Melanoma-specific survival of patients with uveal melanoma and liver metastases diagnosed between 2005 and 2021
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PROVIDER: S-EPMC11342429 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:The profound disparity in response to immune checkpoint blockade (ICB) by cutaneous melanoma (CM) and uveal melanoma (UM) patients is not well understood. Therefore, we characterized metastases of CM and UM from the same metastatic site (liver), in order to dissect the potential underlying mechanism in differential response on ICB. Tumor liver samples from CM (n=38) and UM (n=28) patients were analyzed at the genomic (whole exome sequencing), transcriptional (RNA sequencing) and protein (immunohistochemistry and GeoMx Digital Spatial Profiling) level. Comparison of CM and UM metastases from the same metastatic site revealed that, although originating from the same melanocyte lineage, CM and UM differed in somatic mutation profile, copy number profile, tumor mutational burden (TMB) and consequently predicted neoantigens. A higher melanin content and higher expression of the melanoma differentiation antigen MelanA was observed in liver metastases of UM patients. No difference in B2M and human leukocyte antigen-DR (HLA-DR) expression was observed. A higher expression of programmed cell death ligand 1 (PD-L1) was found in CM compared with UM liver metastases, although the majority of CM and UM liver metastases lacked PD-L1 expression. There was no difference in the extent of immune infiltration observed between CM and UM metastases, with the exception of a higher expression of CD163 (p<0.0001) in CM liver samples. While the extent of immune infiltration was similar for CM and UM metastases, the ratio of exhausted CD8 T cells to cytotoxic T cells, to total CD8 T cells and to Th1 cells, was significantly higher in UM metastases. While TMB was different between CM and UM metastases, tumor immune infiltration was similar. The greater dependency on PD-L1 as an immune checkpoint in CM and the identification of higher exhaustion ratios in UM may both serve as explanations for the difference in response to ICB. Consequently, in order to improve current treatment for metastatic UM, reversal of T cell exhaustion beyond programmed cell death 1 blockade should be considered.
| S-EPMC7713183 | biostudies-literature
Project description:This study reports the role played by the mutation status of Uveal Melanoma (UM) in relation to hepatic metastatic patterns as seen on imaging modalities. Radiological images were obtained from 123 patients treated at the Erasmus Medical Center Rotterdam or the Rotterdam Eye Hospital. Radiological images were derived from either computed tomography or magnetic resonance imaging. Hepatic metastatic patterns were classified by counting the number of metastases found in the liver. Miliary metastatic pattern (innumerable small metastases in the entire liver) was analyzed separately. Mutation status was determined in 85 patients. Median disease-free survival (DFS) and survival with metastases differed significantly between each of the metastatic patterns (respectively, p = 0.009, p < 0.001), both in favor of patients with less hepatic metastases. The mutation status of the primary tumor was not correlated with any hepatic tumor profiles (p = 0.296). Of the patients who had a solitary metastasis (n = 18), 11 originated from a primary BAP1-mutated tumors and one from a primary SF3B1-mutated tumor. Of the patients who had a miliary metastasis pattern (n = 24), 17 had a primary BAP1-mutated tumor and two had a primary SF3B1-mutated tumor. Chromosome 8p loss was significantly more in patients with more metastases (p = 0.045). Moreover, the primary UMs of patients with miliary metastases harbored more chromosome 8p and 1p loss, compared to patients with single solitary metastasis (p = 0.035 and p = 0.026, respectively). In conclusion, our study shows that there is an inverse correlation of the number of metastasis with the DFS and metastasized survival, indicating separate growth patterns. We also revealed that the number and type of metastases is irrelevant to the prognostic mutation status of the tumor, showing that both BAP1- and SF3B1-mutated UM can result in solitary and miliary metastases, indicating that other processes lay ground to the different metastatic patterns.
