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Simple Summary: In the assessment of pigmented lesions, it is crucial to avoid unnecessary procedures while ensuring that melanomas are not missed. This study aims to understand how the number needed to treat (NNT) in melanoma detection varies with a patient's age and the type of referring physician. By analyzing data from the University Hospital Regensburg, we found that the NNT decreased with advancing age. The type of referring physician was also significant: dermatologists from university settings had the most accurate referrals, requiring fewer procedures compared to office-based dermatologists and non-dermatologists. Additionally, the introduction of Germany's skin cancer screening program in 2008 significantly reduced the NNT. These findings may help refine melanoma detection strategies and improve screening practices in the future. Background/Objectives: With regard to excision of pigmented lesions for detection of malignant melanoma (MM), the number needed to treat (NNT) describes the number of melanocytic nevi that need to be biopsied/excised to detect one MM. The aim should be a low NNT. Methods: Single-center data analysis, including dermatohistopathological records of all nevi and MM cases during 2004–2013 at the Department of Dermatology, University Hospital Regensburg (UKR), was performed. We calculated the NNT, correlating it with the patient's age and referring physician. The MM to MM in situ ratio was calculated to quantify early detection. As a secondary objective, we stratified into a pre- and post-2008 dataset, coinciding with the introduction of statutory skin cancer screening in Germany. Results: The overall NNT of 118,668 pigmented lesions was 17.2. We found a linear decrease in NNT towards older patients (R2 = 62%; p < 0.001). The impact of skin cancer screening in 2008 was marked by a reduction in biopsies/excisions, a shift in age distribution, and a decrease in the NNT from 20.3 to 14.7. Office-based dermatologists had an NNT of 22.3, UKR-based dermatologists had an NNT of 8.0, and non-dermatologists had an NNT of 16.5. Conclusions: The age-related decrease in the NNT emphasizes the importance of age stratification for pigmented lesions. The NNT differed between professional settings. The implementation of skin cancer screening in 2008 was associated with a reduced NNT. [ABSTRACT FROM AUTHOR]

Simple Summary: Melanoma is a particularly aggressive form of skin cancer that is diagnosed worldwide. While most cases of melanoma are diagnosed early and treated properly, patients with delayed diagnoses have a poor prognosis. Likewise, as tumor staging progresses, common therapies lose their effectiveness. This observation punctuates the need for new treatments that are effective in every stage of melanoma, particularly the advanced stages. This review focuses on immunotherapy, a form of treatment that utilizes the immune system to treat melanoma. We aim to summarize and highlight the advances in immunotherapy for the treatment of melanoma with hopes to aid clinicians who are treating melanoma. Immunotherapy offers a novel and promising option in the treatment of late-stage melanoma. By utilizing the immune system to assist in tumor destruction, patients have additional options after tumor progression. Immune checkpoint inhibitors reduce the ability for tumors to evade the immune system by inhibiting key surface proteins used to inactivate T-cells. Without these surface proteins, T-cells can induce cytotoxic responses against tumors. Tumor infiltrating lymphocyte therapy is a form of adoptive cell therapy that takes advantage of a small subset of T-cells that recognize and infiltrate tumors. Isolation and rapid expansion of these colonies assist the immune system in mounting a charged response that can induce remission. Tumor vaccines deliver a high dose of unique antigens expressed by tumor cells to the entire body. The introduction of large quantities of tumor antigens upregulates antigen presenting cells and leads to effective activation of the immune system against tumors. Cytokine therapy introduces high amounts of chemical messengers that are endogenous to the immune system and support T-cell expansion. While other methods of immunotherapy exist, immune checkpoint inhibitors, tumor infiltrating lymphocytes, tumor vaccines, and cytokine therapy are commonly used to treat melanoma. Like many other cancer treatments, immunotherapy is not without adverse effects, as toxicities represent a major obstacle. However, immunotherapy has been efficacious in the treatment of melanoma. [ABSTRACT FROM AUTHOR]

With the promising results of immunotherapy in patients with stage III melanoma, the role of adjuvant radiotherapy after resection and complete lymph-node dissection must be reassessed. We evaluate the outcomes and safety of adjuvant radiotherapy and immunotherapy compared to immunotherapy only in patients with resected stage III melanoma. This retrospective and single institution study included patients treated for a stage III melanoma with complete lymph-node dissection and adjuvant immunotherapy from January 2019 to December 2022. The radiotherapy associated with immunotherapy group was defined by completion of immunotherapy and adjuvant radiotherapy in the lymph-node dissection area. The primary endpoint was disease-free survival. The secondary endpoints were locoregional progression, incidence of adverse events grade 3 or above and disease-free survival rate in patients with high risk of locoregional recurrence. Thirty-three patients were included. Among them, twelve received adjuvant lymph-node field radiotherapy. The median duration of follow-up was 17 months (range: 8–45 months). Patients receiving radiotherapy and immunotherapy had a significantly higher disease stage and more frequent extracapsular extension. At 12 months, the disease-free survival rate was 66.7 % for the patients receiving immunotherapy alone (95 % CI: 42.5–82.5 %) and 83.3 % for those receiving radiotherapy and immunotherapy (95 % CI: 48.2–95.6 %; P = 0.131). The locoregional progression rate was 24 % in patients receiving immunotherapy and 8 % in patients receiving immunotherapy and radiotherapy (P = 0.379). After adjuvant treatment, 6 % of patients developed grade 3 or above immunotherapy-related events and none developed grade 3 or above radiation-related adverse events. In patients with stage III melanoma, adjuvant lymph-node field radiotherapy combined with immunotherapy seems to be associated with longer disease-free survival, with acceptable tolerance. However, these results need to be confirmed by long-term and prospective studies. [ABSTRACT FROM AUTHOR]

Background We aim to provide survival scenario estimates for patients with advanced melanoma starting targeted therapies and immunotherapies. Materials and Methods We sought randomized trials of targeted therapies and immunotherapies for advanced melanoma and recorded the following percentiles (represented survival scenario) from each overall survival (OS) curve: 90th (worst-case), 75th (lower-typical), 50th (median), 25th (upper-typical), and 10th (best-case). We tested whether these scenarios can be estimated for each OS curve by multiplying its median by 4 multiples: 0.25 (worst-case), 0.5 (lower-typical), 2 (upper-typical), and 3 (best-case). Results We identified 15 trials with 8025 patients. For first-line combination targeted therapy treatment groups, the median (interquartile range, IQR) in months for each percentile was: 90th, 6.2 (6.0-6.5); 75th, 11.3 (11.3-11.4); and median, 24.4 (23.5-25.3). For the first-line combination immunotherapy treatment group, the percentiles in months were: 90th, 3.9 (2.8-4.5); 75th, 13.4 (10.1-15.4), median 73 (not applicable). In targeted therapy groups, simple multiples of the median OS were accurate for estimating the 90th percentile in 80%; 75th percentile in 40%; 25th percentile in 100%. In immunotherapy groups, these multiples were accurate at 0% for the 90th percentile, and 43% for the 75th percentile. The 90th percentile (worst-case scenario) was better estimated as 1/6× median OS, and the 75th percentile (lower-typical) as 1/3× median OS. Conclusions Simple multiples of the median OS are a useful framework to estimate scenarios for survival for patients receiving targeted therapies, not immunotherapy. Longer follow-up is required to estimate upper-typical and best-case scenarios. [ABSTRACT FROM AUTHOR]

Background: Studies addressing social determinants of health (SDH) in head-neck melanomas (HNM) have only assessed socioeconomic factor impact but not a wider scope of SDH. Objective: Utilizing the Social Vulnerability Index (SVI), to assess the influence of specific SDH and their quantifiable associations with HNM management disparities across the varied community contexts in the United States. Methods: This retrospective cohort study analyzed adults diagnosed with HNM from 1975 to 2017 from the Surveillance, Epidemiology, and End Results Program database. Results: A total of 374,138 HNM in adults from 1975 to 2017 were assessed for disparities affiliated with increasing overall vulnerability/SVI scores and SDH themes. For several melanoma subtypes, higher social vulnerability significantly decreased odds (lowest for amelanotic, odds ratio 0.74; 95% confidence interval, 0.63-0.86) for indicated surgery, increased odds of indicated radiation (highest for epithelioid cell, 1.44; 1.08-1.96), and advanced staging on first presentation (highest for acral lentiginous, 1.13; 1.01-1.27). Household composition, followed by socioeconomic status and minority-language status contributed significantly to the overall trend. Limitations: Limitations include unknown cause of death and SVI score calculation based on county of residency. Conclusions: This investigation highlights significant detrimental trends in HNM management with overall social vulnerability while showcasing the quantifiable associations of specific SDH themes on HNM-disparities.

