AIM: To present the experience and outcomes of the surgical treatment for the patients with anorectal melanoma from the Cancer Hospital, Chinese Academy of Medical Sciences. METHODS: Medical records of the diagnosis, ...AIM: To present the experience and outcomes of the surgical treatment for the patients with anorectal melanoma from the Cancer Hospital, Chinese Academy of Medical Sciences. METHODS: Medical records of the diagnosis, surgery, and follow-up of 56 patients with anorectal melanoma who underwent surgery between 1975 and 2008 were retrospectively reviewed. The factors predictive for the survival rate of these patients were identified using multivariate analysis. RESULTS: The 5-year survival rate of the 56 patients with anorectal melanoma was 20%, 36 patients underwent abdominoperineal resection (APR) and 20 patients underwent wide local excision (WLE). The rates of local recurrence of the APR and WLE groups were 16.13% (5/36) and 68.75% (13/20), (P = 0.001), and the median survival time was 22 mo and 21 mo, respectively (P = 0.481). Univariate survival analysis demonstrated that the number of tumor and the depth of invasion had significant effects on the survival (P < 0.05). Multivariate analysis showed that the number of tumor [P = 0.017, 95% confidence interval (CI) = 1.273-11.075] and the depth of invasion (P = 0.015, 95% CI = 1.249-7.591) were independent prognostic factors influencing the survival rate. CONCLUSION: Complete or R0 resection is the first choice of treatment for anorectal melanoma, prognosis is poor regardless of surgical approach, and early diagnosis is the key to improved survival rate for patients with anorectal melanoma.展开更多
Cutaneous malignant melanoma is the most aggressive form of skin cancer with an extremely poor survival rate for the patients diagnosed with locally invasive and metastatic disease states. Intensive research has led i...Cutaneous malignant melanoma is the most aggressive form of skin cancer with an extremely poor survival rate for the patients diagnosed with locally invasive and metastatic disease states. Intensive research has led in last few years to an improvement of the early detection and curative treatment of primary cutaneous melanomas that are confined to the skin by tumor surgical resection. However, locally advanced and disseminated melanomas are generally resistant to conventional treatments, including ionizing radiation, systemic chemotherapy, immunotherapy and/or adjuvant stem cellbased therapies, and result in the death of patients. The rapid progression of primary melanomas to locally invasive and/or metastatic disease states remains a major obstacle for an early effective diagnosis and a curative therapeutic intervention for melanoma patients. Importantly, recent advances in the melanoma research have led to the identification of different gene products that are often implicated in the malignant transforma-tion of melanocytic cells into melanoma cells, including melanoma stem/progenitor cells, during melanoma initiation and progression to locally advanced and metastatic disease states. The frequent deregulated genes products encompass the oncogenic B-Raf V600 E and N-RasQ 61 R mutants, different receptor tyrosine kinases and developmental pathways such as epidermal growth factor receptor(EGFR), stem cell-like factor(SCF) receptor KIT, hedgehog, Wnt/β-catenin, Notch, stromal cell-derived factor-1(SDF-1)/CXC chemokine receptor-4(CXCR4) and vascular endothelial growth factor(VEGF)/VEGFR receptor. These growth factors can cooperate to activate distinct tumorigenic downstream signaling elements and epithelial-mesenchymal transition(EMT)-associated molecules, including phosphatidylinositol 3'-kinase(PI3K)/Akt/ molecular target of rapamycin(mT OR), nuclear factor-kappaB(NF-κB), macrophage inhibitory cytokine-1(MIC-1), vimentin, snail and twist. Of therapeutic relevance, these deregulated signal transduction components constitute new potential biomarkers and therapeutic targets of great clinical interest for improving the efficacy of current diagnostic and prognostic methods and management of patients diagnosed with locally advanced, metastatic and/or relapsed melanomas.展开更多
We read with interest the article entitled： ‘Jejuno-jejunal invagination due to intestinal melanoma’ by Resta , et al. They reported a rare clinical case of a young woman with a bleeding jejunal melanoma, whose ear...We read with interest the article entitled： ‘Jejuno-jejunal invagination due to intestinal melanoma’ by Resta , et al. They reported a rare clinical case of a young woman with a bleeding jejunal melanoma, whose early clinical presentation was an intestinal invagination. The article is also referred to the rarity of gastrointestinal melanomas as well as their possible primary nature.展开更多
Melanoma of the gastrointestinal tract is a rare, highly malignant neoplasm of poor prognosis. This is description of an unusual case of surgically treated patient with two metachronous malignant melanomas of the stom...Melanoma of the gastrointestinal tract is a rare, highly malignant neoplasm of poor prognosis. This is description of an unusual case of surgically treated patient with two metachronous malignant melanomas of the stomach and the esophagus. The former lesion was located in the cardia and effectively treated with RO total gastrectomy. The latter was recognized after 67 mo and appeared as irregular, flat, pigmented areas located in the mid esophagus. Subtotal esophagectomy via right-sided thoracotomy, laparotomy and left-sided cervicotomy was performed, but neoplastic cells were found in distal margin (R1). Fourteen months after esophagectomy multiple lung metastases were detected. Patient.died 2 mo later.展开更多
BACKGROUND Anorectal melanoma (AM) is an extremely rare malignant tumor originating from anorectal melanocytes with a poor prognosis. AM has been reported to have a much lower incidence than cutaneous or choroid melan...BACKGROUND Anorectal melanoma (AM) is an extremely rare malignant tumor originating from anorectal melanocytes with a poor prognosis. AM has been reported to have a much lower incidence than cutaneous or choroid melanoma, accounting for 0.4%-1.6% of all melanomas. CASE SUMMARY We report a 76-year-old female patient diagnosed with anorectal malignant melanoma by colonoscopy and biopsy. Intraoperative examination revealed two distinct anorectal tumors, one melanotic and another amelanotic, as well as two pigmented mucosal zones at the dentate line level. Abdominal perineal resection was performed. A pathological report confirmed all four lesions to be melanomas. Postoperatively, we followed an immunotherapy protocol targeting PD-1 (nivolumab). The patient had 24 mo of disease-free follow-up upon completion of nivolumab treatment. CONCLUSION This is the first reported case presenting coexistence of pigmented and unpigmented AMs in the same patient.展开更多
AIM:To evaluate the results and complications of secondary endoresection via pars plana vitrectomy for choroidal melanoma and review the previously reported endoresection studies on the treatment of choroidal melanoma...AIM:To evaluate the results and complications of secondary endoresection via pars plana vitrectomy for choroidal melanoma and review the previously reported endoresection studies on the treatment of choroidal melanoma.METHODS:The medical records of 6 patients with choroidal melanoma who underwent secondary endoresection between March 2012 and March 2020 were retrospectively reviewed.The indications for secondary endoresection were progressive or recurrent tumor and severe exudative retinal detachment after previous treatment with plaque radiotherapy/Cyberknife radiosurgery/transpupillary thermotherapy(TTT).RESULTS:Before endoresection,2 eyes had Iodine-125 plaque radiotherapy and TTT,1 eye had Ruthenium-106 plaque radiotherapy and TTT,1 eye had Cyberknife radiosurgery and TTT,1 eye had Cyberknife radiosurgery,and 1 eye had TTT only.Preoperative visual acuity ranged from 20/63 to 20/1600(Snellen) and from 0.5 to 1.9(mean:1.1) on the log MAR scale.The mean tumor base diameters were 9.5×8.7 mm and the mean tumor thickness was 5.4 mm.After secondary endoresection,transient vitreous hemorrhage developed in 2(33.3%) eyes and retinal detachment in 1(16.7%) eye.Cytopathological examination revealed epithelioid cell melanoma in 4(66.7%) eyes and mixed cell melanoma in 1(16.7%).Melanoma cell type was not specified in 1(16.7%) eye.At a mean follow-up of 49.6 mo(range:16-90 mo),mean visual acuity did not improve and 1 eye was enucleated due to tumor recurrence.Final visual acuity ranged from 20/63 to 20/1600(Snellen) and from 0.5 to 1.9(mean:1.2) on the log MAR scale.Two patients with choroidal melanoma developed metastasis and eventually expired.CONCLUSION:Secondary endoresection seems to be an effective treatment option for globe salvage in choroidal melanoma not responsive to conventional treatment and displaying persistent exudative retinal detachment.There was no visual acuity increase among the treated eyes but globe salvage was possible in most cases in this study.展开更多
