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Hindso TG, Jensen PS, Sjøl MB, Nissen K, Bjerrum CW, von Benzon E, Faber C, Urbak SF, Donia M, Svane IM, Ellebaek E, Heegaard S, Madsen K, Kiilgaard JF. Impact of Metastatic Pattern on Survival in Patients with Posterior Uveal Melanoma: A Retrospective Cohort Study. Cancers (Basel) 2024; 16:3346. [PMID: 39409966 PMCID: PMC11475269 DOI: 10.3390/cancers16193346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 09/26/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
Background/Objectives: Metastatic posterior uveal melanoma (PUM) is one of the deadliest types of melanomas. Though the median survival is short, some patients with metastatic disease live for a long time. In this study, we investigated whether the anatomical location of the metastatic lesions is associated with differences in survival. Methods: One hundred and seventy-eight patients with metastatic PUM with baseline whole-body imaging were retrospectively included. The patients were divided into three groups based on the anatomical location of metastases: (1) exclusive liver metastases (hepatic pattern), (2) both hepatic and extrahepatic metastatic lesions (hepatic-extrahepatic pattern), and (3) exclusive extrahepatic lesions (extrahepatic pattern). Survival was investigated using Kaplan-Meier plots, log-rank test, and the Cox proportional hazard model. Results: In total, 95 patients (53%) presented with hepatic pattern, 66 patients (37%) presented with hepatic-extrahepatic pattern, and 17 patients (10%) presented with extrahepatic pattern. Overall survival was significantly longer in patients with extrahepatic pattern (median 17.0 months) compared to those with hepatic pattern (median 11.0 months) and hepatic-extrahepatic pattern (median 7.0 months) (p < 0.001, log-rank test). Multivariate Cox regression analysis showed increased hazard ratios (HR) for hepatic pattern (HR 2.37, 95% CI 1.08-5.17, p = 0.031) and hepatic-extrahepatic pattern (3.25, 95% CI 1.42-7.41, p = 0.005) compared to extrahepatic pattern. Most patients with hepatic (95%) and hepatic-extrahepatic patterns (82%) were diagnosed with metastases by liver ultrasonography screening, whereas 81% of patients with extrahepatic pattern developed symptoms that led to the diagnosis. Conclusions: Extrahepatic pattern was associated with prolonged survival in patients with metastatic PUM, despite there being a larger proportion of symptomatic patients. It is therefore important to consider the anatomical location of the metastatic lesions when stratifying patients into clinical trials.
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Affiliation(s)
- Tine G. Hindso
- Department of Ophthalmology, Copenhagen University Hospital—Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark; (M.B.S.); (K.N.); (C.F.); (S.H.); (J.F.K.)
| | - Peter S. Jensen
- Department of Ophthalmology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark; (P.S.J.); (S.F.U.)
| | - Mette B. Sjøl
- Department of Ophthalmology, Copenhagen University Hospital—Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark; (M.B.S.); (K.N.); (C.F.); (S.H.); (J.F.K.)
| | - Kristoffer Nissen
- Department of Ophthalmology, Copenhagen University Hospital—Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark; (M.B.S.); (K.N.); (C.F.); (S.H.); (J.F.K.)
| | - Camilla W. Bjerrum
- Department of Radiology, Copenhagen University Hospital—Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark;
| | - Eric von Benzon
- Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital—Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark (K.M.)
| | - Carsten Faber
- Department of Ophthalmology, Copenhagen University Hospital—Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark; (M.B.S.); (K.N.); (C.F.); (S.H.); (J.F.K.)
| | - Steen F. Urbak
- Department of Ophthalmology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark; (P.S.J.); (S.F.U.)
| | - Marco Donia
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital—Herlev and Gentofte, Borgmester Ib Juuls Vej 13, 2730 Herlev, Denmark; (M.D.); (I.M.S.); (E.E.)
| | - Inge M. Svane
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital—Herlev and Gentofte, Borgmester Ib Juuls Vej 13, 2730 Herlev, Denmark; (M.D.); (I.M.S.); (E.E.)
| | - Eva Ellebaek
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital—Herlev and Gentofte, Borgmester Ib Juuls Vej 13, 2730 Herlev, Denmark; (M.D.); (I.M.S.); (E.E.)
| | - Steffen Heegaard
- Department of Ophthalmology, Copenhagen University Hospital—Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark; (M.B.S.); (K.N.); (C.F.); (S.H.); (J.F.K.)
- Department of Pathology, Copenhagen University Hospital—Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark
| | - Karine Madsen
- Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital—Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark (K.M.)
| | - Jens F. Kiilgaard
- Department of Ophthalmology, Copenhagen University Hospital—Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark; (M.B.S.); (K.N.); (C.F.); (S.H.); (J.F.K.)
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Abu Rached N, Reis MMDS, Stockfleth E, Käpynen R, Gambichler T. Analysis of Calculated Liver Scores for Long-Term Outcome in 423 Cutaneous Melanoma Patients. Cancers (Basel) 2024; 16:3217. [PMID: 39335187 PMCID: PMC11429836 DOI: 10.3390/cancers16183217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Background: Neoadjuvant and adjuvant therapies are currently getting increasingly important in cutaneous melanoma (CM) management. However, there is still a lack of prognostic tools to identify which patients have a poor prognosis. There is increasing evidence that the liver score may be a potential prognostic parameter in different tumour types. The aim was to investigate whether established liver scores can establish the prognosis of CM. Methods: According to established methods, the APRI, the MELD score, the MELD-Na score and the De Ritis ratio were calculated from the laboratory values at the time of the initial diagnosis. Survival was compared with the Kaplan-Meier curve and tested with log-rank tests. Risk factors associated with cutaneous melanoma-specific survival (CMSS) and progression-free survival (PFS) were assessed by using the Cox proportional hazards regression model. To determine the diagnostic accuracy, we performed a time-dependent ROC analysis. Results: A total of 423 patients were included, including 141 patients in AJCC stage (2017) I (33.3%), 82 in stage II (19.4%), 128 in stage III (30.3%) and 72 in stage IV (17%). Median time until melanoma-specific death was 99 months (IQR: 37-126). In addition, 37.6% of patients relapsed with a median time to relapse of 88 months (IQR: 17.5-126). In all stages, tumour thickness and ulceration were independent markers for predicting CMSS and PFS (p < 0.05). The multivariable analysis with all stages showed no significant association with CM outcome for liver scores (p > 0.05). The subgroup analysis revealed that the APRI (≥0.2241) was associated with CMSS and PFS in melanoma stages I and II, independently of tumour thickness, age and ulceration (HR 2.57, 95% CI 1.14-5.75; HR 2.94, 95% CI 1.42-6.09, respectively). Conclusions: The 20-year prognosis of AJCC stage I and II CM was dependent on tumour thickness and the APRI. High tumour thickness and an APRI ≥ 0.2241 at the initial diagnosis were associated with a worse prognosis. Future studies should investigate the independent prognostic value of the APRI in low-stage CM. Furthermore, the APRI score could be a potential biomarker for nomograms.
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Affiliation(s)
- Nessr Abu Rached
- Skin Cancer Center, Department of Dermatology, Venereology and Allergology, Ruhr-University Bochum, 44791 Bochum, Germany; (M.M.d.S.R.); (E.S.); (R.K.); (T.G.)
| | - Mariana Marques da Silva Reis
- Skin Cancer Center, Department of Dermatology, Venereology and Allergology, Ruhr-University Bochum, 44791 Bochum, Germany; (M.M.d.S.R.); (E.S.); (R.K.); (T.G.)
| | - Eggert Stockfleth
- Skin Cancer Center, Department of Dermatology, Venereology and Allergology, Ruhr-University Bochum, 44791 Bochum, Germany; (M.M.d.S.R.); (E.S.); (R.K.); (T.G.)
| | - Riina Käpynen
- Skin Cancer Center, Department of Dermatology, Venereology and Allergology, Ruhr-University Bochum, 44791 Bochum, Germany; (M.M.d.S.R.); (E.S.); (R.K.); (T.G.)
| | - Thilo Gambichler
- Skin Cancer Center, Department of Dermatology, Venereology and Allergology, Ruhr-University Bochum, 44791 Bochum, Germany; (M.M.d.S.R.); (E.S.); (R.K.); (T.G.)
- Department of Dermatology and Phlebology, Christian Hospital Unna, 59423 Unna, Germany
- Department of Dermatology, Faculty of Health, School of Medicine, Dortmund Hospital, Witten/Herdecke University, 58455 Dortmund, Germany
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Trivedi DB, Aldulaimi N, Karydis I, Wheater M, Modi S, Stedman B, Karavias D, Primrose J, Pearce N, Takhar AS. Liver resection for metastatic uveal melanoma: experience from a supra-regional centre and review of literature. Melanoma Res 2023; 33:71-79. [PMID: 36409208 DOI: 10.1097/cmr.0000000000000867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Management of liver metastases from uveal melanoma (LMUM) requires multimodal approach. This study describes evolution of liver resection for LMUM, reviewing current literature and institutional outcomes. Records of patients referred to the Melanoma Multi-Disciplinary Team between February 2005 and August 2018 were reviewed. All publications describing surgery for LMUM were identified from PubMed, Embase, and Google Scholar. Thirty-one of 147 patients with LMUM underwent laparoscopic liver biopsy, and 29 (14 females) had liver resections. Nineteen liver resections were performed locally [7 major (≥3 seg), 14 laparoscopic] without major complications or mortality. Overall survival positively correlated with the time from uveal melanoma to LMUM (Spearman's rho rs = 0.859, P < 0.0001). Overall and recurrence-free survivals were comparable following R1 or R0 resections (OS 25 vs. 28 months, P = 0.404; RFS 13 vs. 6 months, P = 0.596). R1 resection cohort had longer lead-time (median 100 vs. 24 months, P = 0.0408). Eleven publications describing liver resection for LMUM were identified and included in the narrative review. Surgery for LMUM is safe and complements multidisciplinary management. Despite heterogeneity in literature, time from diagnosis of uveal melanoma to LMUM remains a key factor affecting survival after liver resection.
