (MCs) produce a variety of mediators, including proteases—tryptase, chymase, and carboxypeptidases—which are important for the immune response. However, a detailed assessment of the mechanisms of biogenesis and excretion of proteases in melanoma has yet to be carried out. In this study, we present data on phenotype and secretory pathways of proteases in MCs in the course of melanoma. The development of melanoma was found to be accompanied by the appearance in the tumor-associated MC population of several pools with a predominant content of one or two specific proteases with a low content or complete absence of others. Elucidation of the molecular and morphological features of the expression of MC proteases in melanoma allows us a fresh perspective of the pathogenesis of the disease, and can be used to clarify MCs classification, the disease prognosis, and evaluate the effectiveness of ongoing antitumor therapy.

Multiple metastases in central nervous system and subdural hematoma in the course of melanoma.

Multiple metastases in central nervous system and subdural hematoma in the course of melanoma.

Survival of Women Previously Diagnosed of Melanoma with Subsequent Pregnancy: A Systematic Review and Meta-Analysis and a Single-Center Experience.

Melanoma incidence has increased over the last few decades. How the prognosis of a previously diagnosed melanoma may be affected by a woman’s subsequent pregnancy has been debated in the literature since the 1950s, and the outcomes are essential to women who are melanoma survivors in their childbearing years. The main objective of this systematic review is to improve the understanding of whether the course of melanoma in a woman may be altered by a subsequent pregnancy and to help clinicians’ diagnosis. Eligible studies for the systematic review were clinical trials, observational cohort studies and case-control studies that compared prognosis outcomes for non-pregnant patients with melanoma, or pregnant before melanoma diagnosis, versus pregnant patients after a diagnosis of melanoma. The search strategy yielded 1101 articles, of which 4 met the inclusion criteria for the systematic review. All the studies were retrospective non-randomised cohorts with patients with melanomas diagnosed before pregnancy. According to our findings, a subsequent pregnancy was not a significant influence on the outcome of a previous melanoma. However, given the small number of identified studies and the heterogeneous data included, it is recommended to approach these patients with caution, and counselling should be given by known prognostic factors. We also reviewed the medical records of 84 patients of childbearing age (35.8 ± 6.3 years, range 21–45 years) who were diagnosed with cutaneous invasive melanoma in our hospital between 2008 and 2018 (N = 724). Of these, 11 (13.1%) had a pregnancy after melanoma diagnosis (age at pregnancy: 35.6 ± 6.3 years). No statistical differences in outcome were detected.

Évolution du statut braf dans le melanome : mythe ou Réalité ?

Knowledge of the BRAF mutational status has become essential for melanoma therapeutic management. B-Raf inhibitors are associated with significant overall survival in patients with BRAFV600-mutated metastatic melanoma. Although the BRAF mutation appears to be an early and driver mutation, some authors hypothesized that its expression was not stable during melanoma progression, suggesting a molecular heterogeneity. This argument is often used to explain discrepancy in molecular status among patients with melanoma, discrepancies that we occasionally met during our practice. We retrospectively compared BRAF mutational status on matched melanoma samples (primary & metastatic lesions), thus 150 samples from 56 patients were analysed through immunohistochemistry anti-BRAF, PCR-HRM and Sanger sequencing, Next Generation Sequencing (NGS) and digital PCR. Seven cases presented an apparent tumor heterogeneity. The analysis of these discrepancies by a technique of increasing sensitivity made it possible to identify 1 false-negative result for the immunohistochemistry, 1 false-negative result for the NGS sequencing and 5 (3%) false-negative results by PCR-HRM SANGER. Our results are consistent with the most recent data, demonstrating the stability of the BRAF mutation during the course of melanoma. Immunohistochemistry shows excellent sensitivity for detecting the main BRAF mutation. In our study, the mutational heterogeneity was actually misleading, a result of imperfect sensitivity of some older molecular approaches.

