Deferral of Treatment for Small Choroidal Melanoma and the Risk of Metastasis: An Investigation Using the Liverpool Uveal Melanoma Prognosticator Online (LUMPO).

BACKGROUND: We estimated metastatic-death risk when the treatment of small choroidal melanomas is deferred until growth is observed. METHODS: In 24 patients with choroidal melanoma (median diameter 5.85 mm), the exponential growth rate estimated by a mixed-effects model was 4.3% per year. Using the Liverpool Uveal Melanoma Prognosticator Online v.3 (LUMPO3), we measured changes in 15-year metastatic and non-metastatic death risks according to whether the tumor is treated immediately or after observing growth 4 or 12 months later, considering age, sex, and metastasis predictors. RESULTS: In 40-year-old females with 10 mm, disomy 3 and monosomy 3 choroidal melanomas (prevalence 16%), the 15-year absolute risks of metastatic death are 4.2% and 76.6%, respectively, increasing after a 4-month delay by 0.0% and 0.2% and by 3.0% and 2.3% with tumor growth rates of 5.0% and 20.0%, respectively. With 12-month delays, these risks increase by 0.0% and 0.5% and by 1.0% and 7.1%, respectively. Increases in metastatic-death risk are less with smaller tumors and with a higher risk of non-metastatic death. CONCLUSIONS: Deferring treatment of choroidal melanomas until documentation of growth may delay iatrogenic visual loss by months or years and is associated with minimal increase in metastatic mortality, at least with small tumors with usual growth rates of up to 40% per year.

Sensitivity and Specificity of Different Prognostic Systems in Guiding Surveillance for Metastases in Uveal Melanoma.

Uveal melanoma (UM) metastasises in ~50% of patients, most frequently to the liver. Surveillance imaging can provide early detection of hepatic metastases; however, guidance regarding UM patient risk stratification for surveillance is unclear. This study compared sensitivity and specificity of four current prognostic systems, when used for risk stratification for surveillance, on patients treated at the Liverpool Ocular Oncology Centre (LOOC) between 2007-2016 (n = 1047). It found that the Liverpool Uveal Melanoma Prognosticator Online III (LUMPOIII) or Liverpool Parsimonious Model (LPM) offered greater specificity at equal levels of sensitivity than the American Joint Committee on Cancer (AJCC) system or monosomy 3 alone, and suggests guidance to achieve 95% sensitivity and 51% specificity (i.e., how to detect the same number of patients with metastases, while reducing the number of negative scans). For example, 180 scans could be safely avoided over 5 years in 200 patients using the most specific approach. LUMPOIII also offered high sensitivity and improved specificity over the AJCC in the absence of genetic information, making the result relevant to centres that do not perform genetic testing, or where such testing is inappropriate or fails. This study provides valuable information for clinical guidelines for risk stratification for surveillance in UM.

Mantle cell lymphoma treatment options for elderly/unfit patients: A systematic review.

Mantle cell lymphoma (MCL) is a rare B-cell non-Hodgkin lymphoma (NHL) that is aggressive and incurable with existing therapies, presenting a significant unmet clinical need. MCL occurs mainly in elderly patients with comorbidities; thus, intense treatment options including allogeneic stem cell transplantation (Allo-SCT) are not feasible. New treatment options are emerging for this elderly/unfit treatment group, we therefore conducted a systematic review to determine whether they offered an advance on the existing recommended treatment, R-CHOP. The search strategies to identify MCL therapies were designed to capture the most relevant studies from 2013 to 2020. Following preferred reporting items for systematic reviews and meta-analyses and population,interventions, observations and study design analysis, R-CHOP, ibrutinib and bendamustine plus rituximab (BR) were taken forward for critical and statistical analysis. All three therapies were effective in increasing the overall survival (OS) and progression-free survival of elderly/unfit patients with MCL. However, none resulted in a significant increase in OS compared to R-CHOP. In addition, R-CHOP had a better toxicity profile when compared to both ibrutinib and BR. We therefore conclude that treatment of elderly/unfit patients with MCL is still a significant unmet clinical need; and suggest that outside of the clinical trial setting, R-CHOP should remain the recommended front-line treatment for this patient group.