This study investigates how melanoma anthropomorphism (i.e., the attribution of humanlike qualities to melanoma) interacts with individual differences in perceived efficacy to influence attitudes and intentions to perform preventive health behaviors. Results suggested that among individuals with lower levels of perceived efficacy, presenting melanoma in anthropomorphic terms (vs. non-anthropomorphic terms) enhanced processing fluency, consequently fostering more favorable attitudes and greater intentions to follow preventive health recommendations. However, this effect was not observed among individuals with higher perceived efficacy. Findings of this study offer important theoretical and practical implications regarding the strategic use of anthropomorphism in health promotion contexts. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer immunotherapy has evolved rapidly in the last decade. A newly emerging immunotherapeutic approach utilizes oncolytic viruses to enhance the ability of the body's own immune system to recognize and clear tumor cells. We have recently developed a novel chimeric oncolytic virus and demonstrated its anti-tumoral effects in various preclinical mouse models. To gain mechanistic insights into the immune response to this form of therapy at the cellular level and to identify targets to potentially further improve the therapy, we analyzed the immune cell signature in the tumors, blood, and lymphoid tissue in a syngeneic melanoma mouse model by flow cytometry. Both local and systemic immune responses were observed. Furthermore, selective depletion of cytotoxic T cells indicated that these cells are the main players in mediating the therapeutic response to this novel virotherapy. Background/Objectives: Oncolytic virotherapy is a promising approach in cancer immunotherapy. We have previously described a recombinant hybrid oncolytic virus (OV), VSV-NDV, which has a favorable safety profile and therapeutic immunogenicity, leading to direct oncolysis, abscopal effects, and prolonged survival in syngeneic in vivo tumor models. While OVs are known to mediate systemic anti-tumor immune responses, the detailed characterization of local and systemic immune responses to fusogenic oncolytic virotherapy remains unexplored. Methods and Results: We analyzed immune cell compartments in the spleen, blood, tumor-draining lymph nodes (TDLNs), and tumors over the course of VSV-NDV therapy in a bilateral syngeneic melanoma mouse model. Our results revealed significant local infiltration and activation of T lymphocytes in tumors and globally in the blood and spleen. Notably, in vivo CD8+ T cell depletion led to complete abrogation of the tumor response, highlighting the crucial role of T cells in promoting the therapeutic effects of oncolytic VSV-NDV. In vitro co-culture experiments enabled the interrogation of human immune cell responses to VSV-NDV-mediated oncolysis. Human peripheral blood mononuclear cells (PBMCs) were efficiently stimulated by exposure to VSV-NDV-infected cancer cells, which recapitulates the in vivo murine findings. Conclusions: Taken together, these data characterize a broad anti-tumor immune cell response to oncolytic VSV-NDV therapy and suggest that CD8+ T cells play a decisive role in therapeutic outcome, which supports the further development of this chimeric vector as a multimechanistic immunotherapy for solid cancers. [ABSTRACT FROM AUTHOR]

Topical treatment offers a viable alternative for melanoma patients incompatible with surgical interventions. Herein, the study develops a skin‐penetrating peptide (SPP)‐based peptide drone (PD) for the transdermal delivery of antitumor proteins. To achieve cost‐effective therapeutics, Concanavalin A (ConA), which can be prepared through an extraction method, is loaded onto PDs. Compared with free proteins, ConA‐PD complexes (CPCs) demonstrate significantly greater skin permeation. Moreover, the CPCs exhibit potent anticancer activity both in vitro and in vivo, which substantially surpass the efficacy of the Aldara (imiquimod) cream. The CPC‐treated mouse skin remains clear, whereas Aldara cream induces side effects, including psoriasis‐like skin inflammation. The antimetastatic activity of the PD is identified as another advantage of CPC. The use of ConA as an anticancer agent has been significantly limited due to its high hepatotoxicity; however, the transdermal delivery strategy minimizes its hepatic absorption and, in turn, results in negligible hepatotoxicity. These results demonstrate the potential of the CPC as a novel therapeutic agent or an adjunct to other modalities for melanoma treatment, overcoming the limitations of existing materials while exhibiting superior efficacy. [ABSTRACT FROM AUTHOR]

Background Only a fraction of patients with metastatic melanoma derive durable benefit from approved treatments. The clinical impact of personalized medicine strategies for melanoma, apart from BRAF , NRAS , or CKIT targeting, has rarely been reported. Materials and Methods By means of the Group of Cutaneous Oncology of the French Society of Dermatology, we retrospectively included all patients with advanced melanoma aged 18 years and older for whom molecular testing identified one or more actionable molecular alterations and who accordingly received molecularly matched therapy. We excluded patients with only BRAF , NRAS , or CKIT alterations and patients who received molecularly matched therapy for less than 15 days. Results We included 26 patients with a median follow-up of 8 months (1-54), a median age of 63 years (24-89), and a sex ratio of 2.7. These patients had been heavily pretreated, and 64% had elevated LDH levels. The disease control rate was 38%, with 4 cases of partial response (overall response rate: 15%) and 6 of stable disease for at least 6 months. The median duration of treatment was 3.1 months (0.9-13.5). Among patients with disease control, the median duration of control was 6.6 months (2.6-13.5) and 3 cases were ongoing at the end of the study. Patients with controlled disease had GNA11 , MAP2K1 , FYCO1-RAF1 , HRAS , ATM , CCND1 , MDM2/CDK4 , and CDKN2A/NRAS alterations. Conclusions High-throughput sequencing followed by matched targeted therapy is a promising approach for patients with advanced melanoma refractory to approved treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: Angiogenesis is a crucial process in the progression and metastasis of melanoma. Recent research has highlighted the significant role of epigenetic modifications in regulating angiogenesis. This review comprehensively examines the current understanding of how epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, influence angiogenic pathways in melanoma, with some important therapeutic approaches. Angiogenesis, the formation of new blood vessels from pre-existing ones, is a crucial process in the progression and metastasis of melanoma. Recent research has highlighted the significant role of epigenetic modifications in regulating angiogenesis. This review comprehensively examines the current understanding of how epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, influence angiogenic pathways in melanoma. DNA methylation, a key epigenetic modification, can silence angiogenesis inhibitors such as thrombospondin-1 and TIMP3 while promoting pro-angiogenic factors like vascular endothelial growth factor (VEGF). Histone modifications, including methylation and acetylation, also play a pivotal role in regulating the expression of angiogenesis-related genes. For instance, the acetylation of histones H3 and H4 is associated with the upregulation of pro-angiogenic genes, whereas histone methylation patterns can either enhance or repress angiogenic signals, depending on the specific histone mark and context. Non-coding RNAs, particularly microRNAs (miRNAs) further modulate angiogenesis. miRNAs, such as miR-210, have been identified as key regulators, with miR-9 promoting angiogenesis by targeting E-cadherin and enhancing the expression of VEGF. This review also discusses the therapeutic potential of targeting epigenetic modifications to inhibit angiogenesis in melanoma. Epigenetic drugs, such as DNA methyltransferase inhibitors (e.g., 5-azacytidine) and histone deacetylase inhibitors (e.g., Vorinostat), have shown promise in preclinical models by reactivating angiogenesis inhibitors and downregulating pro-angiogenic factors. Moreover, the modulation of miRNAs and lncRNAs presents a novel approach for anti-angiogenic therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: There is ongoing controversy regarding the diagnosis and appropriate treatment of small choroidal melanocytic tumors. Identifying lesions that may evolve into melanomas is crucial due to their metastatic potential. The debate centers on whether it is feasible to delay tumor treatment until signs of progression are evident. This study aims to analyze the long-term outcomes of patients with small choroidal melanocytic tumors under observation, to determine their rate of transformation to melanoma and survival rates in this population. The results suggest that active observation until signs of progression to melanoma appear can be a safe alternative, avoiding the potential side effects of treatment. This approach preserves the visual function and quality of life for patients with tumors that will never progress to melanoma, without compromising their overall prognosis. Background: The purpose of this study is to analyze the long-term evolution of patients with small choroidal melanocytic tumors (SCMTs) undergoing observation, and to assess their rate of transformation into melanomas and survival. Methods: A retrospective single-cohort study of patients with SCMTs (1–3 mm in height and 5–10 mm in base) diagnosed from January 1992 to February 2023 was carried out, with observation as the initial treatment. The main criterion for a transformation into melanoma is considered to be an increase in size of more than 1 mm in height and/or more than 1 mm in base measured on an ultrasound/retinography, recorded in two consecutive visits separated by one to three months. Results: 243 patients were included with a mean age of 65.3 years and a mean follow-up of 7.9 years (6 months–27.9 years); 27 patients showed tumor growth. The probabilities of growth at 5, 10, and 15 years are 10%, 14%, and 17%, respectively. Regarding survival, 22 patients died and only 3 deaths were due to melanoma metastasis. Survival rates at 5 and 10 years are 99% and 97%. Conclusions: Observation is a viable therapeutic option for SCMTs, avoiding the side effects of treatment, considering the majority of these tumors do not progress to melanoma. With close monitoring, patients can be treated promptly upon detecting a transformation. Additionally, the findings confirm that small melanocytic tumors can lead to metastatic disease, albeit at a low rate. [ABSTRACT FROM AUTHOR]

