Locoregional Therapies for the Treatment of Uveal Melanoma Hepatic Metastases.
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ABSTRACT:
SUBMITTER: Gonsalves CF
PROVIDER: S-EPMC7732575 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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:Uveal melanoma is the most commonly occurring primary intraocular malignancy in adults, and patients have a high risk of developing metastatic disease, mostly in the liver. Isolated hepatic perfusion (IHP) with melphalan is a liver-directed therapy for patients with liver metastases. Percutaneous hepatic perfusion (PHP), a minimally invasive technique, is available as well. PHP benefits from the fact that the procedure can be repeated and therefore possibly offers better survival. We conducted a systematic review and meta-analysis comparing both techniques. A systematic literature search was performed using the electronic databases of Scopus, MEDLINE, Web of Science, PubMed and Cochrane CENTRAL. A total of nine articles reporting on eight studies were included in the analysis. Individual survival data were extracted from each study. The median overall survival (OS) was 17.1 months for IHP and 17.3 months for PHP. The median progression-free survival (PFS) was 7.2 months for IHP and 9.6 months for PHP. The median hepatic progression-free survival was 10 months for IHP and 9.5 months for PHP. The complication rate and 30-day mortality rate were 39.1% and 5.5% for IHP and 23.8% and 1.8% for PHP. There was no difference in OS or PFS between IHP and PHP for patients with uveal melanoma liver metastases, but patients have significantly less of a risk for complications and mortality following PHP.
| S-EPMC8469397 | biostudies-literature
Project description:ObjectiveUveal melanoma (UM) commonly metastasizes to the liver. Treatment usually consists of liver-directed therapies, such as selective internal radiation therapy (SIRT). This review aimed to assess the effectiveness and safety of SIRT for hepatic metastases from UM.MethodsThe study protocol is available at OSF (https://osf.io/vhyct/). EMBASE and MEDLINE were searched until July 2020, using terms related to SIRT and hepatic metastases from UM. Studies reporting outcomes of SIRT in patients with UM and at least one hepatic metastasis were included. Data on overall survival (OS), hepatic progression free survival (hPFS) or tumor response were collected. The Newcastle-Ottawa Scale (NOS) was used to assess risk of bias.Results11 studies were included, reporting outcomes for 268 patients with hepatic metastases from UM. Most studies (n = 9, 81.8%) were retrospective. Disease control was achieved in 170 patients (67.5%) and the median OS from time of SIRT was 12.3 months. Median hPFS was 5.4 months. Low-grade side-effects were common but serious complications were infrequent. There were two treatment-related deaths. The median NOS score was 6 (moderate risk of bias).ConclusionSIRT appears to be a safe and effective treatment for patients with unresectable hepatic metastases from UM. The certainty of our results is unclear due to predominantly retrospective data with moderate risk of bias. Further prospective studies are required to explore the role of SIRT in UM.Advances in knowledgeSIRT appears to be a safe treatment for patients with unresectable hepatic metastases from UM. Further prospective work is required.