A Retrospective Analysis of 10 Years of Liver Surveillance Undertaken in Uveal Melanoma Patients Treated at the Supraregional "Liverpool Ocular Oncology Centre", UK.

PURPOSE: To determine liver screening frequency and modality in UM patients following primary treatment, and the characteristics of detected metastases. METHODS: A 10-year retrospective study of 615 UM patients undergoing liver surveillance in Liverpool. Information was collected from liver scan reports of these patients. RESULTS: Of 615 UM patients analyzed, there were 337 men (55%) and 278 women (45%). Median age at primary treatment was 61 years (range, 22-94). At study end, median follow-up was 5.1 years, with 375 patients (61%) alive and 240 deceased (39%). Of the deceased patients, 187 (78%) died due to metastatic UM; 24 (10%) deaths were due to other causes; and 29 (12%) patients died of unknown conditions. In total, 3854 liver scans were performed in the 615 UM patients, with a median of 6.2 scans per patient (range, 1-40). Liver MRI was most frequently performed (62.8%). In total, 229 (37%) UM patients developed metastases during the study period: 150 were detected via liver surveillance and 79 were observed post-mortem. CONCLUSIONS: Metastatic UM onset is related to the size and genetic profiles of the primary UM, and can be predicted using the model LUMPO3. Regular liver surveillance allowed for timely detection of metastases, and through metastasectomy can lead to prolongation of life in some patients.

Vascular Lakes in Uveal Melanoma and Their Association With Outcome.

Purpose: Prognostic predictors in uveal melanoma (UM) consist of clinical, histomorphologic, and genetic features. Vascular lakes (VLs) are immature blood vessels within UM with unknown significance for metastatic risk. Methods: A clinically well-phenotyped cohort of 136 hematoxylin and eosin-stained slides of UM enucleation specimens were retrospectively analyzed on scanned whole-slide images. These were annotated for VL in QuPath, assessing VL number and area. Using SPSS (V27.0), the Mann-Whitney U test and Cox regression were applied to evaluate whether there was any correlation between VL number and area within the tumor (VL-TA) compared with other prognostic parameters and patient survival times. Results: UMs with monosomy 3 (M3) have significant differences in their VL numbers (P = 0.008) and VL-TA ratios (P = 0.002) compared with disomy 3-UM. Nuclear BAP1-negative (nBAP1-) UMs have significant differences in their VL-TA ratio (P = 0.002) compared to nBAP1+ UMs. Survival times of patients with UM with epithelioid-celled tumors varied depending on their VL-TA ratio (P = 0.057). Similarly, in M3-UM, significant differences in survival (P = 0.009) were seen in patients, depending on VL number. Finally, patients with UM with shorter overall survival showed significant differences in their tumor VL-TA ratios (P = 0.043) and the number of VLs present (P = 0.002) than patients with UM who had longer survival. Conclusions: Our pilot data suggest that VL-TA is an additional poor prognostic parameter in UM. Translational Relevance: Digital analysis of UM can be easily performed to assess various prognostic parameters. Our pilot study demonstrates that UM-VL could be combined with other parameters to determine metastatic risk of patients with UM.

Small High-Risk Uveal Melanomas Have a Lower Mortality Rate.

Our aim was to determine whether size impacts on the difference in metastatic mortality of genetically high-risk (monosomy 3) uveal melanomas (UM). We undertook a retrospective analysis of data from a patient cohort with genetically characterized UM. All patients treated for UM in the Liverpool Ocular Oncology Centre between 2007 and 2014, who had a prognostic genetic tumor analysis. Patients were subdivided into those with small (≤2.5 mm thickness) and large (>2.5 mm thickness) tumors. Survival analyses were performed using Gray rank statistics to calculate absolute probabilities of dying as a result of metastatic UM. The 5-year absolute risk of metastatic mortality of those with small monosomy 3 UM was significantly lower (23%) compared to the larger tumor group (50%) (p = 0.003). Small disomy 3 UM also had a lower absolute risk of metastatic mortality (0.8%) than large disomy 3 UM (6.4%) (p = 0.007). Hazard rates showed similar differences even with lead time bias correction estimates. We therefore conclude that earlier treatment of all small UM, particularly monosomy 3 UM, reduces the risk of metastatic disease and death. Our results would support molecular studies of even small UM, rather than 'watch-and-wait strategies'.