Melanoma, with its rising incidence, is a significant contributor to skin cancer-related fatalities. Early diagnosis of the tumor remains crucial for improving patients' prognosis. This article describes the rising occurrence of melanoma among individuals with fair skin, particularly those with high sun exposure and tanning habits. It emphasizes significant geographic and ethnic dispari- ties in melanoma incidence worldwide. Factors influencing patients' prognoses, such as tumor biology, patient stress and healthcare system-related aspects, are scrutinized. The article presents comprehensive guidelines for diagnosing melanoma in everyday clinical practice, highlighting the importance of thorough full-body skin examinations, dermoscopy for all lesions and excision of uncertain nodular lesions. Moreover, the integration of clinical context and artificial intelligence tools in dermatology for early disease identifica- tion is explored. The synergy of medical expertise and advancements in artificial intelligence holds great potential for revolutionizing melanoma care and enhancing skin health management. [ABSTRACT FROM AUTHOR]

Simple Summary: The treatment of BRAF-mutant melanoma with BRAF inhibitors is severely limited in clinical practice, in part due to the emergence of drug tolerance via non-genetic adaptation to therapies. Improving our understanding of the molecular mechanisms that underlie drug tolerance may lead to improved treatment strategies. Here, we describe a novel calcium-dependent signaling mechanism induced by BRAF inhibitor (BRAFi) treatment that provides compensatory mitogenic signaling to drug-tolerant persister cells in the form of MAPK reactivation. This calcium signaling mechanism has not previously been recognized in BRAFi-tolerant melanoma, may initiate a novel line of scientific inquiry, and presents a host of novel targets for therapeutic development in this field. Drug tolerance is a major cause of relapse after cancer treatment. Despite intensive efforts, its molecular basis remains poorly understood, hampering actionable intervention. We report a previously unrecognized signaling mechanism supporting drug tolerance in BRAF-mutant melanoma treated with BRAF inhibitors that could be of general relevance to other cancers. Its key features are cell-intrinsic intracellular Ca2+ signaling initiated by P2X7 receptors (purinergic ligand-gated cation channels) and an enhanced ability for these Ca2+ signals to reactivate ERK1/2 in the drug-tolerant state. Extracellular ATP, virtually ubiquitous in living systems, is the ligand that can initiate Ca2+ spikes via P2X7 channels. ATP is abundant in the tumor microenvironment and is released by dying cells, ironically implicating treatment-initiated cancer cell death as a source of trophic stimuli that leads to ERK reactivation and drug tolerance. Such a mechanism immediately offers an explanation of the inevitable relapse after BRAFi treatment in BRAF-mutant melanoma and points to actionable strategies to overcome it. [ABSTRACT FROM AUTHOR]

Simple Summary: Melanoma survival rates have been vastly improved by the use of immune checkpoint inhibitors. However, some patients do not respond to the treatment or experience progression of disease. Because of this variability of response, markers predicting efficacy of these treatments is of interest. This study aimed to clarify the role of primary tumor characteristics in melanoma treatment and survival. The authors demonstrated that cutaneous melanoma and its subtypes were significantly associated with response, progression-free survival, and overall survival compared with acral or unknown primary melanoma. Other primary features did not demonstrate an association on multivariable analyses. Thus, primary features, other than cutaneous primary, should likely not influence metastatic treatment selection. Identifying patients likely to benefit from immune checkpoint inhibitor (ICI) treatment remains a crucial goal for melanoma. The objective of this study is to assess the association between primary tumor features and immunotherapy response and survival in advanced melanoma patients. In this single-center retrospective cohort study, disease characteristics, response to immunotherapy, PFS, and OS were assessed among melanoma patients (excluding mucosal and uveal primaries) treated with ICI. Among 447 patients, 300 (67.1%) received anti-PD-1 monotherapy and 147 (32.9%) received ipilimumab/nivolumab. A total of 338 (75.6%) had cutaneous melanoma, 29 (6.5%) had acral melanoma, and 80 (17.9%) had melanoma of unknown primary. Ulceration and stage at initial presentation were associated with inferior outcomes on univariate analysis. However, on multivariate analysis, this result was not observed, but cutaneous melanoma and each of its subtypes (superficial spreading, nodular, other, unknown) were positively associated with response, longer PFS, and longer OS. Metastatic stage (M1c, M1d) at presentation (OR = 1.8, p < 0.05) and BRAFV600E mutation status (OR = 1.6, p < 0.001) were associated with shorter PFS. This study is limited by its retrospective and single-center design. Cutaneous melanoma and its subtypes were significantly associated with response, PFS, and OS compared with acral or unknown primary melanoma. [ABSTRACT FROM AUTHOR]

Background/Aim: The objective of this study was to assess the role of iodine (125I) plaque brachytherapy in the management of uveal melanoma. Patients and Methods: This is a retrospective study of 50 patients (median age 67 years; range=33-86 years) with uveal melanoma, treated with 125I plaque brachytherapy at the University Hospital of Pisa. Uveal melanoma was diagnosed with A-scan and Bscan standardized echography, fluorescein angiography, indocyanine green-angiography, optical coherence tomography, and/or magnetic resonance imaging. The primary outcomes assessed were local control, overall survival, disease progression, globe preservation, and metastases. Secondary outcomes were acute and late radiation adverse effects. Results: Inclusion criteria comprised Eastern Cooperative Oncology Group performance status ≤2, life expectancy >6 months, and tumor thickness ≤10 mm and\or diameter ≤20 mm. All the patients were treated with 125I plaque brachytherapy, with a prescription dose of 85 Gy to the tumor apex. The 5-year rate of local control, progression-free survival, metastasisfree survival, enucleation-free survival, and overall survival were 83.0%, 81.4%, 90.3%, 83.1%, and 92.1% respectively. Twenty-four patients (48.0%) had one or more acute and late toxicities. The most common acute adverse events (CTCAE vs. 5.0) grade 1-3 were conjunctivitis and eye pain (6.0%). Regarding late events, radiation retinopathy grade 1-3 occurred in 18.0% of cases, while grade 1-3 vitreous hemorrhage in 2.5%. Conclusion: 125I plaque brachytherapy offers an effective and safe approach for selected cases of uveal melanoma, due to the reported satisfactory results in terms of local control, eye conservation and survival. [ABSTRACT FROM AUTHOR]

Background/Aim: Melanoma, a variant of skin cancer, presents the highest mortality rates among all skin cancers. Despite advancements in targeted therapies, immunotherapies, and tissue culture techniques, the absence of an effective early treatment model remains a challenge. This study investigated the impact of dabrafenib on both 2D and 3D cell culture models with distinct molecular profiles. Materials and Methods: We developed a high-throughput workflow enabling drug screening on spheroids. Our approach involved cultivating 2D and 3D cultures derived from normal melanocytes and metastatic melanoma cells, treating them with dabrafenib and conducting viability, aggregation, migration, cell cycle, and apoptosis assays. Results: Dabrafenib exerted multifaceted influences, particularly on migration at concentrations of 10 and 25 μM. It induced a decrease in cell viability, impeded cellular adhesion to the matrix, inhibited cellular aggregation and spheroid formation, arrested the cell cycle in the G1 phase, and induced apoptosis. Conclusion: These results confirm the therapeutic potential of dabrafenib in treating melanoma with the BRAF V600E mutation and that 3D models are validated models to study the potential of new molecules for therapeutic purposes. Furthermore, our study underscores the relevance of 3D models in simulating physiological in vivo microenvironments, providing insights into varied treatment responses between normal and tumor cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite recent advances in diagnosis and therapy, malignant melanoma poses a significant problem both to clinicians and cancer researchers due to its resistance to therapy and unpredictable behavior. In this review, we discuss etiology, risk factors, diagnosis, prognosis, and therapy of melanoma, with a focus on new developments in these areas including bioinformatics. These are analyzed in the context of its unique metabolic characteristics and of recent advances in vitamin D biology with implications for melanoma. Active forms of vitamin D can prevent or inhibit melanoma development and progression, and can be used in therapy of this disease. Knowledge of patient vitamin D status and vitamin D signaling in the tumoral tissue can help in predicting the progression of the disease and in primary or adjuvant therapy. Therefore, vitamin D signaling represents a realistic target for the prevention or therapy of malignant melanoma. Melanoma, originating through malignant transformation of melanin-producing melanocytes, is a formidable malignancy, characterized by local invasiveness, recurrence, early metastasis, resistance to therapy, and a high mortality rate. This review discusses etiologic and risk factors for melanoma, diagnostic and prognostic tools, including recent advances in molecular biology, omics, and bioinformatics, and provides an overview of its therapy. Since the incidence of melanoma is rising and mortality remains unacceptably high, we discuss its inherent properties, including melanogenesis, that make this disease resilient to treatment and propose to use AI to solve the above complex and multidimensional problems. We provide an overview on vitamin D and its anticancerogenic properties, and report recent advances in this field that can provide solutions for the prevention and/or therapy of melanoma. Experimental papers and clinicopathological studies on the role of vitamin D status and signaling pathways initiated by its active metabolites in melanoma prognosis and therapy are reviewed. We conclude that vitamin D signaling, defined by specific nuclear receptors and selective activation by specific vitamin D hydroxyderivatives, can provide a benefit for new or existing therapeutic approaches. We propose to target vitamin D signaling with the use of computational biology and AI tools to provide a solution to the melanoma problem. [ABSTRACT FROM AUTHOR]

