Melanoma Research最新文献

Programmed death ligand-1 (PD-L1) is an inducible protein heterogeneously expressed in melanoma. Assessment of PD-L1 expression is challenging and standard immunohistochemistry (IHC) requires biopsies and cannot capture heterogeneity of expression. Noninvasive imaging methods provide evaluation of expression across lesions in the body. We conducted a prospective pilot trial with PD-L1 PET imaging with [ 18 F]-BMS-986229 as a noninvasive approach to assess PD-L1 expression across lesions, in 10 patients with advanced melanoma, longitudinally during treatment with nivolumab and ipilimumab. PET imaging was performed at baseline and at 6 weeks after initiation of treatment. We examined the relationship of PD-L1 PET uptake to radiographic clinical response. [ 18 F]-BMS-986229 uptake was variably seen across lesions in patients at baseline. All patients showed positive uptake in lesions at baseline PET with a median SUV max of 3.6 (range: 1.7-8.6). PD-L1 PET SUV max decreased in all but two lesions 6 weeks after treatment initiation. Four of five patients had a mean (SUV max ) greater than or equal to 3.00 in Response Evaluation Criteria in Solid Tumors (RECIST) evaluable lesions at baseline, and all had a RECIST response while all progressors ( n  = 3) had baseline PD-L1 mean SUV max less than or equal to 2.60. A higher lesional baseline SUV max was associated with greater individual lesion reduction during treatment. The PD-L1 uptake in lesions showed a low correlation with baseline PD-L1 by IHC. In this small pilot study, PD-L1 PET imaging using [ 18 F]-BMS-986229 showed feasibility in noninvasively assessing lesion uptake and PD-L1 heterogeneity in patients receiving combination immunotherapy. Future exploration of this tracer in larger patient cohorts is necessary to delineate its use in managing immunotherapy treatments.

Surgical stress is gaining increasing focus in surgical oncology due to its impact on complications, prognosis, and survival. The neutrophil-to-lymphocyte ratio (NLR) is a recognized biomarker reflecting inflammation and immune response, key aspects of surgical stress. Sentinel lymph node biopsy (SLNB) and wide local excision (WLE) are considered minimally invasive procedures used in the management of melanoma. Yet, the surgical stress response of WLE and SLNB remains unexplored. This study aims to investigate perioperative changes in the NLR as a marker of surgical stress in patients with melanoma undergoing WLE and SLNB. This prospective pilot study investigated NLR as a marker of surgical stress in patients ( n = 20) with melanoma undergoing WLE and SLNB. NLR was calculated from the plasma differential count and measured preoperatively and at 2 and 6 h postoperatively. Surgical stress was categorized into four groups according to the NLR values: No stress, mild, moderate, and severe stress. Paired t -tests tested differences between time points. Mean NLR increases from 1.94 (±0.86) preoperatively to 9.5 (±4.39) at 2 h ( P < 0.001) and further increases to 16.04 (±11.11) at 6 h ( P = 0.02) postoperatively. This increase reflects a shift from no systemic stress (NLR: 1-3) to a moderate (NLR: 8-18) response, approaching severe thresholds. Changes in NLR are driven by significant neutrophilia and lymphocytopenia. Despite minor procedures, WLE and SLNB elicit a substantial surgical stress response. NLR may serve as a valuable biomarker for monitoring surgical stress in melanoma surgery, with potential implications for surgical and oncologic outcomes.

Pembrolizumab is an immune checkpoint inhibitor targeting programmed cell death protein 1 , used for stage IIB/IIC melanoma. While effective, pembrolizumab can lead to immune-mediated toxicities in various systems; however, nervous system effects are less well-documented. We report the case of a 34-year-old man who developed delayed immune-mediated encephalomyelitis with antiglial fibrillary acidic protein (GFAP) antibodies after completing nine cycles of adjuvant pembrolizumab for stage IIC melanoma. Four months posttreatment, he presented with neurological symptoms, including ataxic gait, sensory deficits in the lower limbs, and urinary retention. Imaging revealed extensive myelitis and encephalitis in the spinal cord and posterior fossa. The etiological evaluation was negative except for the presence of anti-GFAP antibodies in the cerebrospinal fluid. Treatment with high-dose corticosteroids led to significant improvement. This case represents the first reported instance of postimmunotherapy encephalomyelitis with anti-GFAP antibodies following pembrolizumab treatment. Although rare, this is a serious adverse event requiring careful monitoring and early multidisciplinary management.

Phosphodiesterase type 5 (PDE5) inhibitors are the first-line treatment for erectile dysfunction, with modest adverse effects. Since 2011, concerns have arisen about increased melanoma risk in PDE5 inhibitor users. PDE5 inhibitors affect the rat sarcoma virus oncogene-rapidly accelerated fibrosarcoma-mitogen-activated protein kinase-extracellular signal-regulated kinase signaling cascade, which is involved in melanoma formation. This systematic review and meta-analysis investigates melanoma risk in PDE5 inhibitor users. PubMed, Cochrane, and Embase were searched to examine the relationship between PDE5 inhibitors and melanoma. A random-effects model estimated pooled odds ratios (ORs) and hazard ratios (HRs), with the I ² statistic assessing heterogeneity. RStudio v4.4.2 was used for the meta-analysis, and a P value less than 0.05 was deemed significant. Eight studies including 7 620 765 patients were analyzed, with 2 123 165 (27.86%) comprising the PDE5 inhibitor-exposed group. The meta-analysis found a relationship between PDE5 inhibitor use and increased melanoma risk [OR: 1.60, 95% confidence interval (CI): 1.13-2.27, P = 0.009, I ² = 98%] and [HR: 1.10, 95% CI: 1.03-1.17, P = 0.005, I ² = 43%]. When each PDE5 inhibitor was examined separately, increased melanoma incidence was observed, though not statistically significant. The OR for sildenafil was 1.85 (95% CI: 0.97-3.51, P = 0.059, I ² = 99%), tadalafil 1.54 (95% CI: 0.79-3.00, P = 0.203, I ² = 96%), and vardenafil 1.16 (95% CI: 0.82-1.64, P = 0.391, I ² = 89%). This study suggests PDE5 inhibitor users have a higher chance of developing potentially fatal melanoma. Patients with a history of skin cancer, a family history of melanoma, or other risk factors should avoid these medications.