Cost-utility analysis of a decade of liver screening for metastases using the Liverpool Uveal Melanoma Prognosticator Online (LUMPO).

This paper outlines a method for cost-utility analysis of liver screening for metastases in patients with posterior uveal melanoma (UM). A semiparametric model of the cumulative incidence of onset of liver metastases was fitted to a retrospective data set of 615 subjects with clinical follow-up with respect to liver surveillance imaging and outcome. The model was internally validated via bootstrap resampling in terms of its discrimination and calibration performance. Receiver operating characteristics (ROC) were derived at different time points. The discrimination performances are consistent across time. The area under the ROC curve at 5 years post treatment was 0.85 [95% CI: 0.81-0.88]. A goodness-of-fit test gives χ2(10)=5.3,p=0.9 demonstrating no evidence against the null hypothesis of zero difference between observed and expected onset of metastatic events. Results showed that at 80% sensitivity, 87% of UM patients will avoid unnecessary radiological scans. This provides potential cost savings of between £46,000 and £97,000 per year to the National Health Service assuming 600 new cases per year.

Parsimonious Models for Predicting Mortality from Choroidal Melanoma.

Purpose: To develop parsimonious models for estimating metastasis mortality in patients with choroidal melanoma for situations where use of the Liverpool Uveal Melanoma Prognosticator Online (LUMPO) or Tumor, Node, Metastasis (TNM) staging system is not possible. Methods: A backward-selection algorithm identified largest basal tumor diameter (LBTD) and chromosome 3 status (C3S) as the most informative predictors of metastatic death. We defined two prognostic models, based on LBTD with or without known C3S, that took into account competing risks of death from other causes by using the Aalen estimator. The bootstrap procedure was used to estimate discrimination accuracy, expressed by the C-index. Results: The cohort was comprised of 8348 patients with choroidal melanoma, 4174 of whom had known chromosome 3 status; of the 1553 deaths that occurred among these patients, 956 were attributed to metastasis. For LBTD with or without known C3S, the metastatic-death-specific C-indices at 2, 5, and 10 years were 0.85, 0.85, and 0.84 and 0.79, 0.77, and 0.74, respectively, as compared with 0.81, 0.79, and 0.76 for Kaplan-Meier prognostication using the 8th edition of the TNM staging system. Conclusions: We have developed parsimonious models for predicting the absolute risks of metastatic death from choroidal melanoma that take into account competing causes of death and which compare favorably with the current version of the TNM staging system. There is a need for further studies to validate the use of these models in situations where use of the TNM or LUMPO is not possible.

Targeted Next-Generation Sequencing of 117 Routine Clinical Samples Provides Further Insights into the Molecular Landscape of Uveal Melanoma.

Uveal melanoma (UM) has well-characterised somatic copy number alterations (SCNA) in chromosomes 1, 3, 6 and 8, in addition to mutations in GNAQ, GNA11, CYSLTR2, PLCB4, BAP1, SF3B1 and EIF1AX, most being linked to metastatic-risk. To gain further insight into the molecular landscape of UM, we designed a targeted next-generation sequencing (NGS) panel to detect SCNA and mutations in routine clinical UM samples. We compared hybrid-capture and amplicon-based target enrichment methods and tested a larger cohort of primary UM samples on the best performing panel. UM clinical samples processed either as fresh-frozen, formalin-fixed paraffin embedded (FFPE), small intraocular biopsies or following irradiation were successfully profiled using NGS, with hybrid capture outperforming the PCR-based enrichment methodology. We identified monosomy 3 (M3)-UM that were wild-type for BAP1 but harbored SF3B1 mutations, novel frameshift deletions in SF3B1 and EIF1AX, as well as a PLCB4 mutation outside of the hotspot on exon 20 coinciding with a GNAQ mutation in some UM. We observed samples that harboured mutations in both BAP1 and SF3B1, and SF3B1 and EIF1AX, respectively. Novel mutations were also identified in TTC28, KTN1, CSMD1 and TP53BP1. NGS can simultaneously assess SCNA and mutation data in UM, in a reliable and reproducible way, irrespective of sample type or previous processing. BAP1 and SF3B1 mutations, in addition to 8q copy number, are of added importance when determining UM patient outcome.