In a comprehensive literature review,PubMed,Embasem and Web of Science were searched for studies examining targeted therapy of ocular malignant melanomas to present and discuss targeted therapy treatment options of oc...In a comprehensive literature review,PubMed,Embasem and Web of Science were searched for studies examining targeted therapy of ocular malignant melanomas to present and discuss targeted therapy treatment options of ocular tumors,mainly conjunctival and uveal melanoma(UM).Conjunctival malignant melanomas showed similarities in clinical and genetic aspects with cutaneous melanomas.Many therapies with checkpoint inhibitors already established for cutaneous melanomas may be a treatment option for conjunctival malignant melanomas with shared traits.Existing targeted therapies are for example checkpoint inhibitors like pembrolizumab or nivolumab.As a corollary,due to marked differences in clinics and genetics between UMs and conjunctival melanomas(CMs)or cutaneous melanomas,it has remained elusive whether the available possibilities of molecular targeted therapy will be an option for the therapy of metastasizing UMs.Possible novel ways of treating UM are being explored.Fotemustine or the inoculation of dendritic cells with tumorous RNA or sunitinib in combination with cisplatin and or tamoxifen may be used in future to treat UM.While CM are treatable using targeted therapies,UM have not been researched enough to find working targeted therapy options.Further research has to be done in order to find acceptable treatment options.展开更多
Objective:The BRAF inhibitor,vemurafenib,has been widely used in the treatment of patients with melanoma-bearing BRAFV600E mutations.While the initial response to vemurafenib is usually excellent,the majority of patie...Objective:The BRAF inhibitor,vemurafenib,has been widely used in the treatment of patients with melanoma-bearing BRAFV600E mutations.While the initial response to vemurafenib is usually excellent,the majority of patients eventually develop resistance and metastatic disease.However,the underlying molecular mechanism remains elusive.The objective of this study was therefore to identify additional molecular targets responsible for vemurafenib resistance.Methods:Western blots and immunohistochemistry analyses were used to evaluate expressions of PYK2 and p-PYK2 in cultured cells and melanoma tissue microarrays.The relationships of p-PYK2 with clinicopathological parameters were statistically analyzed.Invadopodia cell invasion,and a Ca2+assay were used to determine the effect of vemurafenib resistance-induced p-PYK2 on melanoma progression.A mouse model was used to assess the effects of PYK2 on melanoma metastasis.Results:Elevated p-PYK2 levels were detected in vemurafenib-resistant melanoma cells,and PYK2 was shown to regulate invadopodia formation in melanoma cells.Vemurafenib triggered invadopodia formation by activation of PYK2.Inhibition of PYK2 with either shRNA or the small molecule inhibitor,PF562711,dramatically reduced vemurafenib-induced invadopodia formation.Furthermore,knockdown of PYK2 significantly reduced melanoma lung metastasis in vivo.Increased expressions of p-PYK2 in melanoma patients were positively correlated with advanced stage(P=0.002),metastasis(P<0.001),and Clark grade(P<0.001),and were also associated with short overall survival[hazard ratio(HR)=3.304,P=0.007]and progression-free survival(HR=2.930,P=0.001).Conclusions:PYK2 mediated vemurafenib-induced melanoma cell migration and invasion.Inhibition of PYK2 resensitized melanoma cells to vemurafenib.Phospho-PYK2 was a prognostic biomarker in melanoma patients.展开更多
Background: The anorectal location of melanomas is extremely rare (1% - 3% of all melanomas), and the prognosis remains poor because of the aggressiveness and the high metastatic potential of those tumors. The discove...Background: The anorectal location of melanomas is extremely rare (1% - 3% of all melanomas), and the prognosis remains poor because of the aggressiveness and the high metastatic potential of those tumors. The discovery that the KIT oncogene may be aberrantly activated in a subset of patients with anorectal melanoma creates a realm of possibility for the development of targeted molecular therapy. Aim: to show the epidemiologic, clinico-radiological, histological features and treatment management especially in patients with over-expression of C-KIT treated by Imatinib. Methods: It is a retrospective study conducted in the department of medical oncology at Hassan II University Hospital between January 2007 and January 2012, including all patients with histologically proven melanoma of the anorectal area. Results: 11 cases were collected, with slight female predominance. Nine patients were metastatic at the moment of diagnosis, and only two with local stage, but evolution was marked by local and distant recurrence less than 12 months after abdo-minoperineal resection. First line of chemotherapy was based mainly on paclitaxel, carboplatine and dacarbazine. Response was modest with only 3 partial responses, 4 patients with disease stability, and 4 patients with disease progression. Two patients, with over expression of C-KIT, received Imatinib as second line of treatment with significant improvement of symptoms and radiological response reaching 50%. Seven patients died with a median survival of 11 months from diagnosis to the date of death. Conclusion: Primary anorectal melanomas are very rare, with high aggressiveness and poor prognosis. Treatment management is still a big challenge given to the modest efficacy of conventional chemotherapy. Better understanding of carcinogenesis and signaling pathways will allow development of new targeted therapies.展开更多
AIM:To identify metastasis-associated prognostic genes and construct a robust molecular signature for survival prediction in uveal melanoma(UVM)patients.METHODS:Transcriptomic data and clinical information from 80 UVM...AIM:To identify metastasis-associated prognostic genes and construct a robust molecular signature for survival prediction in uveal melanoma(UVM)patients.METHODS:Transcriptomic data and clinical information from 80 UVM patients in the Cancer Genome Atlas(TCGA)-UVM cohort and an external Gene Expression Omnibus(GEO)microarray dataset(GSE73652;8 non-metastatic vs 5 metastatic cases)were analyzed to identify differentially expressed genes(DEGs).Functional enrichment,proteinprotein interaction(PPI)network construction,and survival analyses identified seven metastasis-and prognosisrelated genes.Their expression was further examined using public single-cell RNA-seq data(GSE139829;11 tumors).Experimental validation was performed in UVM cell lines(92.1,OMM1,MEL270)and adult retinal pigment epithelial(ARPE-19)cells using quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting to confirm transcriptomic trends.A LASSO Cox model was applied to construct a metastasis-related risk Score signature.Tumor immune microenvironment characteristics were evaluated via single-sample gene set enrichment analysis(ssGSEA)and ESTIMATE.Somatic mutation and copy number variation(CNV)profiles were also examined.RESULTS:Seven key genes(UBE2T,KIF20A,DLGAP5,KLC3,TPX2,UBE2C,AURKA)were significantly associated with overall survival and used to construct a metastasisrelated riskScore signature,which effectively stratified patients into high-and low-risk groups and served as an independent prognostic factor.qRT-PCR and Western blot results confirmed that the expression levels of selected key genes in UVM cell lines showed significant differences compared to ARPE-19 cells,which were largely consistent with the transcriptomic findings.The high-risk group exhibited reduced immune infiltration and stromal activity.Single-cell analysis revealed these genes were predominantly expressed in a tumor cell cluster characterized by BAP1 loss and high metastatic potential.Mutation and CNV analyses further supported the relevance of these genes to UVM progression.CONCLUSION:This study establishes and validates a seven-gene signature associated with metastasis and prognosis in UVM.The findings provide a framework for understanding molecular determinants of tumor progression and immune microenvironment alterations,and may offer guidance for future mechanistic studies and therapeutic exploration.展开更多