| S-EPMC8582397 | biostudies-literature
Project description:Isolated hepatic perfusion (IHP) is a procedure where the liver is surgically isolated and perfused with a high concentration of the chemotherapeutic agent melphalan. Briefly, the procedure starts with the setup of a percutaneous veno-venous bypass from the femoral vein to the external jugular vein. Via a laparotomy, catheters are then inserted into the proper hepatic artery and the caval vein. The portal vein and the caval vein, both supra- and infrahepatically, are then clamped. The arterial and venous catheters are connected to a heart lung machine and the liver is perfused with melphalan (1 mg/kg body weight) for 60 min. This way it is possible to locally perfuse the liver with a high dose of a chemotherapeutic agent, without leakage to the systemic circulation. In previous studies including patients with isolated liver metastases of uveal melanoma, an overall response rate of 33-100% and a median survival between 9 and 13 months, have been reported. The aim of this protocol is to give a clear description of how to perform the procedure and to discuss IHP as a treatment option for liver metastases of uveal melanoma.
| S-EPMC4354564 | biostudies-literature
Project description:BackgroundThe immune landscape of uveal melanoma liver metastases (UMLM) has not been sufficiently studied.MethodsImmune cell infiltrates (ICIs), PD-1 and PD-L1 were characterised in 62 UMLM and 28 primary uveal melanomas (PUM). ICI, PD-1 and PD-L1 were scored as: (1) % tumoral area occupied by tumour-infiltrating lymphocytes or macrophages (TILs, TIMs) and (2) % perTumoral (perT) area. ICIs and other variables including histopathologic growth patterns (HGPs), replacement and desmoplastic, of UMLM were analysed for their prognostic value.ResultsICIs recognised by haematoxylin-eosin-saffron (HES) and IHC (e.g., T cells (CD3), B cells (CD20). Macrophages (CD68), (CD163), were primarily localised to the perT region in PUM and UMLM and were more conspicuous in UMLM. HES, CD3, CD4, FoxP3, CD8, CD20, PD-1 TILs were scant (<5%). TIMs were more frequent, particularly in UMLM than in PUM. Both CD68+ TIMs and HGPs remained significant on multivariate analysis, influencing overall (OS) and metastasis-specific overall survival (MSOS). CD68 + , CD163+ and CD20+ perT infiltrates in UMLM predicted increased OS and MSOS on univariate analysis.ConclusionsTILs and PD-L1 have no predictive value in PUM or UMLM. CD68+ and CD163+TIMs, CD20+ perT lymphocytes, and HGPs are important prognostic factors in UMLMs.
| S-EPMC10449826 | biostudies-literature
Project description:BackgroundUveal melanoma is an aggressive cancer which has a high percentage metastasizing to the liver, with a worse prognosis. Identification of patients at high risk of metastases may provide information for early detection of metastases and treatment.MethodsExpression profiling of ocular tumor tissues from 46 liver metastatic uveal melanoma samples and 45 non-metastatic uveal melanoma samples were got from GEO database. Bioinformatic analyses such as the Gene Oncology and Kyoto Encyclopedia of Genes and Genomes were used to identify genes and pathways specifically associated with liver metastases of the uveal melanoma.ResultsA total of 1138 probes were differentially expressed in two group samples. All differential gene interactions in the Signal-Net were analyzed. Of them, 768 probes were up-regulated and 370 down-regulated. They mainly participated in 125 GO terms and 16 pathways. Of the genes differentially expressed between two group cancers, HTR2B, CHL1, the ZNF family, YWHAZ and FYN were the most significantly altered.ConclusionsBioinformatics may help excavate and analyze large amounts of data in microarrays by means of rigorous experimental planning, scientific statistical analysis and collection of complete data about liver metastases of uveal melanoma patients. In the present study, a novel differential gene expression pattern was constructed and advanced study will provide new targets for diagnosis and mechanism of uveal melanoma liver metastases.