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Affiliation(s)
- Dharmadev B Trivedi
- Department of General Surgery, South Warwickshire NHS Foundation Trust, Warwick, Warwickshire
- Department of HPB Surgery, University Hospitals Southampton NHS Foundation Trust, Southampton, Hampshire, UK
| | - Natasha Aldulaimi
- Department of HPB Surgery, University Hospitals Southampton NHS Foundation Trust, Southampton, Hampshire, UK
| | - Ioannis Karydis
- Department of HPB Surgery, University Hospitals Southampton NHS Foundation Trust, Southampton, Hampshire, UK
| | - Matthew Wheater
- Department of HPB Surgery, University Hospitals Southampton NHS Foundation Trust, Southampton, Hampshire, UK
| | - Sachin Modi
- Department of HPB Surgery, University Hospitals Southampton NHS Foundation Trust, Southampton, Hampshire, UK
| | - Brian Stedman
- Department of HPB Surgery, University Hospitals Southampton NHS Foundation Trust, Southampton, Hampshire, UK
| | - Dimitrios Karavias
- Department of HPB Surgery, University Hospitals Southampton NHS Foundation Trust, Southampton, Hampshire, UK
| | - John Primrose
- Department of HPB Surgery, University Hospitals Southampton NHS Foundation Trust, Southampton, Hampshire, UK
| | - Neil Pearce
- Department of HPB Surgery, University Hospitals Southampton NHS Foundation Trust, Southampton, Hampshire, UK
| | - Arjun S Takhar
- Department of HPB Surgery, University Hospitals Southampton NHS Foundation Trust, Southampton, Hampshire, UK
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Yeo M, Masuda Y, Calvo MP, Di Martino M, Ielpo B, Ye-Xin K. Surgery for liver metastases from primary melanoma: a systematic review and meta-analysis. Langenbecks Arch Surg 2022; 407:3235-3247. [PMID: 36201022 DOI: 10.1007/s00423-022-02658-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 08/12/2022] [Indexed: 10/10/2022]
Abstract
BACKGROUND Historically , liver metastases due to melanoma have been associated with dismal prognosis. Moreover, the actual survival benefit from the treatment of melanoma liver metastases is still controversial. Hence, this study aims to evaluate the difference in surgical versus non-surgical options for melanoma liver metastases. METHODS Four databases (PubMed, EMBASE, Scopus, and Cochrane Library) were searched from inception to July 17, 2022. Studies were included if they compared outcomes between surgical and non-surgical treatment for patients with liver metastases from resectable melanoma. Meta-analyses were performed for the outcomes of 1-year, 2-year, 3-year and 5-year OS. Sensitivity analyses were performed for outcomes with substantial statistical heterogeneity. To account for possible moderators that might contribute to statistical heterogeneity, univariate meta-regression with mixed-effects models and subgroup analyses were conducted for the outcome of 2-year OS. RESULTS The search yielded 6610 articles; 13 studies were included in our analysis. Meta-analyses showed that survival outcomes were in favour of patients undergoing surgery as compared to non-surgery: 1-year OS (HR = 0.29, 95%CI 0.19-0.44, p < 0.00001), 2-year OS (HR = 0.19, 95%CI 0.09-0.38, p < 0.00001), 3-year OS (HR = 0.07, 95%CI 0.03-0.19, p < 0.00001) and 5-year OS (HR = 0.07, 95%CI 0.02-0.22, p < 0.00001). All included studies were of high quality. There was moderate-to-high statistical heterogeneity. Findings were robust to sensitivity analyses. Subgroup analyses and univariate meta-regression revealed neoadjuvant therapy and age as statistically significant subgroup and moderator respectively. CONCLUSIONS This study suggests that surgical treatment of melanoma liver metastases could offer better OS outcomes compared with non-surgical treatment.
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Affiliation(s)
- Mark Yeo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yoshio Masuda
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Mikel-Prieto Calvo
- Hepatobiliary Surgery and Liver Transplantation Unit, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, University of the Basque Country, Bilbao, Spain
| | - Marcello Di Martino
- Department of Hepatobiliary and Liver Transplant Surgery, A.O.R.N. Cardarelli, Naples, Italy
| | - Benedetto Ielpo
- Hepatopancreatobiliary Unit, Parc Salut Mar University Hospital, Barcelona, Spain
- Pompeu Fabra University, Barcelona, Spain
| | - Koh Ye-Xin
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, 1 Outram Road, Singapore, 169608, Singapore.
- Duke-National University of Singapore Medical School, Singapore, Singapore.
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Rantala ES, Hernberg MM, Piperno-Neumann S, Grossniklaus HE, Kivelä TT. Metastatic uveal melanoma: The final frontier. Prog Retin Eye Res 2022; 90:101041. [PMID: 34999237 DOI: 10.1016/j.preteyeres.2022.101041] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 12/31/2021] [Accepted: 01/03/2022] [Indexed: 12/11/2022]
Abstract
Treatment of primary intraocular uveal melanoma has developed considerably, its driver genes are largely unraveled, and the ways to assess its risk for metastases are very precise, being based on an international staging system and genetic data. Unfortunately, the risk of distant metastases, which emerge in approximately one half of all patients, is unaltered. Metastases are the leading single cause of death after uveal melanoma is diagnosed, yet no consensus exists regarding surveillance, staging, and treatment of disseminated disease, and survival has not improved until recently. The final frontier in conquering uveal melanoma lies in solving these issues to cure metastatic disease. Most studies on metastatic uveal melanoma are small, uncontrolled, retrospective, and do not report staging. Meta-analyses confirm a median overall survival of 10-13 months, and a cure rate that approaches nil, although survival exceeding 5 years is possible, estimated 2% either with first-line treatment or with best supportive care. Hepatic ultrasonography and magnetic resonance imaging as surveillance methods have a sensitivity of 95-100% and 83-100%, respectively, to detect metastases without radiation hazard according to prevailing evidence, but computed tomography is necessary for staging. No blood-based tests additional to liver function tests are generally accepted. Three validated staging systems predict, each in defined situations, overall survival after metastasis. Their essential components include measures of tumor burden, liver function, and performance status or metastasis free interval. Age and gender may additionally influence survival. Exceptional mutational events in metastases may make them susceptible to checkpoint inhibitors. In a large meta-analysis, surgical treatment was associated with 6 months longer median overall survival as compared to conventional chemotherapy and, recently, tebentafusp as first-line treatment at the first interim analysis of a randomized phase III trial likewise provided a 6 months longer median overall survival compared to investigator's choice, mostly pembrolizumab; these treatments currently apply to selected patients. Promoting dormancy of micrometastases, harmonizing surveillance protocols, promoting staging, identifying predictive factors, initiating controlled clinical trials, and standardizing reporting will be critical steppingstones in reaching the final frontier of curing metastatic uveal melanoma.
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Affiliation(s)
- Elina S Rantala
- Ocular Oncology Service, Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 4 C, PL 220, FI-00029, HUS, Helsinki, Finland.
| | - Micaela M Hernberg
- Comprehensive Cancer Center, Department of Oncology, Helsinki University Hospital and University of Helsinki, Paciuksenkatu 3, PL 180, FI-00029, HUS, Helsinki, Finland.
| | | | - Hans E Grossniklaus
- Section of Ocular Oncology, Emory Eye Center, 1365 Clifton Road B, Atlanta, GA, 30322, USA.
| | - Tero T Kivelä
- Ocular Oncology Service, Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 4 C, PL 220, FI-00029, HUS, Helsinki, Finland.
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Kim YH, Choi NK. Surgical treatment of liver metastasis with uveal melanoma: A case report. World J Clin Cases 2021; 9:8498-8503. [PMID: 34754859 PMCID: PMC8554419 DOI: 10.12998/wjcc.v9.i28.8498] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/27/2021] [Accepted: 07/30/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Uveal melanoma is the most common primary intraocular malignant tumor affecting the eyes in adults. Nearly half of all primary uveal melanoma tumors metastasize; yet, there are currently no effective treatments for metastatic uveal melanoma. At the time of diagnosis, less than 4% of patients with uveal melanoma have detectable metastatic disease. Uveal melanoma disseminates hematogenously, with the most common site of metastasis being liver (93%), followed by lung (24%) and bone (16%).
CASE SUMMARY A 57-year-old woman was diagnosed with a dysplastic nevus on her eyelid, which was histologically confirmed as malignant melanoma after resection. The patient had no evidence of metastasis to other organs and received both radiation therapy and chemotherapy. After systemic treatment, a metastatic left neck lymph node was found and another round of chemotherapy was performed after resection. Positron emission tomography-Computed Tomography tracking after completion of chemotherapy revealed two metastatic liver nodules. The patient underwent partial liver resection and showed no signs of recurrence at 1 year after surgery.