Background:Aberrant expression of transcription factors(TFs)is a key mechanism mediating tumor immune escape and therapeutic resistance.The involvement of E26 transformation-specific(ETS)family of TFs in immune regula...Background:Aberrant expression of transcription factors(TFs)is a key mechanism mediating tumor immune escape and therapeutic resistance.The involvement of E26 transformation-specific(ETS)family of TFs in immune regulation is not fully understood.The study aimed to elucidate the function of E-twenty-six variant 4(ETV4)in tumor immune evasion and its potential as a predictive biomarker for immunotherapy in melanoma.Methods:The expression patterns of ETS family TFs were analyzed in melanoma and hepatocellular carcinoma(HCC).Single-cell RNA sequencing(scRNA-seq)was used to dissect the cellular expression and function of ETV4 in the tumor microenvironment.Functional studies and murine models were employed to investigate the role of ETV4 in T cell-mediated tumor killing and tumor growth.The correlation between ETV4 expression level and patient responsiveness to programmed cell death protein 1(PD-1)blockade therapy was evaluated.Results:TFs in the ETS family were found to effectively stratify melanoma and HCC patients into prognostic subgroups.In melanoma,the polyoma enhancer activator 3(PEA3)subfamily,particularly ETV4 and ETV5,showed a negative correlation with immune infiltration.scRNA-seq analysis showed that ETV4 is preferentially expressed in melanoma cells and involves in mediating tumor-immunocyte interactions.Functional studies demonstrated that ETV4 impairs T cell-mediated tumor killing by transcriptionally upregulating programmed death-ligand 1(PD-L1).In immunocompetent murine models,ETV4 downregulation significantly suppressed tumor growth.Furthermore,high ETV4 expression correlated with poor responses to anti-PD-1 therapy.Conclusion:Our findings identify ETV4 as a key transcriptional regulator of immune evasion in melanoma by controlling PD-L1 expression.ETV4 may act as a predictive biomarker for immunotherapy outcomes.展开更多
Skin cancer remains the most commonly diagnosed malignancy worldwide,with basal cell carcinoma(BCC),cutaneous squamous cell carcinoma(cSCC),and melanoma representing the most clinically significant types.While traditi...Skin cancer remains the most commonly diagnosed malignancy worldwide,with basal cell carcinoma(BCC),cutaneous squamous cell carcinoma(cSCC),and melanoma representing the most clinically significant types.While traditional treatments are effective for early-stage disease,advanced or metastatic cases often pose significant therapeutic challenges.Patients with high-risk or recurrent disease face limited options and poor prognoses.The emergence of immunotherapy has dramatically transformed the treatment landscape across multiple cancer types,including cutaneous malignancies.This review highlights recent advancements in immunotherapeutic strategies for BCC,cSCC,and melanoma,underscoring their growing importance in dermatologic oncology.We synthesize current evidence and ongoing clinical trials for immunotherapy across these three skin cancer types.We also explore the molecular mechanisms underpinning immune responsiveness and potential biomarkers of response.As immunotherapy continues to expand within dermatology,understanding its role,limitations,and future directions is essential for optimizing patient care.The integration of immunotherapy into dermatologic practice represents not only a therapeutic innovation but also a shift toward precision medicine in cutaneous oncology.展开更多
Uveal melanoma(UM)is the most common intraocular cancer,with approximately 5.2 individuals per million affected annually in the United States.It represents approximately 3%of the global malignant melanoma cases,accoun...Uveal melanoma(UM)is the most common intraocular cancer,with approximately 5.2 individuals per million affected annually in the United States.It represents approximately 3%of the global malignant melanoma cases,accounting for 80%of the overall noncutaneous melanomas.Clinically,it remains silent in about 30%of the cases;when symptomatic,it generally causes metamorphopsia(painless loss or distortion of vision)and/or photopsia(flashing or flickering of light in the visual field).Discoloration of the iris,astigmatism,glaucoma,and even blindness are other,less common clinical manifestations.Several pathophysiological mechanisms underlie the development of UM.Genetic mutations,involving especially the G protein subunit alpha q(GNAQ),guanine nucleotide-binding protein subunit alpha-11(GNA11),BRCA1 associated deubiquitinase 1(BAP1),splicing factor 3b subunit 1(SF3B1),and eukaryotic translation initiation factor 1A,X-linked(EIF1AX)genes as well as the MAPK/ERK signaling pathway genes,have been largely associated with the development of UM.Chromosomal aberrations,inflammatory and immunological alterations are often concurrent factors for the development and progression of UM.Therapies targeting specific genetic alterations and immunotherapy agents have been recently developed and introduced in clinical practice for the management of advanced-stage UMs.This review aims to present the latest advances in the clinical molecular pathology of UM,along with the resulting targeted,immunological,and other therapies that have been introduced or are currently under investigation.展开更多
Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop met...Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop methods to overcome this resistance.This study aims to collect the most recent information on melanoma immunotherapy,discuss potential strategies to overcome resistance to immunotherapy,and identify areas that require further analysis.Methods:To achieve this goal,scientific publications from 2021-2024 available in PubMed and Google Scholar databases were analyzed.The databases were searched using the following terms:“melanoma”,“immunotherapy”,“Immune Checkpoint Blockade”,and“immunoresistance”.Results:The results of preclinical and early-stage clinical research indicate the potential application of tank-binding kinase 1(TBK-1),fecal microbiota transplant(FMT),Toll-like Receptor 9(TLR9),lipid nanoparticles(LNPs)containing a stimulator of an interferon gene agonist(STING),BRAF inhibitors,Lymphocyte Activation Gene(LAG-3),T-Cell Immunoglobulin and ITIM Domain(TIGIT),and oncolytic viruses(OVs)as potential methods to enhance melanoma sensitivity to ICB.Discussion:To optimize immunotherapy,further research is needed to determine the detailed mechanisms of action,safety profiles,tolerability,and precise patient selection criteria for methods capable of overcoming melanoma’s immunoresistance.展开更多
Highly potent chemotherapy provides rapid therapeutic efficacy in melanoma, but is often limited by drug resistance, off-target toxicity, and systemic toxicity. Combination therapy with chemotherapy and immunotherapy ...Highly potent chemotherapy provides rapid therapeutic efficacy in melanoma, but is often limited by drug resistance, off-target toxicity, and systemic toxicity. Combination therapy with chemotherapy and immunotherapy has attracted much attention but still faces challenges such as inconsistent immune responses and systemic toxicity. To address these limitations, we developed cathepsin B-activatable doxorubicin(DOX) prodrug nanoparticles(Cat B-NPs) for inducing tumor-specific immunogenic cell death(ICD), while minimizing off-target toxicity in normal tissues with low cathepsin B expression. The cathepsin Bactivatable DOX prodrug was synthesized by conjugating the cathepsin B-cleavable peptide(FRRL) to DOX, yielding FRRL-DOX. The amphiphilic FRRL-DOX formed stable nanoparticles(163.6 ± 13.5 nm) through intermolecular hydrophobic interaction and π-π stacking. In melanoma cells overexpressing cathepsin B, Cat B-NPs effectively induced cancer cellspecific ICD, while sparing normal cells and immune cells. When Cat B-NPs-treated B16F10cells were co-cultured with immune cells, Cat B-NPs enhanced the phagocytic activity of macrophages and induced the maturation of dendritic cells(DCs). In melanoma models,Cat B-NPs passively accumulated at tumor tissues through the enhanced permeability and retention effect and were selectively activated by intratumoral cathepsin B, enabling highdose treatment that induced robust ICD. Importantly, combination therapy with Cat B-NPs and anti-PD-L1 antibody enhanced ICD, DC maturation and T-cell activation, resulting in complete tumor regression in 50% of treated mice by converting the immunosuppressive tumor environment into an immune-responsive state. In a lung metastasis model, highdose Cat B-NPs with anti-PD-L1 also suppressed metastatic burden without systemic toxicity, supporting their potential as a safe and effective chemo-immunotherapy for melanoma.展开更多