| S-EPMC4015751 | biostudies-literature
Project description:PurposeThe long-term survival of uveal melanoma patients in the US is not known. We compared long-term survival estimates using relative survival, excess absolute risk (EAR), Kaplan-Meier (KM), and competing risk analyses.SettingPopulation based cohort study.Study populationPooled databases from Surveillance, Epidemiology, and End Results data (SEER, SEER-9+SEER-13+SEER-18).Main outcome measureOverall Survival (OS), Metastasis Free Survival (MFS) and relative survival, computed directly or estimated via a model fitted to excess mortality.ResultsThere were 10678 cases of uveal melanoma spanning a period of 42 years (1975-2016). The median age at diagnosis was 63 years (range 3-99). Over half the patients were still alive at the end of 2016 (53%, 5625). The KM estimates of MFS were 0.729 (0.719, 0.74), 0.648 (0.633, 0.663), and 0.616 (0.596, 0.636) at 10, 20, and 30 years, respectively. The cumulative probabilities of melanoma metastatic death at 10, 20 and 30 years were 0.241 (0.236, 0.245), 0.289 (0.283, 0.294), and 0.301 (0.295, 0.307). In the first 5 years since diagnosis of uveal melanoma, the proportion of deaths attributable to uveal melanoma were 1.3 with rapid fall after 10 years. Death due to melanoma were rare beyond 20 years. Relative survival (RS) plateaued to ~60% across 20 to 30 years. EAR parametric modeling yielded a survival probability of 57%.ConclusionsRelative survival methods can be used to estimate long term survival of uveal melanoma patients without knowing the exact cause of death. RS and EAR provide more realistic estimates as they compare the survival to that of a normal matched population. Death due to melanoma were rare beyond 20 years with normal life expectancy reached at 25 years after primary therapy.
| S-EPMC8130945 | biostudies-literature
Project description:To evaluate the prognostic implications of melanin quantification assessed by magnetic resonance imaging (MRI) with respect to the clinical, pathological, and genetic features of liver metastases of uveal melanoma (LMUM). This single-center retrospective cohort study included 63 patients eligible for margin-free resection of LMUM between 2007 and 2018. Comparative genomic hybridization of resected liver metastases on microarrays was performed for genetic risk classification. Metastases exhibiting monosomy 3 with any type of gain of chromosome 8 (M3/8g) were considered high-genetic-risk. MRI melanin quantification using the mean T1 signal (mT1s) in liver metastases was assessed quantitatively on preoperative imaging examination and compared to that of gross pathological evaluation. The association between MRI melanin quantification and overall survival (OS) was assessed by multivariate analysis using the Cox proportional hazards model. Gross pathological assessment of melanin content and MRI melanin quantification were strongly correlated (r = 0.8, p < 0.001). Independent prognostic factors associated with OS were disease-free interval ≤ 24 months (HR = 3.1; 95% CI, 1.6-6.0; p < 0.001), high-genetic-risk (HR = 2.2; 95% CI, 1.1-4.8; p = 0.04), mT1s > 1.1 (HR = 2.3; 95% CI, 1.2-4.7; p = 0.019), and complete hepatic resection (HR = 0.3; 95% CI, 0.2-0.7; p = 0.004). In patients with high-genetic-risk, mT1s showed a significant association with OS (HR = 3.7; 95% CI, 1.5-9.3; p = 0.006). The median OS was 17.5 months vs. 27 months for >1.1 and ≤1.1 mT1s tumors, respectively (p = 0.003). We showed that the level of pigmentation in M3/8g LMUM identified two subsets that were correlated with distinct clinical outcomes.
| S-EPMC8198670 | biostudies-literature
Project description:AimTo evaluate the outcomes of isolated liver chemo perfusion in patients with hepatic metastases from uveal melanoma.Materials and methodsCardiovascular surgeons are often involved in the treatment of oncological diseases. Isolated liver chemoperfusion requires the use a heart-lung machine. A little more than 300 operations of isolated liver chemoperfusion have been performed worldwide. From 2020 to 2023, 38 cases of isolated liver chemoperfusion were performed at the Kostroma Clinical Oncological Dispensary.ResultsThere were 3 deaths, 2 due to liver failure. The remaining patient had hepatic artery thrombosis, who despite emergency thrombectomy and repair of common hepatic artery succumbed to multiorgan failure. Bleeding was diagnosed in 7 patients in the postoperative period. In all cases, relaparotomy was performed to stop bleeding. Subsequently, no special features were noted. The median disease-free survival was 5.4 months. The median overall survival was 20.3 months at the time of submission of this manuscript.ConclusionsIsolated liver chemoperfusion is a safe method of regional chemotherapy and can be considered in patients with isolated hepatic metastases from uveal melanoma.Supplementary informationThe online version contains supplementary material available at 10.1007/s12055-023-01620-6.