To explore the functional role of thrombospondin 2 (THBS2) in the metastasis of skin cutaneous melanoma (SKCM), with a focus on its regulation of angiogenesis and extracellular matrix (ECM) remodeling. THBS2 expression was assessed in normal melanocytes and SKCM cell lines with varying metastatic potential. Functional analyses were conducted after THBS2 knockdown in A375 cells and overexpression in G-361 cells. Effects on migration, invasion, endothelial tube formation, and angiogenesis- and ECM-related factors were evaluated. Tumor IMmune Estimation Resource database was used for correlation analyses in SKCM samples. A liver metastasis model was established by intrasplenic injection of B16-F10 cells into Thbs2 knockout and wild-type mice, followed by quantification of hepatic metastases and molecular analysis of peritumoral liver tissue. THBS2 was highly expressed in invasive melanoma cell lines and was positively associated with VEGFA, PECAM1, and MMPs in both databases and experimental models. Knockdown of THBS2 significantly suppressed VEGFA, PECAM1, FGF2, FLT1, MMP2, MMP9, and ECM components (LAMA4, COL1A1, and COL4A1) at mRNA and protein levels, inhibited melanoma cell migration and invasion, and reduced tube formation in human umbilical vein endothelial cells. Overexpression had opposite effects. In vivo , Thbs2 knockout mice exhibited significantly fewer hepatic metastases and reduced metastatic area compared with wild-type controls. Expression of Lama4, Pecam1, Vegfa, Mmp2, and Mmp9 was markedly lower in peritumoral liver tissue of knockout mice. THBS2 promotes SKCM metastasis by enhancing angiogenesis and ECM remodeling. Targeting THBS2 may represent a promising strategy for inhibiting melanoma progression and distant organ colonization.

Inflammation, well-known as one of the hallmarks of cancer, has been demonstrated to have a key role in the incidence and growth of different tumors. However, its role as a prognostic factor for melanoma has not yet been clarified. Our study aimed to evaluate the correlation of neutrophil to lymphocyte ratio (NLR), platelet to monocyte ratio (PMR), systemic inflammation index (SII), and aggregate index of systemic inflammation (AISI) with clinical stages of disease, to define whether higher values of these markers correlate with a more aggressive disease. We retrospectively analyzed NLR, PMR, SII, and AISI in a total of 129 newly diagnosed melanoma patients. All values were calculated using the complete blood count data. Higher NLR was associated with advanced stages ( P  < 0.001). Mean NLR among patients with early stage disease (IB and IIA) was 2.01, while the mean NLR for patients with advanced stage disease (from stage IIB to IV) was 3.22. Mean PMR among patients with early stage disease (IB and IIA) was 520, while the mean PMR for patients with advanced stage disease was 479 ( P  = 0.049). Mean AISI in the early stage was 247 and 482 in advanced stages ( P  < 0.001). Mean SII was 480 in the early stage and 747 in advanced stages ( P  = 0.004). Our data confirmed the association between NLR and newly reported the association of PMR, AISI, and SII with high-risk and aggressive melanoma. Further investigations are required to define a meaningful prognostic system for patients with advanced melanoma. This could help classify patients with advanced stages of disease, demanding a short follow-up.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and are increasingly used, also in the adjuvant and neoadjuvant settings. ICIs, however, can induce immune-related adverse events (irAEs), which range from mild to life-threatening. As the use of ICIs expands, prompt identification and management of especially severe and life-threatening irAEs are crucial. We report a case of grade 4 steroid-refractory immune-related mucositis in a 60-year-old male treated with pembrolizumab following complete resection of stage IIIC melanoma. The patient received seven courses of adjuvant pembrolizumab without adverse events until 2 weeks after the seventh dose, when he presented with acute respiratory distress, dysphagia, and dyspnea. Examination revealed significant throat swelling and mucosal edema. Despite initial treatment with high-dose steroids, the patient's condition deteriorated, and he was admitted to the ICU for intubation and close monitoring. Infliximab was administered for steroid-refractory mucositis, resulting in rapid symptom resolution and successful extubation 5 days later. This case highlights the challenges in managing severe steroid-refractory irAEs. The rapid response to infliximab suggests the benefit of early intervention with alternative immunosuppressive agents in severe irAEs. Increased awareness of rare irAEs is essential for optimizing treatment and improving outcomes for patients receiving ICIs.

Identification of effective systemic therapies for the treatment of metastatic uveal melanoma remains an ongoing challenge. While immune checkpoint inhibitors are frequently used to treat this disease, response rates and survival outcomes remain poor. In this case report, we present two heavily pretreated patients with metastatic uveal melanoma who had robust responses to combination nivolumab (PD-1 inhibitor) with relatlimab (LAG-3 inhibitor) as salvage treatment. We highlight the ongoing research of the uveal melanoma tumor immune microenvironment and the potential role of LAG-3 inhibition as an effective treatment strategy.