Simple Summary: Pregnancy-associated cancers (PACs) represent a significant clinical problem, due to their possibly delayed diagnosis, limitations of the usage of diagnostic and therapeutic methods, and often the necessity to postpone the administration of optimal treatment to the mother until after delivery to protect the health of the fetus. The purpose of this review is to summarize information on the epidemiology, proper diagnosis, and effective treatment of cutaneous malignant melanoma (CMM) during pregnancy. Moreover, our aim is to point out that there are still many topics related to pregnancy-associated melanoma (PAM) that require further research. The following article can help clinicians systematize the updated facts from various studies and case-reports as well as advise them that an interdisciplinary approach combined with broad knowledge from different fields of medicine is crucial in the treatment of PAM. Cutaneous malignant melanoma is one of the most common neoplasms among pregnancy-associated cancers (PACs). Risk factors include excessive exposure to ultraviolet radiation, the presence of benign and dysplastic nevi, and a patient or family history of melanoma. Self-examination and careful inspection of nevi are crucial, especially in the context of their progression over time. Physiological changes that occur during pregnancy, such as the darkening and enlargement of the nevi, delay the diagnosis of CMM. In the fetus, metastases are very rare, and if they do occur, they concern the placenta or fetal tissues. The choice of treatment is influenced by the cancer stage, symptoms, the time of termination of pregnancy, and the patient's decision. Essential procedures which are safe for the fetus are diagnostic biopsy, ultrasound, and the therapeutic excision of the lesion and the affected lymph nodes. Other imaging methods can be used with a safe radiation dose limit of 100 mGy. Immunotherapy and targeted treatments must be carefully considered, because of their possible adverse effects on the fetus. An interdisciplinary approach to the problem of melanoma during pregnancy is necessary, involving doctors of various specialties. [ABSTRACT FROM AUTHOR]

Objective: Malignant melanoma situated in the parotid gland represents a rare clinical presentation, and the prognosis of these patients remains inadequately understood in comparison to other forms of malignant melanoma. This study aims to evaluate cases of parotid gland-located malignant melanoma under follow-up in our clinic. Material and Method: Records of five patients aged 18 and above, diagnosed with melanoma localized within or adjacent to the parotid gland, were retrospectively reviewed. Relevant clinical information such as patients' demographic data including age and gender, medical histories, presenting symptoms, treatment modalities, and outcomes were evaluated. The overall survival of the patients was examined. Results: None of the patients included in the study had primary parotid gland melanoma. Among all patients, 4 patients had primary lesions that were cutaneous melanomas originating from the head and neck region, while in one patient, the primary lesion was uveal melanoma of the eye. While 3 patients included in the study had died, 2 patients were still being followed up. Conclusion: Primary melanomas localized to the parotid gland are extremely rare, and when encountered, a thorough medical history and careful physical examination can often reveal that the primary lesion is cutaneous melanoma, predominantly located in the head and neck region. It should be kept in mind that although rare, there may be primary intranodal melanoma cases whose primary is unknown or cannot be found in the parotid gland. [ABSTRACT FROM AUTHOR]

Simple Summary: Intramedullary spinal cord melanocytomas are exceedingly rare. Here, we present a systematic review of the available literature and a case illustration from our surgical experience: a T1-weighted hyperintense lesion emerges with a focal contrast-enhancing nodule. Despite their benign histology, these tumors often present local aggressiveness with a high tendency towards local invasiveness, which is associated with frequent post-operative neurological deficits, and relapse, which eventually overwhelms adjuvant therapies, such as RT or salvage surgery. We present a case illustration of an intramedullary thoracic melanocytoma in a middle-aged woman. Despite the employment of complete intraoperative neuromonitoring and a frozen section, the adherence of the lesion to the surrounding spinal cord made it impossible to preserve neurological functioning. The current systematic review and case illustration highlight radiographic findings suspected of intramedullary melanocytoma, present the available surgical techniques, and address the importance of preserving neurological functions during the surgical treatment of intramedullary melanocytomas. Background: Intramedullary melanocytomas are exceedingly rare, with only twenty-four cases reported up to now. They present as local invasive tumors despite their benign biological behavior. Attempting a complete safe resection often results in severe post-operative neurological deficits, as in our case presented here. Methods: A systematic review was conducted across the PubMed and Scopus databases including studies published till February 2024. Results: A total of 19 studies were included, encompassing 24 cases. A similar distribution between sexes was noted (M:F 13:11), with ages ranging from 19 to 79 years. The thoracic segment was most affected, and intermediate-grade melanocytoma (19 cases) was the most common histotype. Radiographically, intramedullary melanocytomas usually appear as hyperintense hemorrhagic lesions peripheral to the central canal with focal nodular enhancement. Intraoperatively, they are black–reddish to tan and are tenaciously adherent lesions. In the sampled studies, IONM employment was uncommon, and post-operative new-onset neurological deficits were described in 16 cases. Adjuvant RT was used in four cases and its value is debatable. Recurrence is common (10 cases), and adjuvant therapies (RT or repeated surgery) seem to play a palliative role. Case presentation: A 68-year-old woman presented with a three-year history of worsening spastic paraparesis and loss of independence in daily activities (McCormick grade 4). An MRI revealed an intramedullary tumor from Th5 to Th7, characterized by T1-weighted hyperintensity and signs of recent intralesional hemorrhage. Multimodal neuromonitoring, comprising the D-Wave, guided the resection of a black–tan-colored tumor with hyper-vascularization and strong adherence to the white matter. During final dissection of the lesion to obtain gross total resection (GTR), a steep decline in MEPs and D-Wave signals was recorded. Post-operatively, the patient had severe hypoesthesia with Th9 level and segmental motor deficits, with some improvement during neurorehabilitation. Histopathology revealed an intermediate-grade melanocytoma (CNS WHO 2021 classification). A four-month follow-up documented the absence of relapse. Conclusions: This literature review highlights that intramedullary T1 hyperintense hemorrhagic thoracic lesions in an adult patient should raise the suspicion of intramedullary melanocytoma. They present as locally aggressive tumors, due to local invasiveness, which often lead to post-operative neurological deficits, and frequent relapses, which overwhelm therapeutic strategies leading to palliative care after several years. [ABSTRACT FROM AUTHOR]

Background/Aim: Meningeal melanocytomas are rare tumors of the central nervous system and optimal treatment needs further clarification. This study compared subtotal resection (STR), STR plus radiation therapy (RT), gross total resection (GTR), and GTR+RT to better define the role of postoperative RT. Patients and Methods: All cases reported in the literature were reviewed. Patients (n=184) with complete data were analyzed for local control (LC) and overall survival (OS). Results: On univariate analysis, GTR (vs. STR) was associated with improved LC (p=0.016). When comparing the treatment regimens, best and worst results were found after GTR+RT and STR alone, respectively (p<0.001). On univariate analysis, GTR resulted in better OS than STR (p=0.041). Moreover, the treatment regimen had a significant impact on OS (p=0.049). On multivariate analyses of LC and OS, extent of resection and treatment regimen were found to be significant factors. After STR, RT significantly improved LC but not OS. After GTR, RT did not significantly improve LC or OS. Conclusion: GTR was significantly superior to STR regarding LC and OS. STR+RT resulted in significantly better LC when compared to STR alone. [ABSTRACT FROM AUTHOR]

Objective: To explore the efficacy and safety of PD-1 antibody versus high-dose interferon in the adjuvant treatment of stage IIB-IIID melanoma patients after surgery. Methods: Clinical data of patients with stage IIB-IIID cutaneous and acral melanoma admitted into Nanjing Drum Tower Hospital, the affiliated hospital of Nanjing University Medical School between September 2013 and September 2022 were retrospectively collected. All patients received high-dose interferon (HDI) or PD-1 antibody as adjuvant therapy after surgery. Univariate survival analysis was performed and survival curves were plotted by the Kaplan-Meier method; Log-Rank method was used to analyze and assess whether the differences in RFS, DMFS, and OS between the groups were statistically significant, and prognostic factors were evaluated by univariate and multivariate Cox regression. Results: A total of 91 patients were enrolled in this study with a median follow-up of 31.0 months. The median RFS was 29.2 and 32.3 months in the HDI group and the PD-1 antibody group, respectively, and the difference was not statistically significant (HR=0.90, 95%CI [0.50, 1.64]; P=0.736). The median DMFS and the median OS in the HDI group were 36.0 and 109.2 months respectively, and neither was reached in the PD-1 antibody group (both P>0.05). The most common site of first distant metastasis in both groups was the lung, and there was no statistically significant difference in the incidence of distant metastasis at any site (P>0.05). By univariate Cox analysis, compared with PD-1, antibody HDI reduced the risk of distant metastasis in patients with BRAFV600E/K mutations (HR=10.03, 95% CI [1.10, 91.35]; P=0.041). Subgroup analyses showed that in patients with cutaneous and acral melanoma, the difference in RFS between the HDI group and the PD-1 antibody group was not statistically significant (both P>0.05). The incidence of adverse reactions in the HDI group and the PD-1 antibody group was 83.3% and 79.1%, respectively, most of which were grade 1 or 2. No deaths related to adverse reactions occurred in both groups. Conclusion: In this study, there was no statistically significant difference in clinical efficacy and safety between PD-1 antibody and HDI adjuvant therapy for malignant melanoma patients. Patients with BRAFV600E/K mutations may benefit more from HDI. Numerous prospective studies are needed to further explore the optimal adjuvant treatment options for melanoma patients in Asian populations. [ABSTRACT FROM AUTHOR]

Malignant melanoma is the most lethal form of skin cancer. As a promising anti-cancer agent, plasma-activated water (PAW) rich in reactive oxygen and nitrogen species (RONS) has shown significant potential for melanoma treatment. However, rapid decay of RONS and inefficient delivery of PAW in conventional injection methods limit its practical applications. To address this issue, here we report a new approach for the production of plasma-activated cryo-microneedles (PA-CMNs) patches using custom-designed plasma devices and processes. Our innovation is to incorporate PAW into the PA-CMNs that are fabricated using a fast cryogenic micro-molding method. It is demonstrated that PA-CMNs can be easily inserted into skin to release RONS and slow the decay of RONS thereby prolonging their bioactivity and effectiveness. The new insights into the effective melanoma treatment suggest that the rich mixture of RONS within PA-CMNs prepared by custom-developed hybrid plasma-assisted configuration induces both ferroptosis and apoptosis to selectively kill tumor cells. A significant inhibition of subcutaneous A375 melanoma growth was observed in PA-CMNs-treated tumor-bearing nude mice without any signs of systemic toxicity. The new approach based on PA-CMNs may potentially open new avenues for a broader range of disease treatments.