CONCLUSION Surgery is an effective treatment for metastatic uveal melanoma. In patients with liver metastatic lesions, hepatectomy improves outcome.
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Affiliation(s)
- Young-Hun Kim
- Department of Surgery, Chosun University Hospital, Gwangju Metropolitan City 61453, South Korea
| | - Nam-Kyu Choi
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Chosun University Hospital, Gwangju Metropolitan City 61453, South Korea
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Bustamante P, Piquet L, Landreville S, Burnier JV. Uveal melanoma pathobiology: Metastasis to the liver. Semin Cancer Biol 2020; 71:65-85. [PMID: 32450140 DOI: 10.1016/j.semcancer.2020.05.003] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 05/04/2020] [Accepted: 05/05/2020] [Indexed: 12/12/2022]
Abstract
Uveal melanoma (UM) is a type of intraocular tumor with a propensity to disseminate to the liver. Despite the identification of the early driver mutations during the development of the pathology, the process of UM metastasis is still not fully comprehended. A better understanding of the genetic, molecular, and environmental factors participating to its spread and metastatic outgrowth could provide additional approaches for UM treatment. In this review, we will discuss the advances made towards the understanding of the pathogenesis of metastatic UM, summarize the current and prospective treatments, and introduce some of the ongoing research in this field.
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Affiliation(s)
- Prisca Bustamante
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, Canada; Experimental Pathology Unit, Department of Pathology, McGill University, Montréal, Canada
| | - Léo Piquet
- Département d'ophtalmologie et d'ORL-CCF, Faculté de médecine, Université Laval, Quebec City, Canada; CUO-Recherche and Axe médecine régénératrice, Centre de recherche du CHU de Québec-Université Laval, Quebec City, Canada; Centre de recherche sur le cancer de l'Université Laval, Quebec City, Canada; Centre de recherche en organogénèse expérimentale de l'Université Laval/LOEX, Quebec City, Canada
| | - Solange Landreville
- Département d'ophtalmologie et d'ORL-CCF, Faculté de médecine, Université Laval, Quebec City, Canada; CUO-Recherche and Axe médecine régénératrice, Centre de recherche du CHU de Québec-Université Laval, Quebec City, Canada; Centre de recherche sur le cancer de l'Université Laval, Quebec City, Canada; Centre de recherche en organogénèse expérimentale de l'Université Laval/LOEX, Quebec City, Canada
| | - Julia V Burnier
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, Canada; Experimental Pathology Unit, Department of Pathology, McGill University, Montréal, Canada; Gerald Bronfman Department Of Oncology, McGill University, Montréal, Canada.
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Development of a Prognostic Nomogram for Liver Metastasis of Uveal Melanoma Patients Selected by Liver MRI. Cancers (Basel) 2019; 11:cancers11060863. [PMID: 31234340 PMCID: PMC6627813 DOI: 10.3390/cancers11060863] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 06/17/2019] [Accepted: 06/19/2019] [Indexed: 12/17/2022] Open
Abstract
Patients with liver metastases of uveal melanoma (LMUM) die from their metastatic evolution within 2 years. We established a nomogram to choose a treatment adapted to life expectancy. From 2002 to 2013, we reviewed 224 patients with LMUM selected by liver MRI. A nomogram was developed based on a Cox model. The predictive performance of the model was assessed according to the C-statistic, Kaplan–Meier curve, and calibration plots. The median follow-up was 49.2 months (range, 0.6–70.9). The survival rates at 6, 12, and 24 months were 0.88 (0.95 CI [0.84–0.93]), 0.68 (0.95 CI [0.62–0.75]), and 0.26 (0.95 CI [0.21–0.33]), respectively. The four factors selected for the nomogram with a worse prognosis were: A disease-free interval between the UM and LMUM groups of less than 6 months (HR = 3.39; 0.95 CI [1.90–6.05]), more than 10 LMUM (HR = 3.95; 0.95 CI [1.97–4.43]), a maximum LMUM of more than 1200 mm2 (HR = 2.47; 0.95 CI [1.53–3.98]), and a lactate dehydrogenase (LDH) value greater than 1.5 (HR = 3.72; 0.95 CI [2.30–6.00]). The model achieved relatively good discrimination and calibration (C-statistic 0.71). This nomogram could be useful for decision-making and risk stratification for therapeutic options.
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Lorenzo D, Piulats JM, Ochoa M, Arias L, Gutiérrez C, Català J, Cobos E, Garcia-Bru P, Dias B, Padrón-Pérez N, Caminal JM. Clinical predictors of survival in metastatic uveal melanoma. Jpn J Ophthalmol 2019; 63:197-209. [PMID: 30796549 DOI: 10.1007/s10384-019-00656-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 12/25/2018] [Indexed: 12/20/2022]
Abstract
PURPOSE To determine the clinical factors that influence survival in patients with metastatic uveal melanoma. STUDY DESIGN Single-center, retrospective review of patients' medical records. METHODS The following data of ninety-nine consecutive patients (49 men, 50 women) with metastatic uveal melanoma were registered: patient demographics; primary tumor characteristics; features of first melanoma-related metastasis; symptoms and patient status at distant disease debut and metastasis treatment. Overall survival was analyzed by Kaplan-Meier estimates. A Cox proportional hazards regression model was applied to identify independent predictors associated with survival. RESULTS Mean patient age at metastatic diagnosis was 60.7 years (standard deviation, 12.8). The liver was the first metastatic site in most (92.9%) cases. The median disease-free interval was 26 months (interquartile range, 34). Median overall survival after detection of the first metastasis was 8 months (interquartile range, 14). The baseline characteristics of the primary uveal melanoma were not associated with survival in patients with stage IV disease. In the multivariate analysis, the following factors at first metastatic diagnosis were associated with improved overall survival: disease-free interval > 36 months; better performance status; and normal serum lactate dehydrogenase and gamma glutamyl transpeptidase levels. Overall survival was not influenced by specific metastatic treatment. CONCLUSION Although metastatic uveal melanoma has a poor prognosis, this study reveals the existence of several independent prognostic factors for prolonged overall survival. These findings may help improve survival estimates in patients with advanced disease.
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Affiliation(s)
- Daniel Lorenzo
- Department of Ophthalmology, Bellvitge University Hospital, Feixa Llarga, s/n, 08907, L'Hospitalet de Llobregat, Barcelona, Spain.
| | | | - María Ochoa
- Department of Oncology, Catalan Institute of Oncology, Barcelona, Spain
| | - Luis Arias
- Department of Ophthalmology, Bellvitge University Hospital, Feixa Llarga, s/n, 08907, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Cristina Gutiérrez
- Department of Brachytherapy, Catalan Institute of Oncology, Barcelona, Spain
| | - Jaume Català
- Department of Ophthalmology, Bellvitge University Hospital, Feixa Llarga, s/n, 08907, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Estefanía Cobos
- Department of Ophthalmology, Bellvitge University Hospital, Feixa Llarga, s/n, 08907, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Pere Garcia-Bru
- Department of Ophthalmology, Bellvitge University Hospital, Feixa Llarga, s/n, 08907, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Bruno Dias
- Department of Ophthalmology, Bellvitge University Hospital, Feixa Llarga, s/n, 08907, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Noel Padrón-Pérez
- Department of Ophthalmology, Bellvitge University Hospital, Feixa Llarga, s/n, 08907, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Josep Maria Caminal
- Department of Ophthalmology, Bellvitge University Hospital, Feixa Llarga, s/n, 08907, L'Hospitalet de Llobregat, Barcelona, Spain
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Mahendraraj K, Lau CS, Lee I, Chamberlain RS. Trends in incidence, survival, and management of uveal melanoma: a population-based study of 7,516 patients from the Surveillance, Epidemiology, and End Results database (1973-2012). Clin Ophthalmol 2016; 10:2113-2119. [PMID: 27822007 PMCID: PMC5087706 DOI: 10.2147/opth.s113623] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Introduction Uveal melanoma (UM) is the most common primary intraocular malignancy, despite comprising <5% of all melanomas. To date, relatively few case series of UM have been published. Moreover, the factors influencing survival remain largely unknown. This study sought to analyze the impact of demographics, histology, clinical presentation, and treatments on the clinical outcomes of UM in a large modern nationwide patient cohort. Methods Demographics and clinical data were abstracted on 277,120 histologically confirmed melanoma patients from the Surveillance, Epidemiology, and End Results database between 1973 and 2012. Results A total of 7,516 cases of UM represented 3.2% of all recorded cases of melanoma. The mean age-adjusted incidence was 5.1 per million (95% CI 4.2–6.1) and was higher in males (5.9, CI =4.4–7.6) compared to females (4.5, CI =3.3–5.8), P<0.001. UM occurred most commonly in the sixth decade of life (61.4±15) and among Caucasians (94.7%). A total of 52.3% of cases were reported in the Western US (35.7% in California). The initial diagnoses in 65.2% of cases were by histopathology, followed by clinical diagnosis (18.8%) and radiographic imaging (16.0%). The percentage of UM cases managed by surgery alone decreased by 69.4% between the 1973–1977 and 2006–2012 time periods, concomitant with a 62% increase in primary radiotherapy, P<0.001. The UM mean overall and cancer-specific 5-year relative survival rates were 79.8%±5.8% and 76%±5.3%, respectively. The mean 5-year cancer-specific survival rate (76%) remained stable during the study period between 1973 and 2012. The mean survival for patients treated with primary radiotherapy was significantly improved compared to those treated with surgery alone (15.4±0.4 vs 13.6±0.3, P<0.001). Multivariate analysis identified male sex (odds ratio [OR] 1.1, CI =1.0–1.3), age >50 years (OR 4.0, CI =3.4–4.6), distant metastases (OR 8.6, CI =4.7–15), and primary surgical treatment (OR 2.6, CI =2.0–3.3) as independently associated with increased mortality, P<0.005. Conversely, patients identified as Hispanic (OR 0.6, CI =0.5–0.8) and patients receiving radiation treatment (OR 0.5, CI =0.4–0.7) were independently associated with reduced mortality, P<0.005. Conclusion UM remains a rare form of melanoma that occurs primarily in Caucasian patients older than 50 years. More than two-thirds of UM patients are curatively treated with primary radiotherapy as opposed to surgery, which has resulted in a significant improvement in both overall survival and cancer-specific survival. Despite this shift in management strategy, the mean 5-year cancer-specific survival rate remained relatively unchanged during the study period. Male sex, older age, distant disease, and primary surgical therapy rather than radiotherapy are associated with an increased risk of mortality.