Malignant melanoma(MM)is a highly aggressive skin cancer known for its rapid progression,potential for metastasis,and resistance to treatment.Despite advances in targeted therapies and immunotherapy,the prognosis for ...Malignant melanoma(MM)is a highly aggressive skin cancer known for its rapid progression,potential for metastasis,and resistance to treatment.Despite advances in targeted therapies and immunotherapy,the prognosis for metastatic melanoma remains unfavorable.Recent research has shed light on the significance of epigenetic modifications in the pathogenesis of melanoma,revealing critical mechanisms of melanoma development and progression.Epigenetic modifications,including DNA and RNA modifications,histone modifications,chromatin remodeling,and non-coding RNA regulation,disrupt normal gene expression without modifying the DNA sequence,leading to cellular transformation,invasion,immune evasion,and therapeutic resistance.The reversible nature of epigenetic modifications opens up new opportunities for melanoma recognition and classification,as well as therapeutic applications,including the development of diagnostic and prognostic biomarkers and innovative targeted therapies aimed at restoring normal gene function and enhancing the efficacy of existing treatments.This review will focus on the multifaceted role of epigenetic dysregulation in melanoma.The future integration of epigenetic data and genomic profiling with clinical outcomes,likely facilitated by artificial intelligence(AI)algorithms,holds promise for personalized treatment strategies that are informed by precise and combinatorial diagnostic tools,ultimately improving melanoma care.The study aims to deliver a comprehensive overview of the current state of epigenetics in melanoma.展开更多
The published article titled“Long Noncoding RNA PVT1 PromotesMelanoma Progression via Endogenous Sponging miR-26b”has been retracted from Oncology Research,Vol.26,No.5,2018,pp.675–681.DOI:10.3727/096504017X14920318...The published article titled“Long Noncoding RNA PVT1 PromotesMelanoma Progression via Endogenous Sponging miR-26b”has been retracted from Oncology Research,Vol.26,No.5,2018,pp.675–681.DOI:10.3727/096504017X14920318811730 URL:https://www.techscience.com/or/v26n5/56680 Following the publication,concerns have been raised about a number of figures in this article.An unexpected area of similarity was identified in terms of the cellular data,where the results from differently performed experiments were intended to have been shown,although the areas immediately surrounding this area featured comparatively different distributions of cells.In addition,the western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in many cases.展开更多
Visual diagnosis of skin cancer is challenging due to subtle inter-class similarities,variations in skin texture,the presence of hair,and inconsistent illumination.Deep learning models have shown promise in assisting ...Visual diagnosis of skin cancer is challenging due to subtle inter-class similarities,variations in skin texture,the presence of hair,and inconsistent illumination.Deep learning models have shown promise in assisting early detection,yet their performance is often limited by the severe class imbalance present in dermoscopic datasets.This paper proposes CANNSkin,a skin cancer classification framework that integrates a convolutional autoencoder with latent-space oversampling to address this imbalance.The autoencoder is trained to reconstruct lesion images,and its latent embeddings are used as features for classification.To enhance minority-class representation,the Synthetic Minority Oversampling Technique(SMOTE)is applied directly to the latent vectors before classifier training.The encoder and classifier are first trained independently and later fine-tuned end-to-end.On the HAM10000 dataset,CANNSkin achieves an accuracy of 93.01%,a macro-F1 of 88.54%,and an ROC–AUC of 98.44%,demonstrating strong robustness across ten test subsets.Evaluation on the more complex ISIC 2019 dataset further confirms the model’s effectiveness,where CANNSkin achieves 94.27%accuracy,93.95%precision,94.09%recall,and 99.02%F1-score,supported by high reconstruction fidelity(PSNR 35.03 dB,SSIM 0.86).These results demonstrate the effectiveness of our proposed latent-space balancing and fine-tuned representation learning as a new benchmark method for robust and accurate skin cancer classification across heterogeneous datasets.展开更多
Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CR...Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CRC)and melanoma.Methods:A combination of in vitro and in vivo approaches was employed.Cell proliferation,apoptosis,migration,and invasion were assessed using Cell Counting Kit-8(CCK-8),colony formation,ATP viability,Western blotting,flow cytometry,wound-healing and Transwell assays.Subcutaneous,lung metastases,and Azoxymethane/Dextran Sulfate Sodium Salt(AOM/DSS)-induced colitis-associated CRC models were established to examine antitumor efficacy and safety.The functional role of mercury ions was validated using structural analogues.Mechanistic studies included RNA sequencing,Western blot,and immunohistochemical analysis of CD8^(+)T cell infiltration.The synergistic effect with programmed cell death protein 1(PD-1)antibody therapy was also evaluated.Results:Thimerosal potently inhibited tumor growth(with IC_(50) values ranging from 0.1 to 1μM in vitro)and significantly prolonged survival without overt toxicity in vivo.Mechanistically,mercury ions were identified as critical functional sites mediating Thimerosal’s antitumor effects.Specifically,Thimerosal inhibited the phosphorylation of Janus kinase 1(JAK1)and signal transducer and activator of transcription 3(STAT3).Furthermore,it enhanced the infiltration of CD8^(+)T cells into the tumor microenvironment and synergistically augmented the efficacy of anti-PD-1 therapy.Conclusion:Thimerosal exerts dual antitumor roles by direct JAK1/STAT3 inhibition and immune modulation via CD8^(+)T cell recruitment.It represents a promising repurposed drug and immunotherapeutic adjuvant for CRC and melanoma.展开更多
Objectives:The eukaryotic initiation factor 4F(eIF4F)translation initiation complex inhibitors(eIF4Fi)were recently found to hyperactivate extracellular signal-regulated kinases 1/2(ERK1/2)signals,which contribute to ...Objectives:The eukaryotic initiation factor 4F(eIF4F)translation initiation complex inhibitors(eIF4Fi)were recently found to hyperactivate extracellular signal-regulated kinases 1/2(ERK1/2)signals,which contribute to acquired resistance to BRAF(B-Raf proto-oncogene,serine/threonine kinase)inhibitors in melanoma.This present study aims to elucidate how to overcome the resistance of the eIF4Fi in BRAFV600E mutant melanoma cells and explore the underlying mechanisms.Methods:Melanoma A375(vemurafenib[VEM]-sensitive)and A375R(VEM-resistant)cells were exposed to eIF4Fi RocA at varying doses and durations in vitro.We investigated the impact of RocA on the activity of ERK1/2,AKT serine/threonine kinase 1(AKT1),eIF4E,and enhancer of zeste homolog 2(EZH2).We then examined the impact of RocA on pro-apoptotic BH3-only proteins and proliferative proteins.We subsequently determined the effect of combined eIF4Fi,AKT1 inhibitor,EZH2 inhibitor or VEM on tumor growth in vitro and in vivo.Results:RocA inhibited proliferation and induced apoptosis in A375 cells,but inhibited proliferation in A375R cells.RocA rapidly reactivated ERK1/2 at 3 h and returned to baseline levels at 48 h.However,eIF4E and AKT1 activation began at 12 h and peaked at 48 h.ERK1/2 positively regulated EZH2 and EZH2-dependent expression of c-Fos and EGR1,while AKT1 negatively regulated c-Myc,c-Jun,and BMF,but positively regulated eIF4E.RocA downregulated ERK1/2(or EZH2,AKT1,and eIF4E)independent bcl-2 and Mcl-1 expression.AKT1i enhanced RocA-induced cell apoptosis,while EZH2i reduced RocA-induced cell proliferation.Combined CR-1-31-B,EZH2i,and AKT1i effectively overcame resistance to RocA and VEM resistance both in vitro and in vivo.Conclusion:The eIF4F complex inhibitor reactivates ERK1/2-EZH2 and AKT1 signaling pathways,resulting in resistance to both eIF4Fi and VEM.Combined administration of an eIF4Fi with EZH2 and AKT1 inhibitors effectively enhances sensitivity to both eIF4F complex and BRAF inhibitors.展开更多
文摘AIM: To present the experience and outcomes of the surgical treatment for the patients with anorectal melanoma from the Cancer Hospital, Chinese Academy of Medical Sciences. METHODS: Medical records of the diagnosis, surgery, and follow-up of 56 patients with anorectal melanoma who underwent surgery between 1975 and 2008 were retrospectively reviewed. The factors predictive for the survival rate of these patients were identified using multivariate analysis. RESULTS: The 5-year survival rate of the 56 patients with anorectal melanoma was 20%, 36 patients underwent abdominoperineal resection (APR) and 20 patients underwent wide local excision (WLE). The rates of local recurrence of the APR and WLE groups were 16.13% (5/36) and 68.75% (13/20), (P = 0.001), and the median survival time was 22 mo and 21 mo, respectively (P = 0.481). Univariate survival analysis demonstrated that the number of tumor and the depth of invasion had significant effects on the survival (P < 0.05). Multivariate analysis showed that the number of tumor [P = 0.017, 95% confidence interval (CI) = 1.273-11.075] and the depth of invasion (P = 0.015, 95% CI = 1.249-7.591) were independent prognostic factors influencing the survival rate. CONCLUSION: Complete or R0 resection is the first choice of treatment for anorectal melanoma, prognosis is poor regardless of surgical approach, and early diagnosis is the key to improved survival rate for patients with anorectal melanoma.