| S-EPMC8722257 | biostudies-literature
Project description:Metastatic uveal melanoma (MUM) is chemoresistant and usually fatal within one year of diagnosis. There is an urgent need to better understand disease pathogenesis, in order to determine key drivers of the metastatic process that could be effectively targeted by therapy. Gene copy number variations occurring in a rare cohort of 13 metastatic and six matched primary, formalin-fixed, paraffin-embedded uveal melanoma samples were identified using the Affymetrix Genome-Wide Human SNP 6.0 Array. Gross chromosomal abnormalities commonly seen in primary UM and associated with the development of metastasis were observed in the MUMs. The most common CNVs were gene amplifications on chromosome 8q, especially in the region 8q24.3. Interestingly, deletions on chromosome 3 were detected at a lower frequency. Genomic profiles of PUM-MUM pairs varied in their degree of similarity and complexity. No genes were altered being unique to either all PUMs or all MUMs of the pairs, but 135 gene CNVs were consistently shared. Of these genes, 125 were amplifications located on chr. 8q24.3. Five genes in the region 8q24.3 and two genes on chromosome 3 were selected for validation by immunohistochemistry because of their known function in cancer (BCL6, C-MYC, E2F5, PTP4A3, SNAI2, and WISP1), or known importance in UM pathology (BAP1). The functional effect of these CNVs on protein expression was confirmed; amplified genes showed increased expression and deleted genes reduced expression. To conclude, our data demonstrate frequent amplification of chromosome 8q in MUMs, suggesting that genes facilitating the expansion of UM in the metastatic niche occur in this region. Furthermore, validation of a range of amplified 8q genes at the protein level strongly indicates the CNVs may be functional and, contribute to MUM biology. 19 samples in total: 13 metastatic uveal melanoma (MUMs) and in six cases their paired primary UM (PUMs)
2016-05-18 | E-GEOD-69614 | biostudies-arrayexpress
Project description:Metastatic uveal melanoma (MUM) is chemoresistant and usually fatal within one year of diagnosis. There is an urgent need to better understand disease pathogenesis, in order to determine key drivers of the metastatic process that could be effectively targeted by therapy. Gene copy number variations occurring in a rare cohort of 13 metastatic and six matched primary, formalin-fixed, paraffin-embedded uveal melanoma samples were identified using the Affymetrix Genome-Wide Human SNP 6.0 Array. Gross chromosomal abnormalities commonly seen in primary UM and associated with the development of metastasis were observed in the MUMs. The most common CNVs were gene amplifications on chromosome 8q, especially in the region 8q24.3. Interestingly, deletions on chromosome 3 were detected at a lower frequency. Genomic profiles of PUM-MUM pairs varied in their degree of similarity and complexity. No genes were altered being unique to either all PUMs or all MUMs of the pairs, but 135 gene CNVs were consistently shared. Of these genes, 125 were amplifications located on chr. 8q24.3. Five genes in the region 8q24.3 and two genes on chromosome 3 were selected for validation by immunohistochemistry because of their known function in cancer (BCL6, C-MYC, E2F5, PTP4A3, SNAI2, and WISP1), or known importance in UM pathology (BAP1). The functional effect of these CNVs on protein expression was confirmed; amplified genes showed increased expression and deleted genes reduced expression. To conclude, our data demonstrate frequent amplification of chromosome 8q in MUMs, suggesting that genes facilitating the expansion of UM in the metastatic niche occur in this region. Furthermore, validation of a range of amplified 8q genes at the protein level strongly indicates the CNVs may be functional and, contribute to MUM biology.
2016-05-18 | GSE69614 | GEO
Project description:BackgroundUveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 50% of patients, with the liver being the most common site for metastases. The median survival for patients with liver metastases is between 6 and 12 months, and no treatment has in randomized trials ever been shown to prolong survival. A previous phase II trial using isolated hepatic perfusion (IHP) has suggested a 14-month increase in overall survival compared with a historic control group consisting of the longest surviving patients in Sweden during the same time period (26 versus 12 months).Methods/designThis is the protocol for a multicenter phase III trial randomizing patients with isolated liver metastases of uveal melanoma to IHP or best alternative care (BAC). Inclusion criteria include liver metastases (verified by biopsy) and no evidence of extra-hepatic tumor manifestations by positron emission tomography-computed tomography (PET-CT). The primary endpoint is overall survival at 24 months, with secondary endpoints including response rate, progression-free survival, and quality of life. The planned sample size is 78 patients throughout five years.DiscussionPatients with isolated liver metastases of uveal melanoma origin have a short expected survival and no standard treatment option exists. This is the first randomized clinical trial to evaluate IHP as a treatment option with overall survival being the primary endpoint.Trial registrationClinicalTrials.gov registration number: NCT01785316 (registered 1 February 2013). EudraCT registration number: 2013-000564-29.
