Melanoma Research最新文献

Decrease of vitamin D receptor (VDR) expression is observed in melanocytic naevi and melanoma compared to normal skin. Little is known about factors influencing VDR expression in cutaneous melanoma (CM). We investigated the correlation of VDR expression in CM with 25-hydroxy vitamin D (25OHD) levels, demographic/clinical parameters, genetic variants of VDR and pathology of the primary tumor. Demographic/clinical parameters were recorded in 407 prospectively recruited CM patients of a multi-center controlled study (ViDMe trial). We determined VDR expression both in the nucleus and in the cytoplasm by semi-quantitative assessment in CM tissue using histochemistry in 279 patients, expressed in percentages and histoscore (H-score). Genomic DNA from 332 patients was extracted to genotype thirteen VDR single nucleotide polymorphisms (SNPs) using TaqMan. VDR expression in CM tissue from 279 patients was correlated with clinical/demographic parameters and 25OHD levels (univariable and multivariable analysis), VDR SNPs (univariable analysis) and pathology parameters of primary CM tissue (univariable analysis). Cytoplasmic VDR expression was increased in patients who stated to have a high sun exposure during their life compared to patients with low sun exposure (p H-score,univariable : 0.001, p H-score,multivariable : 0.004). The A allele of the genetic VDR polymorphism Fok1 was associated with a higher expression of the VDR in the cytoplasm (p cytoplasmic, univariable : 0.001 and p H-score, univariable : 0.02). In the primary tumor, presence of mitosis (p nucleus,%, univariable : 0.002) and perineural invasion (p nucleus,%,univariable : 0.03) were significantly associated with low nuclear VDR expression. ClinicalTrials.gov Identifier: NCT01748448.

Metastatic uveal melanoma (mUM) is a rare type of melanoma with poor outcomes. The first systemic treatment to significantly prolong overall survival (OS) in patients with mUM was tebentafusp, a bispecific protein that can redirect T-cells to gp-100 positive cells. However, the objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate the clinical impact of tebentafusp. As metabolic response assessed by PET Response Criteria in Solid Tumors (PERCIST) has been reported to better correlate with clinical outcome, we here compared the patterns of radiological and morphological responses in HLA-A*02:01-positive patients with mUM treated with tebentafusp. In the 19 enrolled patients, RECIST showed an overall response rate (ORR) of 10%, median progression-free survival of 2.8 months (95% CI 2.5-8.4), and median OS (mOS) of 18.8 months. In 10 patients, where both RECIST and PERCIST evaluation was available, the ORR was 10% for both; however, the PFS was longer for PERCIST compared to RECIST, 3.1 and 2.4 months, respectively. A poor agreement between the criteria was observed at all assessments (Cohen's kappa ≤0), yet they differed significantly only at the first on-treatment imaging ( P  = 0.037). Elevated baseline LDH and age were associated with an increased risk for RECIST progression, while lymphocyte decrease after the first infusions correlated to reduced risk of RECIST progression. Detectable ctDNA at baseline did not correlate with progression. Early response to tebentafusp may be incompletely captured by conventional imaging, leading to a need to consider both tumor morphology and metabolism.

Pan-negative melanomas account for 30% of melanomas. In case of immunotherapy failure, therapeutic options are limited. Oncogene fusions represent a target of interest in many solid cancers. In melanoma, the frequency of oncogene fusion is not well documented and not routinely investigated. We conducted a single-center retrospective study. The objective was to determine the frequency of oncogene fusion detected by RNA sequencing, in patients with advanced or metastatic pan-negative melanoma. In parallel, an extended molecular alteration search was performed using extended targeted next-generation sequencing. We identified 59 patients with advanced pan-negative melanoma between January 2021 and January 2023. It was a cutaneous melanoma in 71.1% of the cases, a mucous melanoma in 15.2% of the cases. We identified nine patients with a RAF fusion, including seven BRAF gene fusion and two RAF1 fusion. Of the other molecular alterations, NF1 mutation was the most frequent molecular alteration identified. Among the nine patients with RAF fusions, all the patients initially received treatment with anti-PD1 ± anti-CTLA4 immunotherapy. After immunotherapy failure, five patients benefited from second-line targeted therapy (two with BRAF and MEK inhibitors combination, three MEK inhibitors alone). The response rate was 20%. In a population of pan-negative melanoma, we detected 15.2% of RAF fusion. Fusion detection allowed the introduction of a second line of targeted therapy, in the absence of a validated therapeutic option in 55.5% of cases. This study suggests the relevance of detecting RAF fusion in a selected population.

Background: Recent studies indicate that melphalan percutaneous hepatic perfusion (M-PHP) for liver metastases from ocular melanoma (mUM) improves survival. Importantly, this benefit must be carefully balanced with changes in a patient's quality of life (QoL). This study examines the QoL changes post-M-PHP.

Methods: Retrospective analysis of the change in QoL using the Functional Assessment of Cancer Therapy-General (FACT-G) with mUM patients receiving M-PHP ( n  = 20). The FACT-G scores, which comprise physical (PWB), social (SWB), emotional (EWB) and functional (FWB) wellbeing were measured pre-procedure and at day 1, day of discharge (mean = 2.4 days), 7, 14 and 28 days after M-PHP therapy. Wilcoxon signed-rank test gauged QoL domain changes.