基金Supported by The National Institutes of Health National Cancer Institute(Grants EDRN CA111294,and SPORE CA127297)
文摘Cutaneous malignant melanoma is the most aggressive form of skin cancer with an extremely poor survival rate for the patients diagnosed with locally invasive and metastatic disease states. Intensive research has led in last few years to an improvement of the early detection and curative treatment of primary cutaneous melanomas that are confined to the skin by tumor surgical resection. However, locally advanced and disseminated melanomas are generally resistant to conventional treatments, including ionizing radiation, systemic chemotherapy, immunotherapy and/or adjuvant stem cellbased therapies, and result in the death of patients. The rapid progression of primary melanomas to locally invasive and/or metastatic disease states remains a major obstacle for an early effective diagnosis and a curative therapeutic intervention for melanoma patients. Importantly, recent advances in the melanoma research have led to the identification of different gene products that are often implicated in the malignant transforma-tion of melanocytic cells into melanoma cells, including melanoma stem/progenitor cells, during melanoma initiation and progression to locally advanced and metastatic disease states. The frequent deregulated genes products encompass the oncogenic B-Raf V600 E and N-RasQ 61 R mutants, different receptor tyrosine kinases and developmental pathways such as epidermal growth factor receptor(EGFR), stem cell-like factor(SCF) receptor KIT, hedgehog, Wnt/β-catenin, Notch, stromal cell-derived factor-1(SDF-1)/CXC chemokine receptor-4(CXCR4) and vascular endothelial growth factor(VEGF)/VEGFR receptor. These growth factors can cooperate to activate distinct tumorigenic downstream signaling elements and epithelial-mesenchymal transition(EMT)-associated molecules, including phosphatidylinositol 3'-kinase(PI3K)/Akt/ molecular target of rapamycin(mT OR), nuclear factor-kappaB(NF-κB), macrophage inhibitory cytokine-1(MIC-1), vimentin, snail and twist. Of therapeutic relevance, these deregulated signal transduction components constitute new potential biomarkers and therapeutic targets of great clinical interest for improving the efficacy of current diagnostic and prognostic methods and management of patients diagnosed with locally advanced, metastatic and/or relapsed melanomas.
文摘We read with interest the article entitled： ‘Jejuno-jejunal invagination due to intestinal melanoma’ by Resta , et al. They reported a rare clinical case of a young woman with a bleeding jejunal melanoma, whose early clinical presentation was an intestinal invagination. The article is also referred to the rarity of gastrointestinal melanomas as well as their possible primary nature.
文摘Melanoma of the gastrointestinal tract is a rare, highly malignant neoplasm of poor prognosis. This is description of an unusual case of surgically treated patient with two metachronous malignant melanomas of the stomach and the esophagus. The former lesion was located in the cardia and effectively treated with RO total gastrectomy. The latter was recognized after 67 mo and appeared as irregular, flat, pigmented areas located in the mid esophagus. Subtotal esophagectomy via right-sided thoracotomy, laparotomy and left-sided cervicotomy was performed, but neoplastic cells were found in distal margin (R1). Fourteen months after esophagectomy multiple lung metastases were detected. Patient.died 2 mo later.
文摘BACKGROUND Anorectal melanoma (AM) is an extremely rare malignant tumor originating from anorectal melanocytes with a poor prognosis. AM has been reported to have a much lower incidence than cutaneous or choroid melanoma, accounting for 0.4%-1.6% of all melanomas. CASE SUMMARY We report a 76-year-old female patient diagnosed with anorectal malignant melanoma by colonoscopy and biopsy. Intraoperative examination revealed two distinct anorectal tumors, one melanotic and another amelanotic, as well as two pigmented mucosal zones at the dentate line level. Abdominal perineal resection was performed. A pathological report confirmed all four lesions to be melanomas. Postoperatively, we followed an immunotherapy protocol targeting PD-1 (nivolumab). The patient had 24 mo of disease-free follow-up upon completion of nivolumab treatment. CONCLUSION This is the first reported case presenting coexistence of pigmented and unpigmented AMs in the same patient.
文摘AIM:To evaluate the results and complications of secondary endoresection via pars plana vitrectomy for choroidal melanoma and review the previously reported endoresection studies on the treatment of choroidal melanoma.METHODS:The medical records of 6 patients with choroidal melanoma who underwent secondary endoresection between March 2012 and March 2020 were retrospectively reviewed.The indications for secondary endoresection were progressive or recurrent tumor and severe exudative retinal detachment after previous treatment with plaque radiotherapy/Cyberknife radiosurgery/transpupillary thermotherapy(TTT).RESULTS:Before endoresection,2 eyes had Iodine-125 plaque radiotherapy and TTT,1 eye had Ruthenium-106 plaque radiotherapy and TTT,1 eye had Cyberknife radiosurgery and TTT,1 eye had Cyberknife radiosurgery,and 1 eye had TTT only.Preoperative visual acuity ranged from 20/63 to 20/1600(Snellen) and from 0.5 to 1.9(mean:1.1) on the log MAR scale.The mean tumor base diameters were 9.5×8.7 mm and the mean tumor thickness was 5.4 mm.After secondary endoresection,transient vitreous hemorrhage developed in 2(33.3%) eyes and retinal detachment in 1(16.7%) eye.Cytopathological examination revealed epithelioid cell melanoma in 4(66.7%) eyes and mixed cell melanoma in 1(16.7%).Melanoma cell type was not specified in 1(16.7%) eye.At a mean follow-up of 49.6 mo(range:16-90 mo),mean visual acuity did not improve and 1 eye was enucleated due to tumor recurrence.Final visual acuity ranged from 20/63 to 20/1600(Snellen) and from 0.5 to 1.9(mean:1.2) on the log MAR scale.Two patients with choroidal melanoma developed metastasis and eventually expired.CONCLUSION:Secondary endoresection seems to be an effective treatment option for globe salvage in choroidal melanoma not responsive to conventional treatment and displaying persistent exudative retinal detachment.There was no visual acuity increase among the treated eyes but globe salvage was possible in most cases in this study.