Multicenter External Validation of the Liverpool Uveal Melanoma Prognosticator Online: An OOG Collaborative Study.

Uveal melanoma (UM) is fatal in ~50% of patients as a result of disseminated disease. This study aims to externally validate the Liverpool Uveal Melanoma Prognosticator Online V3 (LUMPO3) to determine its reliability in predicting survival after treatment for choroidal melanoma when utilizing external data from other ocular oncology centers. Anonymized data of 1836 UM patients from seven international ocular oncology centers were analyzed with LUMPO3 to predict the 10-year survival for each patient in each external dataset. The analysts were masked to the patient outcomes. Model predictions were sent to an independent statistician to evaluate LUMPO3's performance using discrimination and calibration methods. LUMPO3's ability to discriminate between UM patients who died of metastatic UM and those who were still alive was fair-to-good, with C-statistics ranging from 0.64 to 0.85 at year 1. The pooled estimate for all external centers was 0.72 (95% confidence interval: 0.68 to 0.75). Agreement between observed and predicted survival probabilities was generally good given differences in case mix and survival rates between different centers. Despite the differences between the international cohorts of patients with primary UM, LUMPO3 is a valuable tool for predicting all-cause mortality in this disease when using data from external centers.

Effects of plaque brachytherapy and proton beam radiotherapy on prognostic testing: a comparison of uveal melanoma genotyped by microsatellite analysis.

BACKGROUND/AIMS: Proton beam radiotherapy and plaque brachytherapy are commonly applied in primary uveal melanoma (UM); however, their effect on chromosome 3 classification of UM by microsatellite analysis (MSA) for prognostication purposes is unknown, where the tumour is sampled post-irradiation. This study examined the prognostic accuracy of genotyping UM biopsied before or after administration of radiotherapy, by MSA. METHODS: 407 UM patients treated at the Liverpool Ocular Oncology Centre between January 2011 to December 2017, were genotyped for chromosome 3 by MSA; 172 and 176 primary UM were sampled prior to and post irradiation, respectively. RESULTS: Genotyping by MSA was successful in 396/407 (97%) of UM samples (196 males, 211 females; median age of 61 years (range 12 to 93) at primary treatment). There was no demonstrable association between a failure of MSA to produce a chromosome 3 classification and whether radiation was performed pre-biopsy or post-biopsy with an OR of 0.96 (95% CI 0.30 to 3.00, p=0.94). There was no evidence of association (measured as HRs) between risk of metastatic death and sampling of a primary UM before administration of radiotherapy (HR 1.1 (0.49 to 2.50), p=0.81). Monosomy 3 (HR 12.0 (4.1 to 35.0), p<0.001) was significantly associated with increased risk of metastatic death. CONCLUSIONS AND RELEVANCE: This study revealed that successful genotyping of UM using MSA is possible, irrespective of irradiation status. Moreover, we found no evidence that biopsy prior to radiotherapy increases metastatic mortality.

MORTALITY OF PATIENTS WITH UVEAL MELANOMA DETECTED BY DIABETIC RETINOPATHY SCREENING.

PURPOSE: To investigate whether early detection and treatment of uveal melanoma by screening was associated with a lower mortality rate. METHODS: Retrospective assessment of prospectively collected data comparing 132 patients with uveal melanoma referred by the National Diabetic Screening Service with 608 control patients referred through other means. RESULTS: Mean tumor diameter was smaller in the diabetic screening group (11.1 mm vs. 12.5 mm) as was tumor thickness (3.4 mm vs. 5.4 mm). The prevalence of high-risk monosomy 3 was also lower (17/40, 43% vs. 62/110, 56%). Despite a higher rate of systemic comorbidities in the patients diagnosed through screening and despite older age at diagnosis, the 5-year all-cause mortality was similar in both groups (17% vs. 20%); however, the metastatic mortality was lower in the diabetic screening group (11/132, 8% vs. 95/608, 16%). CONCLUSION: Despite higher rates of comorbidities, the patients detected at diabetic screening had a lower 5-year mortality rate. The diabetic screening programme enabled detection and treatment of posterior uveal melanomas at an earlier stage. However, the confounding factors of lead and length time bias are not to be ignored.