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Affiliation(s)
| | - Christine Sm Lau
- Department of Surgery, Saint Barnabas Medical Center, Livingston, NJ, USA; St George's University School of Medicine, Grenada, West Indies
| | - Injoon Lee
- St George's University School of Medicine, Grenada, West Indies
| | - Ronald S Chamberlain
- Department of Surgery, Saint Barnabas Medical Center, Livingston, NJ, USA; St George's University School of Medicine, Grenada, West Indies; Department of Surgery, New Jersey Medical School, Rutgers University, Newark, NJ, USA
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Mariani P, Almubarak MM, Kollen M, Wagner M, Plancher C, Audollent R, Piperno-Neumann S, Cassoux N, Servois V. Radiofrequency ablation and surgical resection of liver metastases from uveal melanoma. Eur J Surg Oncol 2016; 42:706-12. [PMID: 26968227 DOI: 10.1016/j.ejso.2016.02.019] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 02/05/2016] [Accepted: 02/12/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The resection of liver metastasis from uveal melanoma (LMUM) remains controversial. In this study, we evaluated treatment with radiofrequency ablation (RFA) for liver metastases alone or in combination with surgical liver resection. METHODS A total of 72 patients with LMUM were evaluated in this study. Of these, 57 patients underwent surgical resection (S) while 15 patients had RFA ± S. Clinicopathologic factors were evaluated in terms of recurrence and survival using Chi-square and log-rank tests, respectively. RESULTS We studied 22 metastases treated by RFA. There were no statistically significant differences between the groups in terms of median age of onset, synchronous nature of the metastases, time from primary tumour treatment to liver metastasis, diameter of the largest metastasis, presence of liver miliary disease, and the type of liver resection. There was a statistically lower number of liver metastases and more bilobar metastases in the RFA group than in the S group. The median overall survival after liver surgery was 27 months in group S and 28 months in the RFA group ± S. The median disease-free survival was 10 months in group S and 7 months in the RFA group ± S. There were no statistically significant differences in the median overall survival and disease-free survival between groups. CONCLUSIONS The results of this retrospective analysis show that RFA can be used to treat liver metastases to spare the hepatic parenchyma. RFA ± liver surgery and liver surgery alone demonstrate similar survival times.
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Affiliation(s)
- P Mariani
- Department of Surgical Oncology, Institut Curie, 26 rue d'Ulm-75248, Paris Cedex 05, France.
| | - M M Almubarak
- Department of Surgical Oncology, Institut Curie, 26 rue d'Ulm-75248, Paris Cedex 05, France
| | - M Kollen
- Department of Radiology, Institut Curie, 26 rue d'Ulm-75248, Paris Cedex 05, France
| | - M Wagner
- Department of Radiology, Institut Curie, 26 rue d'Ulm-75248, Paris Cedex 05, France
| | - C Plancher
- Department of Biostatistics, Institut Curie, 26 rue d'Ulm-75248, Paris Cedex 05, France
| | - R Audollent
- Department of Surgical Oncology, Institut Curie, 26 rue d'Ulm-75248, Paris Cedex 05, France
| | - S Piperno-Neumann
- Department of Medical Oncology, Institut Curie, 26 rue d'Ulm-75248, Paris Cedex 05, France
| | - N Cassoux
- Department of Surgical Oncology, Institut Curie, 26 rue d'Ulm-75248, Paris Cedex 05, France
| | - V Servois
- Department of Radiology, Institut Curie, 26 rue d'Ulm-75248, Paris Cedex 05, France
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Nielsen M, Dogrusöz M, Bleeker J, Kroes W, van Asperen C, Marinkovic M, Luyten G, Jager M. The genetic basis of uveal melanoma. J Fr Ophtalmol 2015; 38:516-21. [DOI: 10.1016/j.jfo.2015.04.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Accepted: 04/20/2015] [Indexed: 01/29/2023]
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13
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Valpione S, Moser JC, Parrozzani R, Bazzi M, Mansfield AS, Mocellin S, Pigozzo J, Midena E, Markovic SN, Aliberti C, Campana LG, Chiarion-Sileni V. Development and external validation of a prognostic nomogram for metastatic uveal melanoma. PLoS One 2015; 10:e0120181. [PMID: 25780931 PMCID: PMC4363319 DOI: 10.1371/journal.pone.0120181] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 02/03/2015] [Indexed: 12/21/2022] Open
Abstract
Background Approximately 50% of patients with uveal melanoma (UM) will develop metastatic disease, usually involving the liver. The outcome of metastatic UM (mUM) is generally poor and no standard therapy has been established. Additionally, clinicians lack a validated prognostic tool to evaluate these patients. The aim of this work was to develop a reliable prognostic nomogram for clinicians. Patients and Methods Two cohorts of mUM patients, from Veneto Oncology Institute (IOV) (N=152) and Mayo Clinic (MC) (N=102), were analyzed to develop and externally validate, a prognostic nomogram. Results The median survival of mUM was 17.2 months in the IOV cohort and 19.7 in the MC cohort. Percentage of liver involvement (HR 1.6), elevated levels of serum LDH (HR 1.6), and a WHO performance status=1 (HR 1.5) or 2–3 (HR 4.6) were associated with worse prognosis. Longer disease-free interval from diagnosis of UM to that of mUM conferred a survival advantage (HR 0.9). The nomogram had a concordance probability of 0.75 (SE .006) in the development dataset (IOV), and 0.80 (SE .009) in the external validation (MC). Nomogram predictions were well calibrated. Conclusions The nomogram, which includes percentage of liver involvement, LDH levels, WHO performance status and disease free-interval accurately predicts the prognosis of mUM and could be useful for decision-making and risk stratification for clinical trials.
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Affiliation(s)
- Sara Valpione
- Melanoma Oncology Unit, Veneto Region Oncology Research Institute (IOV-IRCCS), Padova, Italy; Department of Surgery, Oncology and Gastroenterology, Padova, Italy
| | - Justin C Moser
- Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, US
| | | | - Marco Bazzi
- Department of Statistical Sciences, University of Padova, Padova, Italy
| | - Aaron S Mansfield
- Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Simone Mocellin
- Department of Surgery, Oncology and Gastroenterology, Padova, Italy
| | - Jacopo Pigozzo
- Melanoma Oncology Unit, Veneto Region Oncology Research Institute (IOV-IRCCS), Padova, Italy
| | - Edoardo Midena
- Department of Statistical Sciences, University of Padova, Padova, Italy; Department of Ophthalmology, University of Padova, Padova, Italy
| | - Svetomir N Markovic
- Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Camillo Aliberti
- Interventional Radiology, Veneto Region Oncology Research Institute (IOV-IRCCS) Padova, Italy
| | - Luca G Campana
- Sarcoma and Melanoma Unit, Veneto Region Oncology Research Institute (IOV-IRCCS) Padova, Italy
| | - Vanna Chiarion-Sileni
- Melanoma Oncology Unit, Veneto Region Oncology Research Institute (IOV-IRCCS), Padova, Italy
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Eide N, Faye RS, Høifødt HK, Sandstad B, Qvale G, Faber R, Jebsen P, Kvalheim G, Fodstad Ø. Immunomagnetic detection of micrometastatic cells in bone marrow of uveal melanoma patients: a paradox. Acta Ophthalmol 2015; 93:59-66. [PMID: 25613126 DOI: 10.1111/aos.12462] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 05/01/2014] [Indexed: 02/06/2023]
Abstract
PURPOSE Our objective was to study survival rates with the bone marrow (BM) results in a cohort of uveal melanoma patients with long follow-up. METHODS Mononuclear cell fractions isolated from BM were examined for tumour cells using our immunomagnetic separation (IMS) method. The patients were classified as BM positive or BM negative. Clinical follow-up, histopathological findings, vital status and cause of death were registered. RESULTS The study included 328 consecutive patients with uveal melanoma from 1997 to 2006. Tumour cells were found in BM samples in 29% (95% CI, 25-34) at enrolment (96 cases). After a minimum follow-up time of 6 years, 156 (48%) (95% CI, 42-53) melanoma patients had died. The causes were as follows: melanoma metastases 92 (59%), another cancer 20 (13%) and non-cancer 44 (28%). Nine patients were still living with melanoma metastases. Until the latest work-up, 101(31%) (95% CI, 26-36) patients had developed melanoma metastases. Cyto- or histopathological verification of the metastatic lesions was obtained in 85 cases (84%). In the group with melanoma metastases, 28 tested BM positive at study entry (28%) (95% CI, 19-38). In total, 39 of 101 with metastases tested positive at least once after a maximum of three tests (39%) (95% CI, 29-49). The overall median survival from the first BM test was shorter for the BM negative patients (9.5 years) compared with the BM positive (14.4 years), p = 0.02, log rank test. CONCLUSION Ocular melanoma cells detected in BM seem to have a positive prognostic impact on survival in contrast to our original hypothesis.