The role of the <i>C3435T</i> polymorphic marker of the <i>ABCB1</i> gene in the development of early choroidal melanoma

The aim of the work is to find out how the ABCB1 C3435T polymorphism gene is associated with the risk of early choroid melanoma (ECM) and to study the genotypes distribution frequency of the ABCB1 polymorphic gene in ECM patients. Material and methods . The prospective study included 26 previously untreated ECM patients (7 men and 19 women) aged 32 to 80 (mean age 59.0 ± 14.3 years). All patients underwent general ophthalmological examinations and special instrumental diagnostics (ultrasound examination, spectral optical coherence tomography, OCT angiography). Monolateral ECM was diagnosed in 25 patients (96 %), bilateral ECM in 1 patient (4 %). In all, 27 eyes were affected. The material for the study was genomic DNA taken from peripheral blood leukocytes from patients with ECM. Genotyping was carried out using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Results . Significant associations were found between (1) the CC genotype and the risk of ECM and (2) between the TT genotype and a low risk of tumor development. A reliable association of the CT genotype of the ABCB1 C3435T polymorphism gene with the presence of orange pigment on the tumoral surface and the familial cancer history of ECM patients was revealed. Conclusion . In the future, the obtained results can be used in the development of innovative approaches predicting the course of melanoma, and in patient screening.

A Possible Link of Genetic Variations in ER/IGF1R Pathway and Risk of Melanoma.

The mechanism of gender disparity in cutaneous melanoma incidence remains unclear. Steroid hormones including estrogens have long been implicated in the course of melanoma, but the conclusion is controversial. Estrogen receptors (ERs) and insulin-like growth factor 1 receptor (IGF1R) show extensive crosstalk in cancer development, but how the ER/IGF1R network impacts melanoma is currently unclear. Here we studied the melanoma associations of selected SNPs from the ER/IGF1R network. Part of the International Genes, Environment, and Melanoma (GEM) cohort was used as a discovery set, and the Gene Environment Association Studies Initiative (GENEVA) dataset served as a validation set. Based on the associations with other malignant disease conditions, thirteen single nucleotide polymorphism (SNP) variants in ESR1, ESR2, IGF1, and IGF1R were selected for candidate gene association analyses. The rs1520220 in IGF1 and rs2229765 in IGF1R variants were significantly associated with melanoma risk in the GEM dataset after Benjamini-Hochberg multiple comparison correction, although they were not validated in the GENEVA set. The discrepancy may be caused by the multiple melanoma characteristics in the GEM patients. Further analysis of gender disparity was carried out for IGF1 and IGF1R SNPs in the GEM dataset. The GG phenotype in IGF1 rs1520220 (recessive model) presented an increased risk of melanoma (OR = 8.11, 95% CI: 2.20, 52.5, p = 0.006) in men but a significant opposite effect in women (OR = 0.15, 95% CI: 0.018, 0.86, p = 0.045). The AA genotype in IGF1R rs2229765 (recessive model) showed a significant protective effect in men (OR = 0.24, 95% CI: 0.07, 0.64, p = 0.008) and no effect in women. Results from the current study are warranted for further validation.

BRAF V600E mutation as a prognostic factor in cutaneous melanoma patients.

The prognostic significance of BRAF mutations in the natural course of melanoma is controversial. The aim of study was to assess the prognostic significance of BRAF V600E mutation in cutaneous melanoma patients. A total of 151 melanomas were included in the study. BRAF V600E mutation was detected using the real-time PCR. BRAF V600E mutation rate was 51%. BRAF mutation rate was higher for young patients (61.4%) and upper limbs (63.2%), trunk (59.3%) and head and neck (59.2%) were the most frequently afflicted sites in BRAF-mutant patients, whereas lower limbs were mostly affected in BRAF-wild patients (77.8%). Likewise, acral melanomas rarely harbored BRAF mutation (17.1%). The disease-free survivals regarding the entire and Stage III cohorts were longer in the BRAF-mutant group than in the BRAF-wild group (p = .006 and p = .004, respectively), whereas Stage I-II patients had no survival differences between BRAF statuses (p = .2). Likewise, BRAF-mutant patients had better overall survival (OS) time compared to BRAF-wild patients in all stages (p = .01), in Stage III (p = .01), and in Stage IV patients (p = .001). However, no differences between BRAF statuses were observed in Stage I-II melanomas (p = .3). In conclusion, BRAF V600E-mutant melanomas show favorable prognostic impact on both disease-free and OSs in all staged melanomas except local disease.