The current study explores the potential of ultrasound-assisted laser therapy (USaLT) to selectively destroy melanoma cells. The technology was tested on an ex vivo melanoma model, which was established by growing melanoma cells in chicken breast tissue. Ultrasound-only and laser-only treatments were used as control groups. USaLT was able to effectively destroy melanoma cells and selectively remove 66.41% of melanoma cells in the ex vivo tumor model when an ultrasound peak negative pressure of 2 MPa was concurrently applied with a laser fluence of 28 mJ/cm2 at 532 nm optical wavelength for 5 min. The therapeutic efficiency was further improved with the use of a higher laser fluence, and the treatment depth was improved to 3.5 mm with the use of 1,064 nm laser light at a fluence of 150 mJ/cm2. None of the laser-only and ultrasound-only treatments were able to remove any melanoma cells. The treatment outcome was validated with histological analyses and photoacoustic imaging. This study opens the possibility of USaLT for melanoma that is currently treated by laser therapy, but at a much lower laser fluence level, hence improving the safety potential of laser therapy.

Does treatment order matter for metastatic melanoma? The long-term results of the phase II SECOMBIT trial, now published in NEJM Evidence, surely suggest so.1 The SECOMBIT trial randomly assigned 206 patients with B-type Raf kinase (BRAF)V600-mutated metastatic melanoma into equal treatment groups: the first treatment group started with dual targeted therapy (encorafenib plus binimetinib), switching to immunotherapy (ipilimumab plus nivolumab) after progressive disease was observed; the second reversed that sequence; and the third prepended an induction phase of targeted therapy to the second group's treatment strategy (an addition that might help those whose disease progresses too fast for immunotherapy). [ABSTRACT FROM AUTHOR]

BACKGROUND: Talimogene laherparepvec (T-VEC) is an FDA-approved oncolytic herpesvirus therapy used for unresectable stage IIIB through IV metastatic melanoma. However, the correlation between clinical complete response (cCR) and pathologic complete response (pCR) in patients treated with T-VEC is understudied. STUDY DESIGN: We conducted a retrospective study from a prospectively maintained IRB-approved melanoma single-center database in patients treated with T-VEC from October 2015 to April 2022. Patients were categorized into 3 groups: cCR with pCR, cCR without pCR, and less than cCR. The primary endpoint was overall survival. We used descriptive statistics, chisquare tests, and Wilcoxon rank-sum tests to compare key covariates among exposure groups. We used survival analysis to compare survival curves and reported hazard ratio of death (95% CI) across exposure groups. RESULTS: We included 116 patients with a median overall survival (interquartile range) of 22.7 (14.8-39.3) months. The majority were men (69%) and White (97.4%), with a median age of 74.5 years. More than half of patients (n = 60, 51.6%) achieved cCR. Distribution among the groups was as follows: cCR with pCR (35.3%), cCR without pCR (16.3%), and less than cCR (48.4%). Median overall survival time (interquartile range) was 26.5 (18.6-36.0) months for cCR with pCR, 22.7 (14.4-35.5) months for cCR without pCR, and 17.8 (9.2-47.0) months for less than cCR (log-rank p value = 0.0033). CONCLUSIONS: Patients achieving cCR with pCR after T-VEC therapy have the most favorable overall survival outcomes, whereas those achieving cCR without pCR have inferior survival and those achieving less than cCR have the poorest overall survival outcomes. These findings emphasize the importance of histological confirmation and provide insights for optimizing T-VEC therapy in patients with advanced melanoma. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to describe the patterns of palliative intent treatment and/or palliative care (PC) delivery among a population-based sample of individuals diagnosed with advanced nonsmall cell lung cancer (NSCLC) or advanced melanoma. Methods: Data from 655 advanced-stage melanoma patients and 2688 advanced-stage NSCLC patients included in the National Cancer Institute's 2017/2018 Patterns of Care study were analyzed. Bivariate and multivariate logistic regression analyses examined factors associated with (1) receipt of PC (including palliative surgery, radiation, and/or systemic therapy after cancer diagnosis, and PC consultations); and (2) timing from diagnosis to receipt of PC. Proportional hazards models also examined factors associated with timing of receipt of PC after diagnosis. Results: A total of 23.5% of those with melanoma and 52.6% of those with NSCLC received some type of PC. For melanoma, stage 4 (vs. stage 3) was associated with higher receipt of PC and receipt within three months of diagnosis. For NSCLC, stage 4 (vs. stage 3) and a diagnosis of depression or psychosocial distress within three months of diagnosis were significantly associated with receipt of PC and receipt within three months of diagnosis. Conclusion: Study findings indicate that those with advanced-stage cancer or who report distress are more likely to receive palliative intent treatment and/or PC. Given that individuals with advanced cancers are living longer and often experience long-lasting symptoms, it is critical to identify and overcome barriers for broadly delivering comprehensive palliative and supportive care. [ABSTRACT FROM AUTHOR]

Objective: Skin examination to detect cutaneous melanomas is commonly performed in primary care. In recent years, clinical decision support systems (CDSS) based on artificial intelligence (AI) have been introduced within several diagnostic fields. Setting: This study employs a variety of qualitative and quantitative methodologies to investigate the feasibility of an AI-based CDSS to detect cutaneous melanoma in primary care. Subjects and Design: Fifteen primary care physicians (PCPs) underwent near-live simulations using the CDSS on a simulated patient, and subsequent individual semi-structured interviews were explored with a hybrid thematic analysis approach. Additionally, twenty-five PCPs performed a reader study (diagnostic assessment on the basis of image interpretation) of 18 dermoscopic images, both with and without help from AI, investigating the value of adding AI support to a PCPs decision. Perceived instrument usability was rated on the System Usability Scale (SUS). Results: From the interviews, the importance of trust in the CDSS emerged as a central concern. Scientific evidence supporting sufficient diagnostic accuracy of the CDSS was expressed as an important factor that could increase trust. Access to AI decision support when evaluating dermoscopic images proved valuable as it formally increased the physician's diagnostic accuracy. A mean SUS score of 84.8, corresponding to 'good' usability, was measured. Conclusion: AI-based CDSS might play an important future role in cutaneous melanoma diagnostics, provided sufficient evidence of diagnostic accuracy and usability supporting its trustworthiness among the users. Effective primary care is important for discovering cutaneous melanoma, the deadliest and an increasingly prevalent form of skin cancer. 'Trust', 'usability and user experience', and 'the clinical context' are the qualitative themes that emerged from the qualitative analysis. These areas need to be considered for the successful adoption of AI assisted decision support tools by PCPs. The AI CDSS tool was rated by the PCPs at grade B (average 84.8) on the System Usability Scale (SUS), which is equivalent to 'good' usability. A reader study, (diagnostic assessment on the basis of image interpretation) with 25 PCPs rating dermoscopic images, showed increased value of adding an AI decision support to their clinical assessment. [ABSTRACT FROM AUTHOR]

Radiotherapy can differentially affect the phases of the cell cycle, possibly enhancing suppression of tumor growth, if cells are synchronized in a specific phase. A model is designed to replicate experiments that synchronize cells in the S phase using gemcitabine before radiation at various doses, with the goal of quantifying this effect. The model is used to simulate a clinical trial with a cohort of 100 individuals receiving only radiation and another cohort of 100 individuals receiving radiation after cell synchronization. The simulations offered in this study support the statement that, at suitably high levels of radiation, synchronizing melanoma cells with gemcitabine before treatment substantially reduces the final tumor size. The improvement is statistically significant, and the effect size is noticeable, with the near suppression of growth at 8 Gray and 92% synchronization. [ABSTRACT FROM AUTHOR]