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Affiliation(s)
- Nils Eide
- Eye Department; University Hospital HF; Oslo Norway
| | - Ragnar S. Faye
- Department of Dermatology; Oslo University Hospital HF; Oslo Norway
- Department of Tumor Biology; Oslo University Hospital HF and University of Oslo; Oslo Norway
| | - Hanne K. Høifødt
- Department of Tumor Biology; Oslo University Hospital HF and University of Oslo; Oslo Norway
| | - Berit Sandstad
- Department of Statistics; Oslo University Hospital HF; Oslo Norway
| | - Geir Qvale
- Eye Department; University Hospital HF; Oslo Norway
| | - Rowan Faber
- Eye Department; University Hospital HF; Oslo Norway
| | - Peter Jebsen
- Division of Pathology; Oslo University Hospital HF; Oslo Norway
| | - Gunnar Kvalheim
- Department of Oncology; Oslo University Hospital HF; Oslo Norway
| | - Øystein Fodstad
- Department of Tumor Biology; Oslo University Hospital HF and University of Oslo; Oslo Norway
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15
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Fitzgerald TL, Brinkley J, Banks S, Vohra N, Englert ZP, Zervos EE. The benefits of liver resection for non-colorectal, non-neuroendocrine liver metastases: a systematic review. Langenbecks Arch Surg 2014; 399:989-1000. [PMID: 25148767 DOI: 10.1007/s00423-014-1241-3] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Accepted: 08/11/2014] [Indexed: 02/07/2023]
Abstract
PURPOSE Defining the benefits of resection of isolated non-colorectal, non-neuroendocrine (NCRNNE) liver metastases is difficult. To better understand the survival benefit in this group of patients, we conducted a systematic review of the previous literature. METHODS Medline, Web of Knowledge, and manual searches were performed using search terms, such as "liver resection" and "primary tumor." Inclusion criteria were year>1990, >five patients, and median survival reported or derived. An expected median survival was calculated from weighted averages of median survivals, and differences were assessed using a permutation test. RESULTS A total of 7,857 references were identified. Overall 4,735 abstracts were reviewed; 120 manuscripts evaluated and of these, 73 met the study inclusion criteria. The final population consisted of 3,596 patients with renal (n=234), ovarian (n=119), testicular (n=153), adrenal (n=90), small bowel (n=28), gallbladder (n=21), duodenum (n=38), gastric (n=481), pancreatic (n=55), esophageal (n=23), head and neck (n=15), and lung (n=36) cancers, gastrointestinal stromal tumors (GISTs) (n=106), cholangiocarcinoma (n=13), sarcoma (n=189), and melanoma (n=643). The greatest expected median was 63 months for genitourinary (GU) primaries (n=549; range 5.4-142 months) followed by 44.4 months for breast cancer (n=1,013; range 8-74 months), 22.3 months for gastrointestinal cancer (n=549; range 5-58 months), and 23.7 months for other tumor types (n=1,082; range 10-72 months). Using a permutation test, we observed that survival was best for patients with GU primaries followed by that for breast cancer patients. Additionally, we also observed that survival was similar for those with cancer of the GI tract and other primary sites. CONCLUSIONS There appears to be a benefit to resection for patients with NCRNNE liver metastases. The degree of survival advantage is predicated by primary site.
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Affiliation(s)
- Timothy L Fitzgerald
- Division of Surgical Oncology, Department of Surgery, Brody School of Medicine, East Carolina University, 4S24 600 Moye Boulevard, Greenville, NC, 27834, USA,
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Gomez D, Wetherill C, Cheong J, Jones L, Marshall E, Damato B, Coupland SE, Ghaneh P, Poston GJ, Malik HZ, Fenwick SW. The Liverpool uveal melanoma liver metastases pathway: outcome following liver resection. J Surg Oncol 2014; 109:542-7. [PMID: 24357463 DOI: 10.1002/jso.23535] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Accepted: 11/27/2013] [Indexed: 01/19/2023]
Abstract
AIM To determine the outcome of patients that underwent liver resection for metastases from uveal melanoma. METHODS Over a 9-year period, patients referred with uveal melanoma metastases were included. Following treatment of primary uveal melanoma, high-risk patients were offered to be enrolled into a 6-monthly non-contrast liver magnetic resonance imaging (MRI) surveillance. Following detection of liver metastases, patients were staged with a contrast-enhanced (Primovist(®)) liver MRI, computer tomography (CT) of the thorax and staging laparoscopy. RESULTS 155 patients were referred with uveal melanoma liver metastases, of which 17 (11.0%) patients had liver resection and one patient was treated with percutaneous radio-frequency ablation. The majority of patients undergoing liver resection were treated with multiple metastectomies (n = 8) and three patients had major liver resections. The overall median survival for patients treated with surgery/ablation was 27 (14-90) months, and this was significantly better compared to patients treated palliatively [median = 8(1-30) months, P < 0.001]. Following surgery, 11 patients had recurrent disease [median = 13(6-36) months]. Patients who had undergone a major liver resection had a significantly poorer disease-free survival (P = 0.037). CONCLUSIONS Patients who can undergo surgical resection for metastatic uveal melanoma have a more favorable survival compared to those who do not.
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Affiliation(s)
- D Gomez
- North Western Hepatobiliary Unit, Aintree University Hospital NHS Foundation Trust, Liverpool, UK
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Umemura A, Nitta H, Sasaki A, Takahara T, Hasegawa Y, Wakabayashi G. Pure laparoscopic posterior sectionectomy for liver metastasis resulting from choroidal malignant melanoma: a case report. Asian J Endosc Surg 2013; 6:318-21. [PMID: 24308594 DOI: 10.1111/ases.12043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2013] [Revised: 04/25/2013] [Accepted: 05/07/2013] [Indexed: 12/14/2022]
Abstract
Liver metastases resulting from primary choroidal malignant melanomas occur frequently and have a poor prognosis. As a result of advancements in multidisciplinary approaches, life expectancy can be increased when R0 resection is possible. Herein we report the surgical outcomes of pure laparoscopic posterior sectionectomy (PLPS) in a patient with a solitary liver metastasis resulting from choroidal malignant melanoma. The subject was a 46-year-old Japanese man who had received radiotherapy for primary right choroidal malignant melanoma 2 years before presenting at our hospital; he subsequently underwent ophthalmectomy as a result of the relapse. During follow-up, CT revealed a metastatic lesion in the liver S7, and interventional treatments were performed sequentially. The lesion still showed a tendency to enlarge, so we performed PLPS. On postoperative day 7, the patient was discharged from the hospital, and he started to receive adjuvant chemotherapy 2 weeks after PLPS. Although PLPS is deemed to be difficult for lesions in the upper part or posterior segment of the liver, we performed this modality safely.
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Affiliation(s)
- Akira Umemura
- Department of Surgery, Iwate Medical University, Morioka, Japan
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Proteomics of uveal melanoma: a minireview. JOURNAL OF ONCOLOGY 2013; 2013:820953. [PMID: 24078811 PMCID: PMC3775436 DOI: 10.1155/2013/820953] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2013] [Accepted: 06/25/2013] [Indexed: 12/25/2022]
Abstract
Uveal melanoma (UM) continues to be associated with a high mortality rate of up to 50% due to metastatic spread primarily to the liver. Currently there are relatively effective treatments for the primary tumor, though the management of the metastatic disease remains inadequate. Conventional diagnostic tools have a low sensitivity for detecting metastasis, and early detection of metastatic spread would allow more treatment options that could ultimately increase survival of UM patients. Advanced proteomic methods have already helped to find potential biomarkers associated with UM pathogenesis and metastasis. In the present review we discuss the field of proteomics in relation to studies elucidating biomarkers of UM, where proteins such as S-100 β , osteopontin (OPN), and melanoma inhibitory activity (MIA) have been shown to be associated with metastasis.