文摘In a comprehensive literature review,PubMed,Embasem and Web of Science were searched for studies examining targeted therapy of ocular malignant melanomas to present and discuss targeted therapy treatment options of ocular tumors,mainly conjunctival and uveal melanoma(UM).Conjunctival malignant melanomas showed similarities in clinical and genetic aspects with cutaneous melanomas.Many therapies with checkpoint inhibitors already established for cutaneous melanomas may be a treatment option for conjunctival malignant melanomas with shared traits.Existing targeted therapies are for example checkpoint inhibitors like pembrolizumab or nivolumab.As a corollary,due to marked differences in clinics and genetics between UMs and conjunctival melanomas(CMs)or cutaneous melanomas,it has remained elusive whether the available possibilities of molecular targeted therapy will be an option for the therapy of metastasizing UMs.Possible novel ways of treating UM are being explored.Fotemustine or the inoculation of dendritic cells with tumorous RNA or sunitinib in combination with cisplatin and or tamoxifen may be used in future to treat UM.While CM are treatable using targeted therapies,UM have not been researched enough to find working targeted therapy options.Further research has to be done in order to find acceptable treatment options.
基金supported by National Natural Science Foundation of China(Grant Nos.81871990 and 31671448)Yunnan Applicative and Basic Research Program(Grant Nos.2019FY003030 and 202101AV070002)a grant(2019KF006)from Conservation and Utilization of Bio-Resources in Yunnan(YNCUB).
文摘Objective:The BRAF inhibitor,vemurafenib,has been widely used in the treatment of patients with melanoma-bearing BRAFV600E mutations.While the initial response to vemurafenib is usually excellent,the majority of patients eventually develop resistance and metastatic disease.However,the underlying molecular mechanism remains elusive.The objective of this study was therefore to identify additional molecular targets responsible for vemurafenib resistance.Methods:Western blots and immunohistochemistry analyses were used to evaluate expressions of PYK2 and p-PYK2 in cultured cells and melanoma tissue microarrays.The relationships of p-PYK2 with clinicopathological parameters were statistically analyzed.Invadopodia cell invasion,and a Ca2+assay were used to determine the effect of vemurafenib resistance-induced p-PYK2 on melanoma progression.A mouse model was used to assess the effects of PYK2 on melanoma metastasis.Results:Elevated p-PYK2 levels were detected in vemurafenib-resistant melanoma cells,and PYK2 was shown to regulate invadopodia formation in melanoma cells.Vemurafenib triggered invadopodia formation by activation of PYK2.Inhibition of PYK2 with either shRNA or the small molecule inhibitor,PF562711,dramatically reduced vemurafenib-induced invadopodia formation.Furthermore,knockdown of PYK2 significantly reduced melanoma lung metastasis in vivo.Increased expressions of p-PYK2 in melanoma patients were positively correlated with advanced stage(P=0.002),metastasis(P<0.001),and Clark grade(P<0.001),and were also associated with short overall survival[hazard ratio(HR)=3.304,P=0.007]and progression-free survival(HR=2.930,P=0.001).Conclusions:PYK2 mediated vemurafenib-induced melanoma cell migration and invasion.Inhibition of PYK2 resensitized melanoma cells to vemurafenib.Phospho-PYK2 was a prognostic biomarker in melanoma patients.
文摘Background: The anorectal location of melanomas is extremely rare (1% - 3% of all melanomas), and the prognosis remains poor because of the aggressiveness and the high metastatic potential of those tumors. The discovery that the KIT oncogene may be aberrantly activated in a subset of patients with anorectal melanoma creates a realm of possibility for the development of targeted molecular therapy. Aim: to show the epidemiologic, clinico-radiological, histological features and treatment management especially in patients with over-expression of C-KIT treated by Imatinib. Methods: It is a retrospective study conducted in the department of medical oncology at Hassan II University Hospital between January 2007 and January 2012, including all patients with histologically proven melanoma of the anorectal area. Results: 11 cases were collected, with slight female predominance. Nine patients were metastatic at the moment of diagnosis, and only two with local stage, but evolution was marked by local and distant recurrence less than 12 months after abdo-minoperineal resection. First line of chemotherapy was based mainly on paclitaxel, carboplatine and dacarbazine. Response was modest with only 3 partial responses, 4 patients with disease stability, and 4 patients with disease progression. Two patients, with over expression of C-KIT, received Imatinib as second line of treatment with significant improvement of symptoms and radiological response reaching 50%. Seven patients died with a median survival of 11 months from diagnosis to the date of death. Conclusion: Primary anorectal melanomas are very rare, with high aggressiveness and poor prognosis. Treatment management is still a big challenge given to the modest efficacy of conventional chemotherapy. Better understanding of carcinogenesis and signaling pathways will allow development of new targeted therapies.
基金Supported by the National Natural Science Foundation of China(No.82460215)National Natural Science Foundation of China Pre-experimental Project(No.2025GZRYSY006)+4 种基金2025 Youth Training Project of the Xi’an Municipal Health Commission(No.2025qn05)Xi’an Medical Research-Discipline Capacity Building Project(No.23YXYJ0002)Key R&D Plan of Shaanxi Province:Key Industrial Innovation Chain(Cluster)-Social Development Field(No.2022ZDLSF03-10)Research Incubation Fund of Xi’an People’s Hospital(Xi’an Fourth HospitalNo.LH-13).
文摘AIM:To identify metastasis-associated prognostic genes and construct a robust molecular signature for survival prediction in uveal melanoma(UVM)patients.METHODS:Transcriptomic data and clinical information from 80 UVM patients in the Cancer Genome Atlas(TCGA)-UVM cohort and an external Gene Expression Omnibus(GEO)microarray dataset(GSE73652;8 non-metastatic vs 5 metastatic cases)were analyzed to identify differentially expressed genes(DEGs).Functional enrichment,proteinprotein interaction(PPI)network construction,and survival analyses identified seven metastasis-and prognosisrelated genes.Their expression was further examined using public single-cell RNA-seq data(GSE139829;11 tumors).Experimental validation was performed in UVM cell lines(92.1,OMM1,MEL270)and adult retinal pigment epithelial(ARPE-19)cells using quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting to confirm transcriptomic trends.A LASSO Cox model was applied to construct a metastasis-related risk Score signature.Tumor immune microenvironment characteristics were evaluated via single-sample gene set enrichment analysis(ssGSEA)and ESTIMATE.Somatic mutation and copy number variation(CNV)profiles were also examined.RESULTS:Seven key genes(UBE2T,KIF20A,DLGAP5,KLC3,TPX2,UBE2C,AURKA)were significantly associated with overall survival and used to construct a metastasisrelated riskScore signature,which effectively stratified patients into high-and low-risk groups and served as an independent prognostic factor.qRT-PCR and Western blot results confirmed that the expression levels of selected key genes in UVM cell lines showed significant differences compared to ARPE-19 cells,which were largely consistent with the transcriptomic findings.The high-risk group exhibited reduced immune infiltration and stromal activity.Single-cell analysis revealed these genes were predominantly expressed in a tumor cell cluster characterized by BAP1 loss and high metastatic potential.Mutation and CNV analyses further supported the relevance of these genes to UVM progression.CONCLUSION:This study establishes and validates a seven-gene signature associated with metastasis and prognosis in UVM.The findings provide a framework for understanding molecular determinants of tumor progression and immune microenvironment alterations,and may offer guidance for future mechanistic studies and therapeutic exploration.