Late recurrence of melanoma after 10years - Is the course of the disease different from early recurrences?

It is known that melanoma can metastasize and recur many years after the first diagnosis. Although predictive and prognostic factors for melanoma are well defined, there is still insufficient information about the factors affecting the recurrence period and the effect of the recurrence time to survival. This study investigates the course of melanoma to show prognostic factors comparing early and late recurrence patients. The main objective is to uncover the effect of the recurrence time on the progression of the disease. In this retrospective study, late recurrence (LR) was defined as melanoma recurrence 10years after the first diagnosis and early recurrence (ER) was defined as recurrence within 10years. Gender, age, localization of primary tumour, time to first metastasis, survival rates, histological subtype, stage, tumour thickness, invasion level, ulceration and regression of the primary melanoma were documented. Survival curves were evaluated using the Kaplan-Meier and compared with the log-rank test. Multivariate Cox proportional hazard models were used to identify significant independent prognostic factors for melanoma-specific survival (MSS). A total of 1537 melanoma patients were analysed. Early metastasis was developed in 1438 patients (93.6%), and 99 patients (6.4%) developed late metastasis. Late recurrence patients were younger (P<0.001) and had fewer ulcerated (P=0.005), fewer head/neck localized (P=0.009) and thinner (P<0.001) melanomas than ER patients. The MSS time (mean±SD) was nearly identical for LR (31±4.4months 95% CI [22.3-39.7]) and ER (32±1.9months [28.3-35.7]). Multivariate regression analysis revealed male gender (hazard ratio [HR=1.4, P<0.001), truncal tumour localization (HR=1.7, P<0.001), tumour thickness (HR=1.4, P<0.045) and ulceration (HR=1.3, P<0.008) as significant independent prognostic factors for MSS. Although ER and LR patients are found to have different clinicopathologic features, the time of the first recurrence after diagnosis do not seem to have an effect on the survival.

Primary diffuse meningeal melanomatosis \u2013 a rare form of meningeal melanoma: case report

BackgroundMeningeal melanomatosis is a rare type of central nervous system neoplasm (with incidence ranging between 3 and 5%) that develops in the course of malignant melanoma. In a small percentage of cases, meningeal melanomatosis may develop without a primary focus. It affects the leptomeninx. The clinical activity of the disease is uncharacteristic, with a number of neurological symptoms developing over weeks or months.Case presentationA 45-year-old male patient presented with consciousness disturbance, cognitive dysfunctions, seizures and progressive paresis. None of the examinations performed, including cerebrospinal fluid examination, neuroimaging and biopsy of the leptomeninges, permitted us to establish a diagnosis during the patient’s hospital stay. The diagnosis of meningeal melanomatosis was established after an autopsy had been carried out.ConclusionsIn the absence of unequivocal test results, it is also worth taking into account the primary changes in the leptomeninx, including those caused by melanoma.

Cannabinoids as a Potential New and Novel Treatment for Melanoma: A Pilot Study in a Murine Model