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Logan P, Burnier J, Burnier MN. Vascular endothelial growth factor expression and inhibition in uveal melanoma cell lines. Ecancermedicalscience 2013; 7:336. [PMID: 23914254 PMCID: PMC3729237 DOI: 10.3332/ecancer.2013.336] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Indexed: 12/28/2022] Open
Abstract
Background: Uveal melanoma (UM) is a disease that affects approximately five people per million in the United States. This disease metastasises predominantly to the liver, and treatment options following the clinical detection of these sequelae are limited. Vascular endothelial growth factor-A (VEGF-A) is the primary activator of tumour angiogenesis and functions by binding to VEGF-Receptor 2 (VEGF-R2) and is often required for tumour growth beyond 2–3 mm. The purpose of this study was to investigate the expression of VEGF-A and the primary VEGF-R2 in three UM cell lines. Furthermore, we investigated the effects of VEGF-A inhibition on receptor activation and production of other cytokines. Finally, the effects of VEGF-A inhibition on the proliferation, migration, and invasion in the cell lines were ascertained. Materials: Three UM cell lines (92.1, OCM-1, and UW-1) were incubated with and without the addition of 100 μg/mL of bevacizumab. VEGF-A expression under both conditions was determined by sandwich enzyme-linked immunosorbent assay (ELISA), and phosphorylated VEGF-R2 expression was determined using western blot. The effects of VEGF-A inhibition on 20 cytokines (IL-1a, IL-2, IL-5, IL-8, IL-12p70, GM-CSF, IFNy, CCL3, MMP-9, TNF-a, IL-1b, IL-4, IL-6, IL-10, IL-13, GRO, MCP-1, MIP-1b, and RANTES) were determined using a multiplex sandwich ELISA. Proliferation rates before and after treatment were evaluated via sulforhodamine B assay, and migration and invasion assays implementing the Boyden chamber technique, the latter with artificial extracellular matrix, were used to assess their respective abilities. The Student’s t-test was used to compare changes in cytokine expression following VEGF-A inhibition. Analysis of variance was used to compare changes in the functional abilities of three uveal melanoma cell lines following VEGF-A inhibition. A P-value < 0.05 was considered statistically significant. Results: All three cell lines produced copious amounts of VEGF-A in culture (92.1, 11785.5 ± 231.8 pg/μL; OCM-1, 4608.0 ± 324.0 pg/μL; UW-1, 8309.3 ± 634.5 pg/μL), which was reduced to undetectable levels following the administration of bevacizumab (P< 0.05). Similarly, detectable phosphorylated VEGF-R2 was present in all cells, which was reduced significantly in all cell lines following bevacizumab treatment (107525.2 ± 8602.0 versus 1024.5 ± 98.2, 46587.3 ± 4192.9 versus 12821.1 ± 1666.7, and 60394.3 ± 4026.4 versus 6908.2 ± 607.2; 92.1, OCM-1, and UW-1, respectively; P< 0.05). Of the cytokines investigated, only MMP-9 and CCL3 were ubiquitously altered across all three cell lines following bevacizumab treatment; they were upregulated (CCL3: 1072.50 ± 18.77 pg/mL versus 1281.00 ± 72.34 pg/mL; 22.5 ± 7.85 pg/mL versus 62.00 ± 9.16 pg/mL; 20.33 ± 6.35 pg/mL versus 35.00 ± 6.22 pg/mL; control versus bevacizumab; MMP-9: 25.50 ± 5.47 pg/mL versus 88.25 ± 13.38 pg/mL; 19.75 ± 4.14 pg/mL versus 45.25 ± 8.36 pg/mL; 3.25 ± 1.09 pg/mL versus 19.25 ± 3.77 pg/mL; control versus bevacizumab; 92.1, OCM-1, and UW-1, respectively; P< 0.05). Bevacizumab significantly reduced the proliferation of one cell line (92.1: 0.405 ± 0.012 versus 0.509 ± 0.033; bevacizumab versus control; values OD; P< 0.05), the migration of two cell lines (92.1: 0.071 ± 0.003 versus 0.115 ± 0.003; OCM-1: 0.049 ± 0.005 versus 0.117 ± 0.014; bevacizumab versus control; values OD; P< 0.05), and did not significantly affect invasion. Conclusion: Despite the significant reduction in phosphorylated VEGF-R2 levels, bevacizumab did not have a dramatic impact on the functional abilities of the three UM cell lines studied. Our results indicate that compensatory mechanisms, such as the upregulation of MMP-9 and CCL-3, following bevacizumab administration may mitigate its effects on these abilities.
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Affiliation(s)
- Patrick Logan
- The Henry C. Witelson Ocular Pathology Laboratory, McGill University, Montreal, Quebec H3A 2B4, Canada
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Muller K, Naus N, Nowak PJ, Schmitz PI, de Pan C, van Santen CA, Marijnissen JP, Paridaens DA, Levendag PC, Luyten GP. Fractionated stereotactic radiotherapy for uveal melanoma, late clinical results. Radiother Oncol 2012; 102:219-24. [DOI: 10.1016/j.radonc.2011.06.038] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2010] [Revised: 04/16/2011] [Accepted: 06/24/2011] [Indexed: 12/17/2022]
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Caralt M, Martí J, Cortés J, Fondevila C, Bilbao I, Fuster J, García-Valdecasas JC, Sapisochín G, Balsells J, Charco R. Outcome of patients following hepatic resection for metastatic cutaneous and ocular melanoma. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2011; 18:268-75. [PMID: 21057964 DOI: 10.1007/s00534-010-0341-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND/PURPOSE The aim of this study was to analyze the outcome of patients undergoing hepatic resection for melanoma liver metastases. METHODS Patients undergoing liver resection for melanoma metastases at the Hospital Vall d'Hebron and Hospital Clinic, Barcelona, were reviewed. Selection criteria were: good performance status, feasibly complete and safe resection, and absence of visceral extrahepatic metastases. RESULTS Between 1994 and 2007, 14 liver resections were performed for melanoma liver metastases. The primary tumor was cutaneous in 8 patients and ocular in 6. Two patients underwent urgent liver surgery due to tumor bleeding. In these patients, complete melanoma staging was not performed and extrahepatic metastases were found during surgery or during the postoperative course. Six of 13 patients (46.2%) developed liver recurrence during follow-up. One- and 3-year actuarial patient survivals were 77 and 49%, respectively. Excluding the patients who underwent urgent liver surgery, the 1- and 3-year actuarial patient survivals in those with primary ocular and cutaneous melanoma were 83 and 56% and 80 and 60%, respectively. CONCLUSIONS Liver resection may be considered as part of oncosurgical treatment in patients with melanoma liver metastases, since prolonged survival was observed, albeit with a high recurrence rate. Nevertheless, it should be taken into account that our study included only a small number of patients.
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Affiliation(s)
- Mireia Caralt
- Department of HepatoBilioPancreatic Surgery and Transplants, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.
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Augsburger JJ, Corrêa ZM, Trichopoulos N. Surveillance testing for metastasis from primary uveal melanoma and effect on patient survival. Am J Ophthalmol 2011; 152:5-9.e1. [PMID: 21601175 DOI: 10.1016/j.ajo.2011.03.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Revised: 02/28/2011] [Accepted: 03/01/2011] [Indexed: 11/29/2022]
Abstract
PURPOSE To evaluate the quality of evidence about effectiveness of regular periodic surveillance testing for metastasis in patients with primary uveal melanoma (PUM) following treatment of the primary tumor in prolonging survival. DESIGN Literature review and personal perspective of the authors. METHODS Identification and analysis of peer-reviewed articles on human PUM published between 1980 and 2009 that reported on "screening," "surveillance," or "systemic follow-up evaluation" for metastasis in patients with PUM following treatment of primary tumor. RESULTS Of 4222 identified articles, only 31 were considered satisfactory for inclusion in this study. Satisfactory articles reported levels of specific biomarkers when metastasis was first confirmed (14), percentage of patients with abnormal results on surveillance testing (13), values of diagnostic markers (eg, sensitivity, specificity) associated with evaluated components of a surveillance regimen (7), survival time after first detection of metastasis from primary uveal melanoma (7), total survival time after initial diagnosis or initial treatment of primary uveal melanoma (3), percentage of patients whose metastatic tumors were detected by presymptomatic testing (5), surveillance regimens employed by different groups (1), and relationship with generally accepted clinical and histopathologic prognostic factors for primary uveal melanoma metastasis (1). However, none of these articles reported survival times of comparable subgroups of patients in which regular periodic surveillance for metastasis vs no surveillance was performed. CONCLUSION Available evidence from the peer-reviewed literature does not provide any compelling evidence of survival benefit for any regimen or frequency of surveillance for metastasis relative to no such testing. In view of this, advisability of periodic surveillance for metastasis in routine clinical practice must be questioned.
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Affiliation(s)
- James J Augsburger
- Department of Ophthalmology, University of Cincinnati College of Medicine, Cincinnati, Ohio
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Brasiuniene B, Sokolovas V, Brasiunas V, Barakauskiene A, Strupas K. Combined treatment of uveal melanoma liver metastases. Eur J Med Res 2011; 16:71-5. [PMID: 21463985 PMCID: PMC3353425 DOI: 10.1186/2047-783x-16-2-71] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Uveal melanoma (UM) is the most prevalent intraocular malignant tumor in the Western world. The prognosis of survival in the presence of metastatic disease is 2-7 months, depending on the treatment applied. This article presents a case of metastatic UM with successful complex treatment of liver metastases. A 49-year old female, underwent removal of the right eyeball in 1996 due to a histologically confirmed uveal melanoma. After 11 years, CT revealed a mass in the left kidney and multiple metastases in the liver. After left nephrectomy, 6 chemotherapy courses with dacarbazine were performed. The increasing liver metastases were observed. Additional 4 intraarterial (i/a) chemotherapy courses were administered using cisplatin, doxorubicin, fluorouracil, and interferon alfa. After few courses increase in CTC Grade 4 liver transaminases was seen. A partial response was observed, and in December 2008 the patient underwent surgery removing all liver metastases by 7 wedge or atypical resections. All margins were tumor-free. 21 months after liver resections and 14 years since diagnosis, the patient is alive without evidence of disease. Successful treatment of metastatic uveal melanoma was due to a timely application of a combination of several treatment methods and good prognostic factors of the patient.