| S-EPMC10879073 | biostudies-literature
Project description:The aim of the study was to investigate the molecular genetics of uveal melanoma (UM) metastases and correlate it with disease progression. Twelve pathologically confirmed UM metastases from 11 patients were included. Molecular genetic alterations in chromosomes 3 (including the BAP1 region), 8q, 6p, and 1p were investigated by microsatellite genotyping. Mutations in codon 209 of GNAQ and GNA11 genes were studied by restriction-fragment length polymorphism (RFLP). We identified monosomy of chromosome 3 in tumors from four patients with an average survival of 5 months (range 1-8 months) from time of diagnosis of metastatic disease. In contrast, tumors with either disomy or partial chromosome 3 alterations showed significantly slower metastatic disease progression with an average survival of 69 months (range 40-123 months, p = 0.003). Alterations in chromosomal arms 1p, 6p, and 8q and mutations in either GNAQ or GNA11 showed no association with disease progression. Prominent mononuclear inflammatory infiltrate was observed in tumors from patients with slowly progressive disease. In conclusion, in UM metastases, monosomy 3 is associated with highly aggressive, rapidly progressive disease while disomy or partial change of 3 and prominent mononuclear inflammatory infiltrate in the tumor is associated with better prognosis. These findings should be considered when designing clinical trials testing effectiveness of various therapies of metastatic UM.
| S-EPMC4294816 | biostudies-literature
Project description:Simple Summary 100 uveal melanomas from the UK were analyzed for molecular biomarkers, including alterations of chromosomes 3 and 8, cellular localization of BAP1, and genes known to be mutated in uveal melanoma. Consistent with earlier studies, loss of nuclear BAP1 (nBAP1) predicted shorter overall survival. Tumors with BAP1 loss of function mutations frequently exhibited heterogeneous BAP1 staining, and tumors with ≥25% loss of nBAP1 were a more reliable prognosistic indicator than chromosome 3 loss (LOH3) or chromosome 8q gain. Regardless of mutation class, most BAP1 mutations led to loss of nBAP1 and aberrant expression of cBAP1. Abstract Uveal melanoma (UM) is an uncommon but highly aggressive ocular malignancy. Poor overall survival is associated with deleterious BAP1 alterations, which frequently occur with monosomy 3 (LOH3) and a characteristic gene expression profile. Tumor DNA from a cohort of 100 UM patients from Moorfields Biobank (UK) that had undergone enucleation were sequenced for known UM driver genes (BAP1, SF3B1, EIF1AX, GNAQ, and GNA11). Immunohistochemical staining of BAP1 and interphase FISH for chromosomes 3 and 8 was performed, and cellular localization of BAP1 was correlated with BAP1 mutations. Wildtype (WT) BAP1 staining was characterized by nBAP1 expression with <10% cytoplasmic BAP1 (cBAP1). Tumors exhibited heterogeneity with respect to BAP1 staining with different percentages of nBAP1 loss: ≥25% loss of nuclear BAP1 (nBAP1) was superior to chr8q and LOH3 as a prognostic indicator. Of the successfully sequenced UMs, 38% harbored oncogenic mutations in GNA11 and 48% harbored mutations in GNAQ at residues 209 or 183. Of the secondary drivers, 39% of mutations were in BAP1, 11% were in EIF1AX, and 20% were in the SF3B1 R625 hotspot. Most tumors with SF3B1 or EIF1AX mutations retained nuclear BAP1 (nBAP1). The majority of tumor samples with likely pathogenic BAP1 mutations, regardless of mutation class, displayed ≥25% loss of nBAP1. This included all tumors with truncating mutations and 80% of tumors with missense mutations. In addition, 60% of tumors with truncating mutations and 82% of tumors with missense mutations expressed >10% cBAP1.
| S-EPMC9454448 | biostudies-literature