| S-EPMC4138407 | biostudies-literature
Project description:Despite successful treatment of primary uveal melanoma, up to 50% of patients will develop systemic metastasis. Metastatic disease portends a poor outcome, and no adjuvant or metastatic therapy has been FDA approved. The genetic landscape of uveal melanoma is unique, providing prognostic and potentially therapeutic insight. In this review, we discuss our current understanding of the molecular and cytogenetic mutations in uveal melanoma, and the importance of obtaining such information. Most of our knowledge is based on primary uveal melanoma and a better understanding of the mutational landscape in metastatic uveal melanoma is needed. Clinical trials targeting certain mutations such as GNAQ/GNA11, BAP1, and SF3B1 are ongoing and promising. We also discuss the role of liquid biopsies in uveal melanoma in this review.
| S-EPMC8582814 | biostudies-literature
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:Opinion statementBrain metastases are a major clinical challenge occurring in up to 60% of patients suffering from metastatic melanoma. They cause significant clinical symptoms and impair the overall survival prognosis. The introduction of targeted therapies including BRAF and MEK inhibitors as well as CTLA-4 and PD-1 axis targeting immune checkpoint inhibitors have dramatically improved the treatment and prognosis of patients with extracranial metastatic melanoma. Although, similar response rates for extra- and intracranial metastases have been reported, only few data from brain metastasis specific trails are available so far. The following review will provide an overview on the currently available data on targeted therapies, remaining questions and the most important side effects in the special clinical situation of melanoma brain metastases.
| S-EPMC5378732 | biostudies-literature
Project description:Background Overall survival (OS) for patients with uveal melanoma (UM) hepatic metastases is extremely poor. Therefore, stabilization of hepatic metastases is essential to prolonging OS. Purpose To assess the safety and effectiveness of radioembolization (RE) for treatment of UM hepatic metastases. Materials and Methods Enrollment for this prospective phase II trial began November 2011 and concluded January 2017. Treatment-naïve participants (group A) and participants who progressed after immunoembolization (group B) with hepatic tumor burden less than 50% underwent RE. Participants were followed for 1 month and every 3 months for acute and delayed toxicities, respectively. MRI, CT, and PET were performed every 3 months to evaluate for tumor response and extrahepatic disease. Participants were followed for at least 2 years or until death. Kaplan-Meier method and multivariable Cox proportional hazard models were used for data analysis. Results In group A, 24 participants (mean age ± standard deviation, 59 years ± 13; 13 men and 11 women) underwent unilobar (n = 7), fractionated whole-liver (n = 1), or sequential lobar (n = 16) RE. One participant was excluded from the trial. Complete response (n = 0), partial response (n = 9), or stable disease (n = 11) was achieved in 20 of 23 (87.0%; 95% confidence interval [CI]: 66.4%, 97.2%) participants. Median progression-free survival from liver metastasis was 8.1 months (95% CI: 6.4, 11.8; range, 3.3-33.7 months). Median OS was 18.5 months (95% CI: 11.3, 23.5; range, 6.5-73.7 months). In group B, 24 participants (mean age, 58 years ± 10; nine men and 15 women) underwent unilobar (n = 5) or sequential lobar (n = 19) RE. Complete response (n = 0), partial response (n = 8), or stable disease (n = 6) was achieved in 14 of 24 (58.3%; 95% CI: 36.3%, 77.9%) participants. Median progression-free survival from liver metastasis was 5.2 months (95% CI: 3.7, 9.8; range, 2.9-22.0 months). Median OS was 19.2 months (95% CI: 11.5, 24.0; range, 4.8-76.6 months). Grade 3 treatment-related toxicities included transient lymphopenia (group A, n = 1; group B, n = 1), pain (group A, n = 2) and nausea or vomiting (group A, n = 1). Conclusion Radioembolization is a promising treatment for patients with uveal melanoma hepatic metastases. © RSNA, 2019 Online supplemental material is available for this article.
| S-EPMC6776232 | biostudies-literature