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Affiliation(s)
- Birute Brasiuniene
- Centre of Hematology, Oncology and Transfusion Medicine, Vilnius University Hospital Santariskiu Clinics, Santariskiu 2, LT-08661, Vilnius, Lithuania.
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Jager MJ, Ly LV, El Filali M, Madigan MC. Macrophages in uveal melanoma and in experimental ocular tumor models: Friends or foes? Prog Retin Eye Res 2011; 30:129-46. [DOI: 10.1016/j.preteyeres.2010.11.004] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2010] [Revised: 11/16/2010] [Accepted: 11/22/2010] [Indexed: 01/05/2023]
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Abi-Ayad N, Couturier J, Devouassoux-Shisheboran M, Grange JD, Kodjikian L, Calender A. [Genomic profiling by comparative genomic hybridization: analysis of ten enucleated uveal melanoma cases]. J Fr Ophtalmol 2010; 34:17-23. [PMID: 21145127 DOI: 10.1016/j.jfo.2010.10.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2010] [Revised: 10/10/2010] [Accepted: 10/19/2010] [Indexed: 01/15/2023]
Abstract
AIM To detect major chromosomal aberrations from enucleated uveal melanoma and relate them to hepatic metastasis and survival. PATIENTS AND METHODS Ten uveal melanomas enucleated between 2005 and 2008 in the Lyon Croix-Rousse Hospital were retrospectively analyzed using a 19 000-clone comparative genomic hybridization microarray. RESULTS The most frequent imbalances were the loss of chromosome 3 (8/10), gain of the 8q arm (7/10) or the entire chromosome 8 (2/10), and gain of the 6p arm (2/10). Most metastatic tumors (6/7) and all cases of death (5/5) concerned melanoma with monosomy 3 and gain of the 8q arm. DISCUSSION AND CONCLUSION Genome-wide array comparative genomic hybridization is a reliable tool for identifying uveal melanoma genomic imbalances. Gains of the 8q arm with monosomy 3 are frequent and are strongly associated with poor outcome. Gains of the 6p arm are rare and have a better prognosis. There is a mutually exclusive relationship between monosomy 3 and chromosome 6 abnormalities in our study. These results confirm previously published reports.
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Affiliation(s)
- N Abi-Ayad
- Service d'ophtalmologie, hôpital de la Croix-Rousse, 103, Grande rue de la Croix-Rousse, 69317 Lyon cedex 04, France.
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Russell-Hermanns D, Fernandes B, PV S, Burnier Jr M. Eye growth transformation: uveal melanoma. EXPERT REVIEW OF OPHTHALMOLOGY 2010. [DOI: 10.1586/eop.10.36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Yamamoto A, Chervoneva I, Sullivan KL, Eschelman DJ, Gonsalves CF, Mastrangelo MJ, Berd D, Shields JA, Shields CL, Terai M, Sato T. High-dose immunoembolization: survival benefit in patients with hepatic metastases from uveal melanoma. Radiology 2009; 252:290-8. [PMID: 19561263 DOI: 10.1148/radiol.2521081252] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
PURPOSE To retrospectively evaluate prognostic factors for survival in patients with uveal melanoma who received chemoembolization (CE) with 1,3-bis (2-chloroethyl)-1-nitrosourea or immunoembolization (IE) with granulocyte-macrophage colony-stimulating factor (GM-CSF) for hepatic metastases. MATERIALS AND METHODS Fifty-three consecutive patients with uveal melanoma were treated by using CE or IE in clinical trials approved by the Institutional Review Board. Prognostic factors associated with overall survival (OS) and progression-free survival (PFS) in the liver and extrahepatic (systemic) organs were retrospectively evaluated. Covariates of age, sex, preexisting extrahepatic metastases, liver enzyme levels, tumor volume, radiologic response in hepatic metastases, and treatment type were analyzed. RESULTS Compared with CE, high-dose (>or=1500 microg of GM-CSF) IE resulted in significantly better OS (20.4 vs 9.8 months, P = .005) and systemic PFS (12.4 vs 4.8 months, P = .001) at univariate analysis. Overall, women outlived men (14.4 vs 9.8 months, P = .01). Patients who achieved regression of hepatic metastases after embolization lived much longer than did those who did not achieve regression (27.2 vs 9.9 months, P < .001). At multivariate analysis, prolonged OS was confirmed for women, patients who underwent high-dose IE, younger patients (age < 60 years), and patients with regression of hepatic metastases. Independent predictors of longer systemic PFS included high-dose IE, younger age, and regression of hepatic metastases. No covariate predicted liver PFS except for hepatic response. CONCLUSION Treatment with high-dose IE prolonged survival of patients with uveal melanoma who received embolization of hepatic metastases and possibly delayed progression of extrahepatic metastases.
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Affiliation(s)
- Akira Yamamoto
- Department of Medical Oncology, Jefferson Medical College, Thomas Jefferson University, 1025 Walnut St, Philadelphia, PA 19107, USA
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Augsburger JJ, Corrêa ZM, Shaikh AH. Effectiveness of treatments for metastatic uveal melanoma. Am J Ophthalmol 2009; 148:119-27. [PMID: 19375060 DOI: 10.1016/j.ajo.2009.01.023] [Citation(s) in RCA: 200] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2008] [Revised: 01/20/2009] [Accepted: 01/27/2009] [Indexed: 10/20/2022]
Abstract
PURPOSE To evaluate and comment on published peer-reviewed literature for evidence of effectiveness of treatments for metastatic uveal melanoma. DESIGN Analytical nonexperimental study of published peer-reviewed data. METHODS Literature search and analysis of pertinent articles published between January 1, 1980 and June 30, 2008. RESULTS Of 80 identified publications, 12 (15.0%) were review articles without original information, 2 (2.5%) were review articles combined with case reports, 22 (27.5%) were case reports, 16 (20.0%) were retrospective descriptive case series reports, 3 (3.75%) were pilot studies of a novel intervention, 2 (2.5%) were prospective phase I clinical trials, 8 (10.0%) were prospective phase I/II clinical trials, and 15 (18.75%) were prospective phase II clinical trials. None of the articles reported a prospective, randomized phase III clinical trial. The largest reported unselected patient groups had a median survival of 3 to 4 months after detection of metastasis, whereas the largest selected patient groups showed substantially longer median survival times. CONCLUSIONS Although median survival time after diagnosis of metastatic uveal melanoma tends to be substantially longer in selected patient subgroups subjected to aggressive invasive interventions than it is in unselected groups, much if not most of this apparent difference in survival is likely to be attributable to selection bias, surveillance bias, and publication bias rather than treatment-induced alteration of expected outcome. Published peer-reviewed articles do not provide compelling scientific evidence of any survival benefit of any method of treatment for any subgroup of patients with metastatic uveal melanoma.
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Al-Jamal RT, Eskelin S, Pyrhönen S, Kivelä T. Long-term progression-free survival in metastatic uveal melanoma after chemoimmunotherapy and consolidation thermoablation. Acta Oncol 2009; 48:476-9. [PMID: 19031163 DOI: 10.1080/02841860802570529] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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O-Mel-Inib: a Cancéro-pôle Nord-Ouest multicenter phase II trial of high-dose imatinib mesylate in metastatic uveal melanoma. Invest New Drugs 2008; 26:561-5. [PMID: 18551246 DOI: 10.1007/s10637-008-9143-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2008] [Accepted: 05/15/2008] [Indexed: 12/20/2022]
Abstract
BACKGROUND Nowadays, there is no consensual and effective treatment in metastatic uveal melanoma (MUM). Numerous preclinical data (for example, 75% of MUM express c-kit) suggest that imatinib mesylate (IM) may be a potential treatment of UMM. METHODS The primary objective of this phase II trial was to determine the non-progression rate at 3 months for patients receiving IM at dose of 400 mg twice per day orally. The study was based on a Simon's optimal design, which allows entry a total of 29 patients, if at least two non-progressions among ten first patients were observed. RESULT Thirteen patients including ten assessable patients were enrolled in 12 months. No objective response and only one stable disease with duration of 5 months were noted. Five and one out of 13 enrolled patients experienced grade 3 and grade 4 toxicities, respectively. The most common severe adverse events were abdominal pain. The overall survival was 10.8 months. CONCLUSIONS Despite promising preclinical data, IM is an inactive single agent in MUM. This phase II clinical trial has been stopped at the first step.