In ethnomedicine, Motandra guineensis (Thonn.) A.DC. (Apocynaceae) is used to massage abscessed gums and manage pain. This study aimed to evaluate the antiproliferative effect of leaves of M. guineensis against human ovarian (OVCAR3) and melanoma (MDA-MB-435) skin cancer cells. Crude ethanol extract and fractions of M. guineensis leaves were evaluated for antiproliferative effect on OVCAR3 and MDA-MB-435 cells using cell viability assay at 2 and 20 µg/ml. In addition, the inhibitory effect of extract and fractions on nitric oxide (NO) production with lipopolysaccharide (LPS) stimulation (Greiss assay) on murine macrophage cells (RAW 264.7) at 0.3125 - 10 µg/ml was evaluated. Cell viability was evaluated using murine macrophage cells while toxicity assessment was done on Vero cells. Antiproliferative activity profile (% cell death) of extract and fractions followed the order: butanol (30% and 23%) > aqueous (28% and 21%) > ethyl acetate (22% and 19%) > crude (22% and 0%) at 20 µg/ml in OVCAR3 and MDAMB-435 cell lines respectively. Percentage NO inhibitory activity showed hexane fraction with the highest activity and aqueous fraction with the least activity at 10 µg/ml. Extract and fractions were less toxic in Vero cells when compared to the standard drug, Tamoxifen. Toxicity assessment using murine macrophage cells showed no significant difference in cell viability when compared to standard. Results indicate antiproliferative potential, NO inhibitory potential and safety of crude ethanol leaf extract and fractions of M. guineensis. [ABSTRACT FROM AUTHOR]

Simple Summary: New technologies, particularly artificial intelligence (AI) and machine learning, enable the utilization of extensive data for personalized medicine. Future challenge involve acquiring limited biological data and extracting information for predictive models. This perspective focuses on triple-negative breast cancer (TNBC), a disease lacking specific treatment, where ongoing investigations explore therapies like immunotherapy. Drawing from the successful use of immunotherapy in melanoma, this perspective explores the identified strengths and weaknesses to inform more successful strategies. In this context, AI and predictive tools are invaluable. Advancements in melanoma immunotherapy serve as a foundation for developing effective immunotherapies for TNBC. Common principles, including immune system activation, checkpoint inhibitors, and personalized treatment, offer prospects for improving the outcomes in aggressive breast cancer cases, presenting new hope for challenging-to-treat patients, avoiding overtreatment, and reducing costs. Thanks to new technologies using artificial intelligence (AI) and machine learning, it is possible to use large amounts of data to try to extract information that can be used for personalized medicine. The great challenge of the future is, on the one hand, to acquire masses of biological data that nowadays are still limited and, on the other hand, to develop innovative strategies to extract information that can then be used for the development of predictive models. From this perspective, we discuss these aspects in the context of triple-negative breast cancer, a tumor where a specific treatment is still lacking and new therapies, such as immunotherapy, are under investigation. Since immunotherapy is already in use for other tumors such as melanoma, we discuss the strengths and weaknesses identified in the use of immunotherapy with melanoma to try to find more successful strategies. It is precisely in this context that AI and predictive tools can be extremely valuable. Therefore, the discoveries and advancements in immunotherapy for melanoma provide a foundation for developing effective immunotherapies for triple-negative breast cancer. Shared principles, such as immune system activation, checkpoint inhibitors, and personalized treatment, can be applied to TNBC to improve patient outcomes and offer new hope for those with aggressive, hard-to-treat breast cancer. [ABSTRACT FROM AUTHOR]

Background: Patients with cancer often have to make complex decisions about treatment, with the options varying in risk profiles and effects on survival and quality of life. Moreover, inefficient care paths make it hard for patients to participate in shared decision-making. Data-driven decision-support tools have the potential to empower patients, support personalized care, improve health outcomes and promote health equity. However, decision-support tools currently seldom consider quality of life or individual preferences, and their use in clinical practice remains limited, partly because they are not well integrated in patients' care paths. Aim and objectives: The central aim of the 4D PICTURE project is to redesign patients' care paths and develop and integrate evidence-based decision-support tools to improve decision-making processes in cancer care delivery. This article presents an overview of this international, interdisciplinary project. Design, methods and analysis: In co-creation with patients and other stakeholders, we will develop data-driven decision-support tools for patients with breast cancer, prostate cancer and melanoma. We will support treatment decisions by using large, high-quality datasets with state-of-the-art prognostic algorithms. We will further develop a conversation tool, the Metaphor Menu, using text mining combined with citizen science techniques and linguistics, incorporating large datasets of patient experiences, values and preferences. We will further develop a promising methodology, MetroMapping, to redesign care paths. We will evaluate MetroMapping and these integrated decision-support tools, and ensure their sustainability using the Nonadoption, Abandonment, Scale-Up, Spread, and Sustainability (NASSS) framework. We will explore the generalizability of MetroMapping and the decision-support tools for other types of cancer and across other EU member states. Ethics: Through an embedded ethics approach, we will address social and ethical issues. Discussion: Improved care paths integrating comprehensive decision-support tools have the potential to empower patients, their significant others and healthcare providers in decision-making and improve outcomes. This project will strengthen health care at the system level by improving its resilience and efficiency. Plain language summary: Improving the cancer patient journey and respecting personal preferences: an overview of the 4D PICTURE project The 4D PICTURE project aims to help cancer patients, their families and healthcare providers better undertstand their options. It supports their treatment and care choices, at each stage of disease, by drawing on large amounts of evidence from different types of European data. The project involves experts from many different specialist areas who are based in nine European countries. The overall aim is to improve the cancer patient journey and ensure personal preferences are respected. [ABSTRACT FROM AUTHOR]

As the deadliest form of skin cancer, advanced-stage melanoma is a devastating disease. Encouragingly, with the introduction of immunotherapy, the overall survival of metastatic melanoma has improved drastically. However, access to novel immunotherapeutic drugs is not universal for all patients. Herein, we examined the association between various sociodemographic factors and the likelihood of using immunotherapy for melanoma treatment. This is a retrospective cohort study using the Texas Cancer Registry data for the years 2011–2018. Multivariable regression analysis was done to evaluate the association between patient characteristics and likelihood of receipt of immunotherapy. The association between sociodemographic factors and likelihood of presentation with metastasis at diagnosis was also examined. Having metastasis at diagnosis was strongly associated with higher odds of receiving immunotherapy (penalized adjusted OR 28.690, 95% CI 23.470–34.350, p <.0001). Compared to having private insurance, patients were less likely to receive immunotherapy if they were uninsured, had Medicare, or had missing/unknown insurance status (penalized adjusted OR's 0.700, 0.790, 0.130, p =.026, 0.027, and p <.0001 respectively). Results from our multivariate model highlighted several factors associated with a higher likelihood of presenting with metastatic disease which included Hispanic ethnicity and black race. Dermatologic disparities affecting the Hispanic population underscore the importance of targeted interventions to overcome community level barriers to melanoma treatment and diagnosis. This study highlights the need to further evaluate different insurance types and their effect on receipt of immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The rising incidence of skin cancer, particularly melanoma, over the last few decades requires natural-product-based treatments with a lack of side effects. To evaluate the anticancer potential of 37 structurally diverse flavonoids, cytotoxic tests, DNA biosynthesis inhibition levels, and apoptosis pathways involved in cell death were investigated in A375 and C32 melanoma cells. Compounds 1, 6, 15, and 37 reduced the viability of cell lines via the intrinsic (caspase-9) and extrinsic (caspase-8) pathways of apoptosis, where 16 and 17 mainly influenced DNA biosynthesis in cancer cells. In our study, we performed an anticancer analysis of compound 15 (5,6-dihydroxyflavone) for the first time. Although our data provide new insights into the molecular mechanisms of flavonoid-induced toxicity, in vivo studies are needed to assess their anti-cancer activities, especially flavonoid-core-containing hydroxyl groups. Skin cancers are a dominant type of cancer that impacts millions per year. Cancer is a heterogeneous disease triggered by the irreversible impairment of cellular homeostasis and function. In this study, we investigated the activity of 37 structurally diverse flavonoids to find potentially active substances using two melanoma cell lines: C32 and A375. First, the cytotoxic potential and DNA biosynthesis inhibition of flavonoids were tested to determine the most active compounds in cancer and normal cells. Second, the molecular mechanism of the anticancer activity of flavonoids was elucidated using Western blot and immunofluorescence analyses. Compounds 1, 6, 15, and 37 reduced the viability of A375 and C32 cell lines via the intrinsic and extrinsic pathways of apoptosis, whereas 16 and 17 acted in a higher degree via the inhibition of DNA biosynthesis. In our experiment, we demonstrated the anticancer activity of compound 15 (5,6-dihydroxyflavone) for the first time. The in vitro studies pointed out the importance of the flavonoid core in hydroxyl groups in the search for potential drugs for amelanotic melanoma. [ABSTRACT FROM AUTHOR]