Results: Baseline FACT-G median (IQR) scores were 101.8 (21.8). QoL scoring significantly decreased immediately after the procedure [day 1; 85 (27.5); P  = 0.002] and gradually improved over time. By day 28, QoL almost returned to pre-procedure levels [100.3 (13.8); P  = 0.31]. Subscore analysis revealed that the initial drop in QoL at day 1 post-procedure was attributable to the PWB (28 vs. 24; P  = 0.001) and FWB domains (26 vs. 18.5; P  < 0.001). By day 28 there was a statistically significant improvement in EWB ( P  = 0.01).

Conclusion: QoL following M-PHP decreases immediately after therapy and is not significantly different from baseline by the day of discharge. By day 28 there is improved emotional well-being. This study could help to optimize the time between treatment cycles when combined with toxicity data and blood count recovery.

Mast cells (MCs) accumulate in a broad range of tumors, including melanomas. While MCs are potent initiators of immunity in infection, and in allergic inflammation, the function of MCs in anti-melanoma immunity is unclear. MCs have the potential to release tumoricidal cytokines and proteases, to activate antigen-presenting cells and to promote anti-tumor adaptive immunity. However, within the immunosuppressive tumor microenvironment (TME), MC activation may promote angiogenesis and contribute to tumor growth. In this review, the relationship between MCs and melanomas is discussed with a focus on the impact of the TME on MC activation.

Cutaneous melanoma, a highly aggressive skin tumor, is characterized by complex signaling pathways in terms of its pathogenesis and progression. Although the degree of pigmentation in melanoma determines its progression, metastasis, and prognosis, its association with inflammatory cytokines remains unclear. Thus, we evaluated the associations between melanoma pigmentation and plasma levels of inflammatory cytokines; furthermore, we investigated the potential variations in this relationship across the primary anatomic sites of melanoma. We enrolled patients with cutaneous melanoma who visited Chonnam National University Hwasun Hospital between January 2021 and December 2021. The anatomical sites of melanoma were categorized as acral and non-acral sites. The degree of pigmentation was quantified using computer software. In total, nine inflammatory cytokines were analyzed, including interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). This study included 80 melanoma patients. Of these, 53 had acral melanoma and 27 had non-acral melanoma. Overall, plasma concentrations of IL-2, IL-4, IL-5, GM-CSF, and IFN-γ demonstrated significant correlations with diminished pigmentation. Furthermore, in the acral melanoma patients group, plasma concentrations of IL-2, IL-4, IL-5, GM-CSF, IFN-γ, and TNF-α revealed significant correlations with diminished pigmentation. Our results reveal significant associations between melanoma pigmentation and various cytokine levels, particularly in acral melanoma patients; these associations can be influenced by factors related to acral melanoma, such as physical stress or trauma. These correlations may also provide directions for the treatment of acral melanoma.

The occurrence of bone marrow metastases (BMM) in melanoma patients is often underestimated, with only 7% detected during in-vivo staging procedures but rising to 45% in autopsy cases. This systematic review aims to shed light on the clinical and laboratory features of BMM in melanoma by analyzing 73 studies selected from 2 482 initially retrieved from PubMed, Embase , and Cochrane CENTRAL databases. Our findings reveal a slight male predominance, with a median age at BMM diagnosis of 56 years. Primary melanoma sites included the skin (52%), mucosa (8.8%), uvea (20.5%) and unidentified (19%). BMM was preceded by lymph node involvement in 36.5% of cases, whereas 63% showed no nodal metastases, with direct BMM occurring in 22.5% and metastases to other sites in 41%. Common BMM symptoms included pain (60.7%), anemia (80%), thrombocytopenia, leukoerythroblastosis, pancytopenia and leukopenia, while disseminated intravascular coagulation was detected in 11% of cases. In 23.6% of cases, BMM was amelanotic. The prognosis for BMM is grim, with a median survival of only 2 months. Conventional therapies for BMM remain largely ineffective, emphasizing the importance of considering bone marrow as a potential metastatic site in melanoma patients.

Pembrolizumab and ipilimumab/nivolumab (ipi/nivo) combination are FDA-approved immune checkpoint inhibitor (ICI) therapies for metastatic melanoma. ICIs could result in various inflammation responses known as immune-related adverse events (IRAEs). We report a patient with metastatic melanoma who developed multiple IRAEs including sarcoidosis-like reaction (SLR), diabetic ketoacidosis (DKA), and worsening hypothyroidism on ICIs. A 71-year-old man with stage IIIC melanoma and lymph node metastasis began adjuvant therapy with pembrolizumab in May 2021. A surveillance positron emission tomography-computed tomography (PET-CT) scan four months later showed diffuse nodal uptake indicating potential metastases although the patient remained asymptomatic. His treatment was temporarily switched to ipi/nivo before biopsy was obtained for definitive diagnosis, which revealed non-caseating granulomas consistent with SLR. After resuming pembrolizumab, he developed DKA and worsening hypothyroidism in November 2021, both of which were attributed to IRAEs. His surveillance PET scan in March 2022 again revealed new hypermetabolic activity in several bones, subcutaneous tissue, and the left inguinal lymph node. Left inguinal node biopsy showed disease recurrence, while biopsies of hypermetabolic subcutaneous nodules and bone demonstrated non-caseating granulomas. Our case described a patient on ICIs who developed several IRAEs. SLR is often asymptomatic but remains a diagnostic challenge due to its indistinguishable appearance on imaging studies compared to metastasis. Better understanding of IRAEs and improved surveillance strategies are needed for optimal patient outcomes.