基金funded by the National Natural Science Foundation of China(Grant Nos.82204517 to T.Z.and 82404756 to J.Z.)the Science and Technology Program in Medicine and Health of Zhejiang Province(Grant No.2023KY726 to T.Z.).
文摘Background:Aberrant expression of transcription factors(TFs)is a key mechanism mediating tumor immune escape and therapeutic resistance.The involvement of E26 transformation-specific(ETS)family of TFs in immune regulation is not fully understood.The study aimed to elucidate the function of E-twenty-six variant 4(ETV4)in tumor immune evasion and its potential as a predictive biomarker for immunotherapy in melanoma.Methods:The expression patterns of ETS family TFs were analyzed in melanoma and hepatocellular carcinoma(HCC).Single-cell RNA sequencing(scRNA-seq)was used to dissect the cellular expression and function of ETV4 in the tumor microenvironment.Functional studies and murine models were employed to investigate the role of ETV4 in T cell-mediated tumor killing and tumor growth.The correlation between ETV4 expression level and patient responsiveness to programmed cell death protein 1(PD-1)blockade therapy was evaluated.Results:TFs in the ETS family were found to effectively stratify melanoma and HCC patients into prognostic subgroups.In melanoma,the polyoma enhancer activator 3(PEA3)subfamily,particularly ETV4 and ETV5,showed a negative correlation with immune infiltration.scRNA-seq analysis showed that ETV4 is preferentially expressed in melanoma cells and involves in mediating tumor-immunocyte interactions.Functional studies demonstrated that ETV4 impairs T cell-mediated tumor killing by transcriptionally upregulating programmed death-ligand 1(PD-L1).In immunocompetent murine models,ETV4 downregulation significantly suppressed tumor growth.Furthermore,high ETV4 expression correlated with poor responses to anti-PD-1 therapy.Conclusion:Our findings identify ETV4 as a key transcriptional regulator of immune evasion in melanoma by controlling PD-L1 expression.ETV4 may act as a predictive biomarker for immunotherapy outcomes.
文摘Skin cancer remains the most commonly diagnosed malignancy worldwide,with basal cell carcinoma(BCC),cutaneous squamous cell carcinoma(cSCC),and melanoma representing the most clinically significant types.While traditional treatments are effective for early-stage disease,advanced or metastatic cases often pose significant therapeutic challenges.Patients with high-risk or recurrent disease face limited options and poor prognoses.The emergence of immunotherapy has dramatically transformed the treatment landscape across multiple cancer types,including cutaneous malignancies.This review highlights recent advancements in immunotherapeutic strategies for BCC,cSCC,and melanoma,underscoring their growing importance in dermatologic oncology.We synthesize current evidence and ongoing clinical trials for immunotherapy across these three skin cancer types.We also explore the molecular mechanisms underpinning immune responsiveness and potential biomarkers of response.As immunotherapy continues to expand within dermatology,understanding its role,limitations,and future directions is essential for optimizing patient care.The integration of immunotherapy into dermatologic practice represents not only a therapeutic innovation but also a shift toward precision medicine in cutaneous oncology.
文摘Uveal melanoma(UM)is the most common intraocular cancer,with approximately 5.2 individuals per million affected annually in the United States.It represents approximately 3%of the global malignant melanoma cases,accounting for 80%of the overall noncutaneous melanomas.Clinically,it remains silent in about 30%of the cases;when symptomatic,it generally causes metamorphopsia(painless loss or distortion of vision)and/or photopsia(flashing or flickering of light in the visual field).Discoloration of the iris,astigmatism,glaucoma,and even blindness are other,less common clinical manifestations.Several pathophysiological mechanisms underlie the development of UM.Genetic mutations,involving especially the G protein subunit alpha q(GNAQ),guanine nucleotide-binding protein subunit alpha-11(GNA11),BRCA1 associated deubiquitinase 1(BAP1),splicing factor 3b subunit 1(SF3B1),and eukaryotic translation initiation factor 1A,X-linked(EIF1AX)genes as well as the MAPK/ERK signaling pathway genes,have been largely associated with the development of UM.Chromosomal aberrations,inflammatory and immunological alterations are often concurrent factors for the development and progression of UM.Therapies targeting specific genetic alterations and immunotherapy agents have been recently developed and introduced in clinical practice for the management of advanced-stage UMs.This review aims to present the latest advances in the clinical molecular pathology of UM,along with the resulting targeted,immunological,and other therapies that have been introduced or are currently under investigation.
文摘Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop methods to overcome this resistance.This study aims to collect the most recent information on melanoma immunotherapy,discuss potential strategies to overcome resistance to immunotherapy,and identify areas that require further analysis.Methods:To achieve this goal,scientific publications from 2021-2024 available in PubMed and Google Scholar databases were analyzed.The databases were searched using the following terms:“melanoma”,“immunotherapy”,“Immune Checkpoint Blockade”,and“immunoresistance”.Results:The results of preclinical and early-stage clinical research indicate the potential application of tank-binding kinase 1(TBK-1),fecal microbiota transplant(FMT),Toll-like Receptor 9(TLR9),lipid nanoparticles(LNPs)containing a stimulator of an interferon gene agonist(STING),BRAF inhibitors,Lymphocyte Activation Gene(LAG-3),T-Cell Immunoglobulin and ITIM Domain(TIGIT),and oncolytic viruses(OVs)as potential methods to enhance melanoma sensitivity to ICB.Discussion:To optimize immunotherapy,further research is needed to determine the detailed mechanisms of action,safety profiles,tolerability,and precise patient selection criteria for methods capable of overcoming melanoma’s immunoresistance.
基金supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT)(RS-2024-00351185, RS-2025-02219039)by the Korea Health Industry Development Institute (KHIDI)grant funded by the Korea government (MOHW)(RS-2023-KH135133)by Korea Drug Development Fund (KDDF)funded by Ministry of Science and ICT,Ministry of Trade,Industry,and Energy,and Ministry of Health and Welfare(RS-2025-02223093)。
文摘Highly potent chemotherapy provides rapid therapeutic efficacy in melanoma, but is often limited by drug resistance, off-target toxicity, and systemic toxicity. Combination therapy with chemotherapy and immunotherapy has attracted much attention but still faces challenges such as inconsistent immune responses and systemic toxicity. To address these limitations, we developed cathepsin B-activatable doxorubicin(DOX) prodrug nanoparticles(Cat B-NPs) for inducing tumor-specific immunogenic cell death(ICD), while minimizing off-target toxicity in normal tissues with low cathepsin B expression. The cathepsin Bactivatable DOX prodrug was synthesized by conjugating the cathepsin B-cleavable peptide(FRRL) to DOX, yielding FRRL-DOX. The amphiphilic FRRL-DOX formed stable nanoparticles(163.6 ± 13.5 nm) through intermolecular hydrophobic interaction and π-π stacking. In melanoma cells overexpressing cathepsin B, Cat B-NPs effectively induced cancer cellspecific ICD, while sparing normal cells and immune cells. When Cat B-NPs-treated B16F10cells were co-cultured with immune cells, Cat B-NPs enhanced the phagocytic activity of macrophages and induced the maturation of dendritic cells(DCs). In melanoma models,Cat B-NPs passively accumulated at tumor tissues through the enhanced permeability and retention effect and were selectively activated by intratumoral cathepsin B, enabling highdose treatment that induced robust ICD. Importantly, combination therapy with Cat B-NPs and anti-PD-L1 antibody enhanced ICD, DC maturation and T-cell activation, resulting in complete tumor regression in 50% of treated mice by converting the immunosuppressive tumor environment into an immune-responsive state. In a lung metastasis model, highdose Cat B-NPs with anti-PD-L1 also suppressed metastatic burden without systemic toxicity, supporting their potential as a safe and effective chemo-immunotherapy for melanoma.