BackgroundMalignant melanoma is a complex malignancy with significant morbidity and mortality. The incidence continues to rise, and despite advances in treatment, the prognosis is poor. Thus, it is necessary to develop novel strategies to treat this aggressive cancer. Synthetic cannabinoids have been implicated in inhibiting cancer cell proliferation, reducing tumor growth, and reducing metastasis. We developed a unique study focusing on the effects of treatment with a cannabinoid derivative on malignant melanoma tumors in a murine model. MethodsMurine B16F10 melanoma tumors were established subcutaneously in C57BL/6 mice. Mice were then treated with intraperitoneal injections of vehicle twice per week (control—group 1, n = 6), Cisplatin 5 mg/kg/wk (group 2; n = 6), and Cannabidiol (CBD) 5 mg/kg twice per week (group 3; n = 6). Tumors were measured and volume calculated as (4π/3) × (width/2)2 × (length/2). Tumor size and survival curves were measured. Results were compared using a one-way ANOVA with multiple comparison test. ResultsA significant decrease in tumor size was detected in mice treated with CBD when compared with the control group (P = 0.01). The survival curve of melanoma tumors treated with CBD increased when compared with the control group and was statistically significant (P = 0.04). The growth curve and survival curve of melanoma tumors treated with Cisplatin were significantly decreased and increased, respectively, when compared with the control and CBD-treated groups. Mice treated with Cisplatin demonstrated the longest survival time, but the quality of life and movement of CBD-treated mice were observed to be better. ConclusionsWe demonstrate a potential beneficial therapeutic effect of cannabinoids, which could influence the course of melanoma in a murine model. Increased survival and less tumorgenicity are novel findings that should guide research to better understand the mechanisms by which cannabinoids could be utilized as adjunctive treatment of cancer, specifically melanoma. Further studies are necessary to evaluate this potentially new and novel treatment of malignant melanoma.

Effect of estrogens on growth factors in melanoma and nevi.

e21628Background: Melanoma pathogenesis is still poorly studied. In more than 70% of cases, melanoma arises from a nevus. Gender differences in the rates and course of melanoma indicate the role of...

Melanoma in patients with GATA2 deficiency.

GATA2 deficiency is a recently described genetic disorder affecting hematopoietic stem cells and is associated with immunodeficiency, hematologic malignancy, and various cutaneous pathologies including cutaneous tumors. To explore the incidence and clinical course of melanoma in patients with germline GATA2 deficiencies, we conducted a retrospective chart review of 71 such patients and identified two with invasive melanoma. One melanoma was diagnosed early because it was associated with pruritus due to a graft-versus-tumor effect following bone marrow transplantation. The other one, a lentigo maligna melanoma, was locally excised but progressed to widespread metastasis and death several years later. Our observations and published studies of melanoma biology suggest an association between decreased GATA2 expression and melanoma progression. These findings suggest that GATA2 deficient patients may have an increased risk of melanoma and should be observed closely for new or changing skin lesions.

Novel Therapies for Metastatic Melanoma: An Update on Their Use in Older Patients.

Cutaneous melanoma is the most aggressive form of skin cancer. With age as a risk factor, melanoma is projected to become a substantial healthcare burden. The clinical course of melanoma in older patients is different from that in middle-aged and younger patients: melanomas are thicker, have higher mitotic rates and are more likely to be ulcerated. Older patients also have a higher mortality rate, yet, paradoxically, have a lower rate of lymph node metastases. After decades of no significant progress in the treatment of this devastating disease, novel insights into the mechanisms underlying the pathophysiology of metastatic melanoma have led to new and remarkably efficient therapeutic opportunities. The discovery that about half of all melanomas carry BRAF mutations led to the introduction of targeted therapy with significant improvements in clinical outcomes. Although these drugs appear to be equally effective in older patients, specific considerations regarding adverse events are required. Besides targeted therapy, immunotherapy has emerged as an alternative therapeutic option. Antibodies that block cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) can induce responses with high durability. Despite an aging immune system, older patients seem to benefit to the same degree from these treatments, apparently without increased toxicity. In this review, we focus on the epidemiology, clinicopathological features, and recent developments of systemic treatment in cutaneous melanoma with regard to older patients.

Analysis of sequence variants in the 3'UTR of CDKN2A gene in melanoma patients.