Purpose: The incidence of cutaneous melanoma is rising, and Melanoma related deaths are highest among people aged 65–74. Herein, we aim to understand the impact of novel and established melanoma treatment methods on CM related mortality and all-cause mortality. We further compared these effects among Hispanic and non-Hispanic Whites (NHW). Methods: The data was extracted from the Texas Cancer Registry from 2007 to 2017. A Cox Proportional Hazard regression analysis was performed to assess treatment effect on melanoma mortality and all-cause mortality, with race-ethnicity as an effect modifier. Results: A higher percentage of Hispanic patients presented with CM-related mortality (22.11%) compared to NHW patients (14.39%). In both the Hispanic and NHW, post-diagnosis radiation (HR = 1.610, 95% CI 0.984–2.634, HR = 2.348, 95% CI 2.082–2.648, respectively), post-diagnosis chemotherapy (HR = 1.899, 95% CI 1.085–3.322, HR = 2.035, 95% CI 1.664–2.489, respectively), and post-diagnosis immunotherapy (HR = 2.100, 95% CI 1.338–3.296, HR = 2.402, 95% CI 2.100–2.748) are each associated with an increased risk in CM-related mortality. Similar results were seen with post-diagnosis radiation (Hispanic HR = 1.640, 95% CI 1.121–2.400, NHW HR = 1.800, 95% CI 1.644–1.971), post-diagnostic chemotherapy (Hispanic HR = 1.457, 95% CI 0.898–2.364, NHW HR = 1.592, 95% CI 1.356–1.869), and post-diagnosis immunotherapy (Hispanic HR = 2.140, 95% CI 1.494–3.065, NHW HR = 2.190, 95% CI 1.969–2.435) with respect to all-cause mortality. Post-diagnosis surgery (HR = 0.581, 95% CI 0.395–0.856, HR = 0.622, 95% CI 0.571–0.678) had the opposite effect in CM-related mortality for Hispanics and NHWs respectively. Conclusion: Our results propose differences in all-cause and CM-only related mortality with separate treatment modalities, particularly with chemotherapy, radiation therapy and immunotherapy. In addition, this retrospective cohort study showed that health disparities exist in the Hispanic Medicare population of Texas with CM. [ABSTRACT FROM AUTHOR]

Simple Summary: Deficiency and targeting of Stabilin-1, which is expressed by liver sinusoidal endothelial cells and subsets of macrophages, has been shown to improve anti-tumor immune responses in preclinical and early clinical studies. This study investigated whether targeting of Stab1 might also influence melanoma liver colonization, as hepatic metastasis of melanoma is a poor prognostic factor. In two models of hepatic melanoma metastasis, no direct influence of anti-Stab1 treatment was found. However, effects on the local microenvironment were observed. We suggest that the organ- and tumor-specific effects of anti-Stab1 therapies should be further considered and analyzed in future human studies. Background: This study analyzed the role of Stabilin-1 on hepatic melanoma metastasis in preclinical mouse models. Methods: In Stabilin-1−/− mice (Stab1 KO), liver colonization of B16F10 luc2 and Wt31 melanoma was investigated. The numbers, morphology, and vascularization of hepatic metastases and the hepatic microenvironment were analyzed by immunofluorescence. Results: While hepatic metastasis of B16F10 luc2 or Wt31 melanoma was unaltered between Stab1 KO and wildtype (Ctrl) mice, metastases of B16F10 luc2 tended to be smaller in Stab1 KO. The endothelial differentiation of both types of liver metastases was similar in Stab1 KO and Ctrl. No differences in initial tumor cell adhesion and retention to the liver vasculature were detected in the B16F10 luc2 model. Analysis of the immune microenvironment revealed a trend towards higher levels of CD45+Gr-1+ cells in Stab1 KO as compared to Ctrl in the B16F10 luc2 model. Interestingly, significantly higher levels of POSTN were found in the matrix of hepatic metastases of Wt31, while liver metastases of B16F10 luc2 showed a trend towards increased deposition of RELN. Conclusions: Hepatic melanoma metastases show resistance to Stabilin-1 targeting approaches. This suggests that anti-Stab1 therapies should be considered with respect to the tumor entity or target organs. [ABSTRACT FROM AUTHOR]

Simple Summary: Mucosal melanoma (MM) is a rare melanoma subtype that affects mucosal surfaces of the head and neck, anorectal region, and vulvovaginal area. Due to its rarity, the management, monitoring, and treatment of MM lack standardization, often relying on protocols designed for cutaneous melanoma (CM). In this retrospective, registry-based cohort study, we analyzed epidemiological and histological data together with the treatments administered to gain insights into the disease's behavior, treatment patterns, and potential predictors of survival. Our findings reveal that lower disease stage, thinner Breslow depth, and surgical resection are associated with improved overall survival, while age, sex, radiotherapy, and BRAF mutant status do not significantly affect survival. Standard systemic management typically includes immunotherapy (anti-PD-1 or anti-PD-1 and anti-CTLA-4). For cases with BRAF or c-KIT mutations, targeted therapies may be considered. The prognosis is unfavorable, with a survival rate of less than 50% at 2 years. Mucosal melanoma (MM) is an uncommon melanoma subtype affecting mucosal surfaces of the head and neck, anorectal region, and vulvovaginal area. We aimed to present our experience at a tertiary-level hospital regarding MM diagnosis, management, monitoring of progression, mutations, and outcome predictors. We performed a registry-based cohort study including MM cases diagnosed from 2012 to 2022 and retrospectively characterized somatic mutations on BRAF, NRAS and c-KIT. We employed Kaplan–Meier curves, log-rank tests, and Cox regression analysis to explore prognostic factors and survival outcomes in a cohort of 35 patients, mainly women (63%) with a median age of 70 years. Predominantly, MM occurred in the vulvovaginal region (48.6%). At diagnosis, 28.6% had lymph node involvement, and 31.4% also had distant metastasis. Mutations in BRAF and c-KIT were identified in 3/35 (9%) and 2/6 patients (33%), respectively. Surgery was performed in 71.4% of patients, and most received systemic treatment (65.7%). Lower disease stage, thinner Breslow depth, and surgical resection were associated with improved overall survival. Notably, age, sex, radiotherapy, and BRAF mutant status did not affect survival. Standard management typically involves immunotherapy. Cases with BRAF or c-KIT mutations may be considered for targeted therapies. Unfortunately, MM prognosis remains unfavorable, with a less than 50% survival rate at 2 years. [ABSTRACT FROM AUTHOR]

Cancer is considered the second leading cause of death worldwide. Skin melanomas account for the highest mortality rate amongst all types of skin cancer. Systemic treatment with vemurafenib has a high rate of adverse effects, so attempts have been made to prepare a topical form of this drug. Microemulsions have been used to improve drug delivery to the skin. The microemulsions were prepared by dissolving vemurafenib in a mixture of peppermint oil and Smix, followed by the addition of water. The characteristics and effectiveness of surface-active ionic liquid-based vemurafenib microemulsions were characterised and evaluated in vitro. The vemurafenib microemulsions (CP5, CP7 and CP8) had droplet sizes in the microemulsion range (less than 200 nm), and they were used to prepare microemulsion-based hydrogels using HPMC K15M via the hot and cold method. The prepared microemulsion-based hydrogels were then evaluated. The microemulsion-based hydrogel GP5 exhibited higher skin deposition (45.4%) than the other hydrogels; thus, GP5 is a promising candidate for the topical treatment of melanoma by vemurafenib. [ABSTRACT FROM AUTHOR]

Simple Summary: Thyroiditis is one of the most common immune toxicities in patients treated with combination immune checkpoint inhibition. Increased metabolic activity in the thyroid can be observed on FDG-PET/CT performed for the purposes of response assessment. The aim of our retrospective study was to assess the association and temporal profile of FDG-PET/CT findings suggesting thyroiditis with the natural history of clinical and biochemical thyroid dysfunction. Our findings demonstrated that an increased metabolic activity of the thyroid seen on routine FDG-PET/CT correlates with a biochemical diagnosis of thyroiditis and persists well after the initial biochemical diagnosis. We demonstrated that patients with FDG-PET/CT changes were more likely to develop overt clinical hypothyroidism. Background: FDG-PET/CT used for immune checkpoint inhibitor (ICI) response assessment can incidentally identify immune-related adverse events (irAEs), including thyroiditis. This study aimed to correlate the time course of FDG-PET/CT evidence of thyroiditis with clinical and biochemical evolution of thyroid dysfunction. Methods: A retrospective review was performed by two independent blinded nuclear medicine physicians (NMPs) of thyroidal FDG uptake in 127 patients who underwent PET/CT between January 2016 and January 2019 at baseline and during treatment monitoring of combination ICI therapy for advanced melanoma. Interobserver agreement was assessed and FDG-PET/CT performance defined by a receiver-operating characteristic (ROC) curve using thyroid function tests (TFTs) as the standard of truth. Thyroid maximum standardized uptake value (SUVmax) and its temporal changes with respect to the longitudinal biochemistry were serially recorded. Results: At a median of 3 weeks after commencing ICI, 43/127 (34%) had a diagnosis of thyroiditis established by abnormal TFTs. FDG-PET/CT was performed at baseline and at a median of 11 weeks (range 3–32) following the start of therapy. ROC analysis showed an area under the curve of 0.87 (95% CI 0.80, 0.94) for FDG-PET/CT for detection of thyroiditis with a positive predictive value of 93%. Among patients with biochemical evidence of thyroiditis, those with a positive FDG-PET/CT were more likely to develop overt hypothyroidism (77% versus 35%, p < 0.01). In the evaluation of the index test, there was an almost perfect interobserver agreement between NMPs of 93.7% (95% CI 89.4–98.0), kappa 0.83. Conclusion: Increased metabolic activity of the thyroid on routine FDG-PET/CT performed for tumoral response of patients undergoing ICI therapy is generally detected well after routine biochemical diagnosis. Elevation of FDG uptake in the thyroid is predictive of overt clinical hypothyroidism and suggests that an ongoing robust inflammatory response beyond the initial thyrotoxic phase may be indicative of thyroid destruction. [ABSTRACT FROM AUTHOR]