文摘Malignant melanoma(MM)is a highly aggressive skin cancer known for its rapid progression,potential for metastasis,and resistance to treatment.Despite advances in targeted therapies and immunotherapy,the prognosis for metastatic melanoma remains unfavorable.Recent research has shed light on the significance of epigenetic modifications in the pathogenesis of melanoma,revealing critical mechanisms of melanoma development and progression.Epigenetic modifications,including DNA and RNA modifications,histone modifications,chromatin remodeling,and non-coding RNA regulation,disrupt normal gene expression without modifying the DNA sequence,leading to cellular transformation,invasion,immune evasion,and therapeutic resistance.The reversible nature of epigenetic modifications opens up new opportunities for melanoma recognition and classification,as well as therapeutic applications,including the development of diagnostic and prognostic biomarkers and innovative targeted therapies aimed at restoring normal gene function and enhancing the efficacy of existing treatments.This review will focus on the multifaceted role of epigenetic dysregulation in melanoma.The future integration of epigenetic data and genomic profiling with clinical outcomes,likely facilitated by artificial intelligence(AI)algorithms,holds promise for personalized treatment strategies that are informed by precise and combinatorial diagnostic tools,ultimately improving melanoma care.The study aims to deliver a comprehensive overview of the current state of epigenetics in melanoma.
文摘The published article titled“Long Noncoding RNA PVT1 PromotesMelanoma Progression via Endogenous Sponging miR-26b”has been retracted from Oncology Research,Vol.26,No.5,2018,pp.675–681.DOI:10.3727/096504017X14920318811730 URL:https://www.techscience.com/or/v26n5/56680 Following the publication,concerns have been raised about a number of figures in this article.An unexpected area of similarity was identified in terms of the cellular data,where the results from differently performed experiments were intended to have been shown,although the areas immediately surrounding this area featured comparatively different distributions of cells.In addition,the western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in many cases.
基金supported and funded by the Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University(IMSIU)(grant number IMSIU-DDRSP2601).
文摘Visual diagnosis of skin cancer is challenging due to subtle inter-class similarities,variations in skin texture,the presence of hair,and inconsistent illumination.Deep learning models have shown promise in assisting early detection,yet their performance is often limited by the severe class imbalance present in dermoscopic datasets.This paper proposes CANNSkin,a skin cancer classification framework that integrates a convolutional autoencoder with latent-space oversampling to address this imbalance.The autoencoder is trained to reconstruct lesion images,and its latent embeddings are used as features for classification.To enhance minority-class representation,the Synthetic Minority Oversampling Technique(SMOTE)is applied directly to the latent vectors before classifier training.The encoder and classifier are first trained independently and later fine-tuned end-to-end.On the HAM10000 dataset,CANNSkin achieves an accuracy of 93.01%,a macro-F1 of 88.54%,and an ROC–AUC of 98.44%,demonstrating strong robustness across ten test subsets.Evaluation on the more complex ISIC 2019 dataset further confirms the model’s effectiveness,where CANNSkin achieves 94.27%accuracy,93.95%precision,94.09%recall,and 99.02%F1-score,supported by high reconstruction fidelity(PSNR 35.03 dB,SSIM 0.86).These results demonstrate the effectiveness of our proposed latent-space balancing and fine-tuned representation learning as a new benchmark method for robust and accurate skin cancer classification across heterogeneous datasets.
基金supported by the National Natural Science Foundation of China(82441036)Ganzhou Municipal Science and Technology Project(2022-RC1342)+3 种基金Guangdong Basic and Applied Basic Research Foundation(2022B1515130004)Key-Area Research and Development Program of Guangdong Province(2019B020234003)Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Cancer(2020B121201004)Open Project Fund Project of Guangdong Academy of Medical Sciences(YKY-KF202210).
文摘Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CRC)and melanoma.Methods:A combination of in vitro and in vivo approaches was employed.Cell proliferation,apoptosis,migration,and invasion were assessed using Cell Counting Kit-8(CCK-8),colony formation,ATP viability,Western blotting,flow cytometry,wound-healing and Transwell assays.Subcutaneous,lung metastases,and Azoxymethane/Dextran Sulfate Sodium Salt(AOM/DSS)-induced colitis-associated CRC models were established to examine antitumor efficacy and safety.The functional role of mercury ions was validated using structural analogues.Mechanistic studies included RNA sequencing,Western blot,and immunohistochemical analysis of CD8^(+)T cell infiltration.The synergistic effect with programmed cell death protein 1(PD-1)antibody therapy was also evaluated.Results:Thimerosal potently inhibited tumor growth(with IC_(50) values ranging from 0.1 to 1μM in vitro)and significantly prolonged survival without overt toxicity in vivo.Mechanistically,mercury ions were identified as critical functional sites mediating Thimerosal’s antitumor effects.Specifically,Thimerosal inhibited the phosphorylation of Janus kinase 1(JAK1)and signal transducer and activator of transcription 3(STAT3).Furthermore,it enhanced the infiltration of CD8^(+)T cells into the tumor microenvironment and synergistically augmented the efficacy of anti-PD-1 therapy.Conclusion:Thimerosal exerts dual antitumor roles by direct JAK1/STAT3 inhibition and immune modulation via CD8^(+)T cell recruitment.It represents a promising repurposed drug and immunotherapeutic adjuvant for CRC and melanoma.
文摘Objectives:The eukaryotic initiation factor 4F(eIF4F)translation initiation complex inhibitors(eIF4Fi)were recently found to hyperactivate extracellular signal-regulated kinases 1/2(ERK1/2)signals,which contribute to acquired resistance to BRAF(B-Raf proto-oncogene,serine/threonine kinase)inhibitors in melanoma.This present study aims to elucidate how to overcome the resistance of the eIF4Fi in BRAFV600E mutant melanoma cells and explore the underlying mechanisms.Methods:Melanoma A375(vemurafenib[VEM]-sensitive)and A375R(VEM-resistant)cells were exposed to eIF4Fi RocA at varying doses and durations in vitro.We investigated the impact of RocA on the activity of ERK1/2,AKT serine/threonine kinase 1(AKT1),eIF4E,and enhancer of zeste homolog 2(EZH2).We then examined the impact of RocA on pro-apoptotic BH3-only proteins and proliferative proteins.We subsequently determined the effect of combined eIF4Fi,AKT1 inhibitor,EZH2 inhibitor or VEM on tumor growth in vitro and in vivo.Results:RocA inhibited proliferation and induced apoptosis in A375 cells,but inhibited proliferation in A375R cells.RocA rapidly reactivated ERK1/2 at 3 h and returned to baseline levels at 48 h.However,eIF4E and AKT1 activation began at 12 h and peaked at 48 h.ERK1/2 positively regulated EZH2 and EZH2-dependent expression of c-Fos and EGR1,while AKT1 negatively regulated c-Myc,c-Jun,and BMF,but positively regulated eIF4E.RocA downregulated ERK1/2(or EZH2,AKT1,and eIF4E)independent bcl-2 and Mcl-1 expression.AKT1i enhanced RocA-induced cell apoptosis,while EZH2i reduced RocA-induced cell proliferation.Combined CR-1-31-B,EZH2i,and AKT1i effectively overcame resistance to RocA and VEM resistance both in vitro and in vivo.Conclusion:The eIF4F complex inhibitor reactivates ERK1/2-EZH2 and AKT1 signaling pathways,resulting in resistance to both eIF4Fi and VEM.Combined administration of an eIF4Fi with EZH2 and AKT1 inhibitors effectively enhances sensitivity to both eIF4F complex and BRAF inhibitors.