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Lai K, Sharma V, Jager MJ, Conway RM, Madigan MC. Expression and distribution of MUC18 in human uveal melanoma. Virchows Arch 2007; 451:967-76. [PMID: 17786470 DOI: 10.1007/s00428-007-0498-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2007] [Revised: 07/31/2007] [Accepted: 08/01/2007] [Indexed: 12/12/2022]
Abstract
The immunoglobulin superfamily protein MUC18 is involved in transendothelial migration and signal transduction, and is expressed in malignancies including cutaneous melanoma. Recent in vitro studies showed evidence of increased MUC18 protein in some uveal melanoma cell lines with an increased potential for invasion. We assessed seven uveal and three metastasis-derived melanoma cell lines for the expression of MUC18 mRNA and protein by RT-PCR, and immunoblotting and immunocytochemistry, respectively. We also examined the expression and distribution of MUC18 in paraffin sections of primary uveal melanomas (n = 23; 5/23 spindle; 18/23 mixed and epithelioid) and normal eyes (n = 3) using a polyclonal goat anti-human antibody to MUC18 visualized with peroxidase and Vector NovaRED. Distribution and intensity of immunostaining was graded semi-quantitatively (grade 0 to 3) by 2 independent observers. All cell lines expressed MUC18 mRNA and protein ( approximately 130 kDa), and showed punctate cell membrane MUC18 immunostaining. Primary melanomas displayed heterogeneous cell membrane and cytoplasmic MUC18, with moderate to strong immunolabelling (> or =grade 2) in approximately 70% of tumours. Vasculature in tumours and in retina and choroid of all melanoma-affected and normal eyes showed intense MUC18 immunostaining. These observations further suggest a role for MUC18 in uveal melanoma growth; moreover, interactions between MUC18-positive melanoma cells and vasculature may be important for the hematogenous spread of cells during metastases.
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Affiliation(s)
- Kenneth Lai
- Save Sight Institute, Discipline of Clinical Ophthalmology, University of Sydney, Sydney NSW 2006, Australia
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Maat W, Jordanova ES, van Zelderen-Bhola SL, Barthen ER, Wessels HW, Schalij-Delfos NE, Jager MJ. The heterogeneous distribution of monosomy 3 in uveal melanomas: implications for prognostication based on fine-needle aspiration biopsies. Arch Pathol Lab Med 2007; 131:91-6. [PMID: 17227129 DOI: 10.5858/2007-131-91-thdomi] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/06/2006] [Indexed: 11/06/2022]
Abstract
CONTEXT The detection of monosomy 3 in uveal melanomas has repeatedly been associated with adverse outcome. Fine-needle aspiration biopsy is being used to detect monosomy 3 in these tumors, based on the assumption that this chromosomal abnormality is distributed homogeneously throughout the tumor. OBJECTIVE To study the distribution of monosomy 3 in primary uveal melanoma by fluorescence in situ hybridization (FISH). DESIGN We studied 50 enucleated eyes with uveal melanoma. In all 50 tumors we performed cytogenetic analysis and FISH using a DNA-specific probe for the centromere region of chromosome 3 on cultured tumor cells. In addition, the percentage of tumor cells with monosomy 3 was assessed by FISH on nuclei, isolated from paraffin-embedded tissue and compared to results of FISH on regular histology sections of the paraffin-embedded tissue. RESULTS Combining karyotyping and FISH on cultured cells identified monosomy 3 in 19 (38%) of 50 tumors, whereas FISH on nuclei isolated from paraffin-embedded tissue showed 31 (62%) of 50 as having monosomy for chromosome 3. FISH analysis on paraffin sections showed tumor heterogeneity for copy number of chromosome 3 in at least 7 cases. CONCLUSIONS FISH analysis on paraffin sections shows that heterogeneity of monosomy of chromosome 3 is a frequent phenomenon in uveal melanoma. FISH on nuclei isolated from paraffin-embedded tissue identifies a higher frequency of monosomy 3 than the traditional combination of karyotyping and FISH on cultured uveal melanoma cells. The practice of assigning patients to risk categories based on fine-needle aspiration biopsy samples from primary uveal melanoma may be subject to error based on the heterogeneous distribution of monosomy 3 in these tumors.
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Affiliation(s)
- Willem Maat
- Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands
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Gambrelle J, Grange JD, Devouassoux Shisheboran M, Rivoire M, Baggetto LG, Jean-Louis B, Fleury J, Kodjikian L. Survival after primary enucleation for choroidal melanoma: changes induced by the introduction of conservative therapies. Graefes Arch Clin Exp Ophthalmol 2006; 245:657-63. [PMID: 17119996 DOI: 10.1007/s00417-006-0477-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2006] [Revised: 10/05/2006] [Accepted: 10/06/2006] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Most uveal melanomas are currently treated by eye-preserving radiotherapies. However, for melanomas of the largest size or with initial complications, enucleation remains the reference treatment. Enucleation is called primary when it is proposed as the only local treatment option for a melanoma. There is very little literature on the use of primary enucleation after the introduction of conservative treatments. Our main goal was to evaluate the survival of melanoma patients treated by primary enucleation since the introduction of proton-beam therapy in France in 1991. METHODS All melanoma patients undergoing primary enucleation in our department between 1991 and 2002 were included in this retrospective study. The 5-year melanoma-specific survival rate was calculated using the Kaplan-Meier method. The multivariate prognostic analysis was performed using the Cox proportional hazards model. RESULTS Forty patients, representing 8% of all patients with choroidal uveal melanoma diagnosed and followed up in our department during an 11-year period, were included in the study. No patient was lost to follow-up. The 5-year melanoma-specific survival rate was 31.45% (SE: 7.8) after primary enucleation. Significant prognosis factors in the multivariate analysis were: tumor thickness > 12 mm (p = 0.03), anterior margin of the tumor involving the iris (p = 0.018), and presence of epithelioid cells (p = 0.02). CONCLUSIONS The very low survival rate reported reflects the evolution of primary enucleation, which is currently indicated only for melanomas with the worst prognosis. The knowledge of current post-enucleation survival rates represents an essential achievement for both correct assessment of conservative therapies and patient counseling.
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Affiliation(s)
- J Gambrelle
- Department of Ophthalmology, Croix-Rousse Hospital, 103, Grande rue de la Croix-Rousse, Lyon, 69004, France
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Schmittel A, Schmidt-Hieber M, Martus P, Bechrakis NE, Schuster R, Siehl JM, Foerster MH, Thiel E, Keilholz U. A randomized phase II trial of gemcitabine plus treosulfan versus treosulfan alone in patients with metastatic uveal melanoma. Ann Oncol 2006; 17:1826-9. [PMID: 16971664 DOI: 10.1093/annonc/mdl309] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Several trials demonstrated efficacy of the gemcitabine/treosulfan (GeT) combination in metastatic uveal melamoma. This randomized phase II trial compared the GeT combination versus treosulfan alone (T) in this rare disease. PATIENTS AND METHODS Chemotherapy-naive patients with proven metastatic uveal melanoma were randomly assigned to receive 1000 mg/m(2) of gemcitabine plus 3500 mg/m(2) of treosulfan (GeT) or 3500 mg/m(2) of T. Chemotherapy was administered on days 1 and 8 in both arms, cycles were repeated on day 29. Primary end point was rate of responses and disease stabilizations. RESULTS Forty-eight patients were randomized. Seven confirmed stable diseases (SDs) and one partial remission (PR) were observed in 24 patients treated with the GeT regimen, whereas no PR and only three SDs were observed in the T arm (P = 0.08). Median progression-free survival (PFS) was 3 months (95% CI 1.1-4.9) and 2 months (95% CI 1.7-2.3) in the GeT and T arm (P = 0.008, log-rank). Six and 12 months PFS was 34.8% and 17.9% and 16.7% and 0% always favoring the GeT arm. CONCLUSIONS This first randomized trial in metastatic uveal melanoma showed a superior PFS and a trend for a higher response/stabilization rate of the GeT combination over T.
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Affiliation(s)
- A Schmittel
- Department of Internal Medicine III (Hematology, Oncology and Transfusion Medicine), Campus Benjamin Franklin, Berlin, Germany.
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Peters S, Voelter V, Zografos L, Pampallona S, Popescu R, Gillet M, Bosshard W, Fiorentini G, Lotem M, Weitzen R, Keilholz U, Humblet Y, Piperno-Neumann S, Stupp R, Leyvraz S. Intra-arterial hepatic fotemustine for the treatment of liver metastases from uveal melanoma: experience in 101 patients. Ann Oncol 2006; 17:578-83. [PMID: 16469752 DOI: 10.1093/annonc/mdl009] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Exclusive liver metastases occur in up to 40% of patients with uveal melanoma associated with a median survival of 2-7 months. Single agent response rates with commonly available chemotherapy are below 10%. We have investigated the use of fotemustine via direct intra-arterial hepatic (i.a.h.) administration in patients with uveal melanoma metastases. PATIENTS AND METHODS A total of 101 patients from seven centers were treated with i.a.h. fotemustine, administered intra-arterially weekly for a 4-week induction period, and then as a maintenance treatment every 3 weeks until disease progression, unacceptable toxicity or patient refusal. RESULTS A median of eight fotemustine infusions per patient were delivered (range 1-26). Catheter related complications occurred in 23% of patients; however, this required treatment discontinuation in only 10% of the patients. The overall response rate was 36% with a median overall survival of 15 months and a 2-year survival rate of 29%. LDH, time between diagnosis and treatment start and gender were significant predictors of survival. CONCLUSIONS Locoregional treatment with fotemustine is well tolerated and seems to improve outcome of this poor prognosis patient population. Median survival rates are among the longest reported and one-third of the patients are still alive at 2 years.
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Affiliation(s)
- S Peters
- Centre Pluridisciplinaire d'Oncologie and Département de Chirurgie, University of Lausanne Hospitals (CHUV), Lausanne, Switzerland
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