Simple Summary: Advanced cutaneous melanoma is the most aggressive type of skin cancer and has variable rates of treatment response. Currently, there are some classes of immunotherapy and target therapies for its treatment. Immunotherapy can inhibit tumor growth and its recurrence by triggering the host's immune system, whereas targeted therapy inhibits specific molecules or signaling pathways. However, melanoma responses to these treatments are highly heterogeneous, and frequently become resistant. Thus, this review article presents newly available therapies and those in development for advanced cutaneous melanoma therapy. Advanced cutaneous melanoma is considered to be the most aggressive type of skin cancer and has variable rates of treatment response. Currently, there are some classes of immunotherapy and target therapies for its treatment. Immunotherapy can inhibit tumor growth and its recurrence by triggering the host's immune system, whereas targeted therapy inhibits specific molecules or signaling pathways. However, melanoma responses to these treatments are highly heterogeneous, and patients can develop resistance. Epigenomics (DNA/histone modifications) contribute to cancer initiation and progression. Epigenetic alterations are divided into four levels of gene expression regulation: DNA methylation, histone modification, chromatin remodeling, and non-coding RNA regulation. Deregulation of lysine methyltransferase enzymes is associated with tumor initiation, invasion, development of metastases, changes in the immune microenvironment, and drug resistance. The study of lysine histone methyltransferase (KMT) and nicotinamide N-methyltransferase (NNMT) inhibitors is important for understanding cancer epigenetic mechanisms and biological processes. In addition to immunotherapy and target therapy, the research and development of KMT and NNMT inhibitors is ongoing. Many studies are exploring the therapeutic implications and possible side effects of these compounds, in addition to their adjuvant potential to the approved current therapies. Importantly, as with any drug development, safety, efficacy, and specificity are crucial considerations when developing methyltransferase inhibitors for clinical applications. Thus, this review article presents the recently available therapies and those in development for advanced cutaneous melanoma therapy. [ABSTRACT FROM AUTHOR]

Introduction melanoma patients who become stage III after a positive sentinel node biopsy (SNB) may have several patterns of recurrence patients and methods retrospective analysis of melanoma patients who have undergone SNB in a single institution from 2000 to 2015. Results There were 111 recurrences (45.1%) among 246 (20.3%) SNB positive patients and median DRFS was 77.7 months. After initial treatment, further recurrences occurred in 68 (77.3%) patients, regardless the site of initial recurrence conclusions multimodal strategies are recommended to achieve better results when managing stage III melanoma patients after a positive SNB [ABSTRACT FROM AUTHOR]

Superficial melanoma is the deadliest form of skin cancer without desirable clinically therapeutic options. Nanozymes, artificial nanomaterials with physicochemical performance and enzyme catalytic properties, have attracted considerable attention for antitumor therapy. However, the therapeutic efficiency of nanozymes is vulnerable to the tumor microenvironment (TME) and delivery process. Herein, a microneedle (MN) patch that integrates porous silicon (PSi) loaded with dual nanozymes is devised to bidirectionally regulate TME and accurately deliver nanocomplex to initiate ferroptosis for melanoma treatment. Benefitting from the channel confinement effect of PSi, the copper‐doped graphene quantum dots and palladium nanoparticles coloaded PSi (CuGQD/PdNPs@PSi) exhibit synergistic effect with enhanced mimicking peroxidase and glutathione oxidase activities, which are ≈2–3‐fold higher than those of monoconfined nanozyme or nonconfined nanozyme complexes. Additionally, the synergistic catalytic performance of CuGQD/PdNPs@PSi can be improved via photostimuli hyperthermia. The CuGQD/PdNPs@PSi can induce ferroptosis manifested by upregulation of lipid peroxides and inactivation of glutathione peroxidase 4. Furthermore, loading of nanocomplexes into MNs for administration resulted in a satisfactory melanoma growth inhibition of 98.8% within 14 days. Therefore, MNs encapsulated with CuGQD/PdNPs@PSi can provide a potentially nanocatalytic strategy for ferroptosis‐inducing tumor treatment while also meeting the medical needs of eradicating superficial tumors. [ABSTRACT FROM AUTHOR]

Tebentafusp is a bispecific protein that recently underwent FDA approval for the treatment of metastatic uveal melanoma that functions by redirecting cytotoxic T cells to glycoprotein-100, a protein highly expressed in melanoma. Although clinical trials have demonstrated that rashes are common in the first few days of treatment, little is known about skin reactions that develop later in the treatment course. Herein, we describe a type IV hypersensitivity reaction and vitiligo-like depigmentation that developed six weeks into treatment and discuss the possible mechanisms underlying these reactions. The type IV hypersensitivity reaction resolved without intervention within seven weeks of onset, suggesting that tebentafusp can be safely continued in select patients who develop this cutaneous react [ABSTRACT FROM AUTHOR]

Why you should read this article: • To understand the importance of post-treatment self-management interventions for patients with melanoma • To enhance your knowledge of the benefits, issues and barriers in relation to health and well-being events • To find information on organising a local health and well-being event for patients with melanoma The incidence of melanoma is increasing, and with the advent of new treatments people with the condition are living longer. In the UK, cancer policies recommend that every patient receives a personalised care package that includes access to a post-treatment health and well-being event. Such events aim to provide patients with the information and resources they need for effective self-care. At the author's trust, a local service evaluation showed that the provision of information to patients with melanoma at the end of treatment was variable and that patients did not have access to a health and well-being event. This article explores some of the literature and guidance on end-of-treatment self-management interventions, with a focus on health and well-being events. The author considers whether a health and well-being event may be an effective way of providing information and advice to melanoma survivors and provides an example of the content and format of such an event. [ABSTRACT FROM AUTHOR]

Objective. This study investigated whether the provision of financial assistance to patients living in regional New South Wales influenced patients' decisions to participate in a cancer clinical trial (cancer treatment or supportive care) and resulted in improved psychosocial outcomes. Methods. Administrative data were collected from participants, including demographics, travel distances and the value of financial support provided. Qualitative interviews were then conducted with a subset of consenting patients who received financial assistance for a clinical trial. Results. Sixty-four patients with cancer received financial support for a clinical trial, 27 (42%) of whom were interviewed. Participants whose distance to a trial site was over 400 km received almost three times as much financial support (M = A$3194.20, s.d. = A$1597.60) as participants whose distance to a trial site was between 50 and 100 km (M = A$1116.29, s.d. = $A1311.23). Half of participants indicated that receiving financial assistance influenced their decision to participate in a clinical trial, and most indicated the support alleviated the financial burden of clinical trial participation. Conclusions. The provision of financial assistance to patients living in regional areas may reduce inequities in cancer clinical trial participation and improve psychosocial outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: This study explores using engineered Myxoma virues (MyxV) encoding CD47 and IFN-γ to fight tumors and boost immune responses in the tumor environment. The findings show that the modified MyxV effectively infects and kills cancer cells, triggers immune responses, and reduces immune-suppressing cells. The dual-armed MyxV increases the presence and activity of T-cells in tumors. When combined with αPD-L1, a known immune therapy, MyxV effectively slows tumor growth and extends survival. These results highlight MyxV's potential as an oncolytic therapy. Further research to enhance its therapeutic efficacy and to determine anti-tumoral mechanisms, will offer a promising avenue for cancer treatment. Myxoma virus (MyxV) is a rabbit-specific poxvirus. However, its ability to selectively target tumor cells has established it as a safe and effective anticancer therapy. To strengthen its preclinical efficacy, transgenes that can prolong cancer cell infection and enhance anti-tumor effector functions are currently being investigated. We engineered MyxV armed with CD47, to turn on a 'do not eat me' signal within infected cells with actively replicating viruses, and with IFN-γ to further activate host immune anticancer responses. Tumor suppressive activities were significantly enhanced by the dual-armed MyxV_CD47/IFN-γ compared to parental MyxV or single-armed MyxV_CD47 or MyxV_IFN-γ. In addition, significant increases in IFN-γ+ CD8+T-cells and CD4+ T-cells populations within tumor-infiltrating lymphocytes (TIL) were observed after MyxV_CD47/IFN-γ treatment. Notably, all groups treated with MyxV showed a marked reduction in Foxp3+ CD4+ regulatory T-cells (Tregs) within TIL. We also show that MyxV infection induces PD-L1 up-regulation in cancer cells, and combinational treatment of MyxV with anti-mouse PD-L1 antibodies (αPD-L1) further controlled tumor burden and increased survival in the syngeneic melanoma model B16F10. Our data demonstrate that a CD47 and IFNγ dual-armed MyxV is an effective oncolytic viral immunotherapeutic. These findings strongly support further preclinical investigations to develop next-generation MyxV-based immunotherapy approaches. [ABSTRACT FROM AUTHOR]