BackgroundThe 3'UTR region plays a crucial role in regulating gene expression at posttranscriptional levels. Any changes in sequence in this region can cause numerous pathologies and can also lead to tumour development. The most common changes reported in in the CDKN2A gene are the 148Ala/Thr in exon 2 and 500C>G and 540C>T in the 3'UTR region. They are suspected of having a great impact on cancer progression. Since the role of these sequence variants in the Polish population in the development of melanoma has not been confirmed, the importance of 3'UTR polymorphisms in the regulation of gene expression was tested.Material and methodsFirst, genetic analysis in a group of 285 melanoma patients was performed and the obtained results were correlated with the clinical course of melanoma. Then vectors carrying 3'UTR sequence variants were prepared and the level expression of the reported gene was measured.ResultsWithin this study no correlation between the presence of 148Ala/Thr polymorphism and cancer in the family was observed. There was a correlation between the presence of this polymorphism and breast cancer and melanoma in the same patient. There was no correlation between 500C>G polymorphism and tumour localisation, age of diagnosis, and type of cancer in patients’ family, but a correlation between the percentage of patients dying and the 500C>G variant was observed.ConclusionThe results of functional tests indicated that the presence of polymorphism in the 3'UTR region of the CDKN2A gene resulted in changes in the level of reporter gene expression.

Diagnostic Imaging in Dermatology: Utility of PET-CT in Cutaneous Melanoma

Malignant melanoma accounts for 5% of all malignant skin tumors and its incidence is increasing. In the natural course of melanoma, tumors grow locally and can spread via the lymph system or the blood. Because survival is directly related to the stage of the disease at diagnosis, early detection (secondary prevention) has an impact on prognosis. Positron emission tomography (PET) is a nuclear medicine technique that generates images using molecules labeled with positron-emitting isotopes. The most widely used molecule is fluorodeoxyglucose (FDG). Because of the elevated glycolytic rate in tumor cells, which results in increased FDG uptake, greater quantities of FDG become trapped in tumor cells, enabling external detection. Today, most PET scanners are multimodal PET–computed tomography (CT) scanners, which provide more detailed information by combining morphological information with functional PET findings. The possible utility of PET-CT in patients with malignant melanoma is a subject of debate. Various questions have been raised: when the scan should be performed, whether PET-CT has advantages over conventional diagnostic methods, and whether PET-CT provides a real benefit to patients. In this review of the literature, we will analyze each of these questions.

Diagnóstico por imagen en dermatología: utilidad de la tomografía por emisión de positrones-tomografía computarizada en el melanoma cutáneo

Malignant melanoma accounts for 5% of all malignant skin tumors and its incidence is increasing. In the natural course of melanoma, tumors grow locally and can spread via the lymph system or the blood. Because survival is directly related to the stage of the disease at diagnosis, early detection (secondary prevention) has an impact on prognosis. Positron emission tomography (PET) is a nuclear medicine technique that generates images using molecules labeled with positron-emitting isotopes. The most widely used molecule is fluorodeoxyglucose (FDG). Because of the elevated glycolytic rate in tumor cells, which results in increased FDG uptake, greater quantities of FDG become trapped in tumor cells, enabling external detection. Today, most PET scanners are multimodal PET–computed tomography (CT) scanners, which provide more detailed information by combining morphological information with functional PET findings. The possible utility of PET-CT in patients with malignant melanoma is a subject of debate. Various questions have been raised: when the scan should be performed, whether PET-CT has advantages over conventional diagnostic methods, and whether PET-CT provides a real benefit to patients. In this review of the literature, we will analyze each of these questions.

Mistletoe in the treatment of malignant melanoma

Malignant melanoma is a malignant neoplasia drives from melanocytes. Malignant melanoma, the most causing death, is seen in the third place at skin cancer. Malignant melanoma shows intrinsic resistance to chemotherapeutic agents and variability in the course of the disease which are distinct features separating from other solid tumors. These features prevent the development and standardization of non-surgical treatment models of malignant melanoma. Although there is a large number of chemotherapeutic agents used in the treatment of metastatic malignant melanoma, it hasn’t been demonstrated the survival advantage of adjuvant treatment with chemotherapeutic agents. Because of the different clinical course of malignant melanoma, the disease is thought to be closely associated with immune system. Therefore, immunomodulatory therapy models were developed. Mistletoe stimulates the immune system by increasing the number and activity of dendritic cells, thus it has been shown to effect on tumor growth and metastasis of malignant melanoma patient. Outlined in this review are the recent developments in the understanding the role of mistletoe as a complementary therapy for malignant melanoma.