Conjunctival melanoma copy number alterations and correlation with mutation status, tumor features, and clinical outcome.

Relatively little is known about the genetic aberrations of conjunctival melanomas (CoM) and their correlation with clinical and histomorphological features as well as prognosis. The aim of this large collaborative multicenter study was to determine potential key biomarkers for metastatic risk and any druggable targets for high metastatic risk CoM. Using Affymetrix single nucleotide polymorphism genotyping arrays on 59 CoM, we detected frequent amplifications on chromosome (chr) 6p and deletions on 7q, and characterized mutation-specific copy number alterations. Deletions on chr 10q11.21-26.2, a region harboring the tumor suppressor genes, PDCD4, SUFU, NEURL1, PTEN, RASSF4, DMBT1, and C10orf90 and C10orf99, significantly correlated with metastasis (Fisher's exact, p ≤ 0.04), lymphatic invasion (Fisher's exact, p ≤ 0.02), increasing tumor thickness (Mann-Whitney, p ≤ 0.02), and BRAF mutation (Fisher's exact, p ≤ 0.05). This enhanced insight into CoM biology is a step toward identifying patients at risk of metastasis and potential therapeutic targets for systemic disease.

Prognostication of metastatic death in uveal melanoma patients: A Markov multi-state model.

BACKGROUND/AIMS: Uveal melanoma is fatal in almost 50% of patients. We previously developed a prognostic model to predict all-cause mortality. The aim of this study was to improve our model by predicting metastatic death as a cause-specific event distinct from other causes of death. METHODS: Patients treated in Liverpool were included if they resided in England, Scotland or Wales and if their uveal melanoma involved the choroid. They were flagged at the National Health Service Cancer Registry, which automatically informed us of the date and cause of death of any deceased patients. A semiparametric Markov multi-state model was fitted. Two different baseline hazard rates were assumed, with state transition-specific covariates. For both failure types, age at treatment and sex were used. For the metastatic death case, these factors were added: anterior margin position, largest basal tumour diameter, tumour thickness, extra-ocular extension, presence of epithelioid melanoma cells, presence of closed connective tissue loops, increased mitotic count, chromosome 3 loss, and chromosome 8q gain. Missing data required a multiple-imputation procedure. RESULTS: The cohort comprised 4161 patients, 893 of whom died of metastastic disease with another 772 dying of other causes. The optimism-corrected, bootstrapped C-index for metastatic death prediction was 0.86, denoting very good discriminative performance. Bootstrapped calibration curves at two and five years also showed very good performance. CONCLUSIONS: Our improved model provides reliable, personalised metastatic death prognostication using clinical, histological and genetic information, and it can be used as a decision support tool to individualize patient care in a clinical environment.

Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma.

Uveal melanoma (UM) is a rare aggressive intraocular tumour with a propensity for liver metastases, occurring in ∼50% of patients. The tumour suppressor BAP1 is considered to be key in UM progression. Herein, we present the largest study to date investigating cellular expression patterns of BAP1 protein in 165 UMs, correlating these patterns to prognosis. Full clinical, histological, genetic, and follow-up data were available for all patients. BAP1 gene sequencing was performed on a subset of 26 cases. An independent cohort of 14 UMs was examined for comparison. Loss of nuclear BAP1 (nBAP1) protein expression was observed in 54% (88/165) UMs. nBAP1 expression proved to be a significant independent prognostic parameter: it identified two subgroups within monosomy 3 (M3) UM, which are known to have a high risk of metastasis. Strikingly, nBAP1-positiveM3 UMs were associated with prolonged survival compared to nBAP1-negative M3 UMs (Log rank, p = 0.014). nBAP1 protein loss did not correlate with a BAP1 mutation in 23% (6/26) of the UMs analysed. Cytoplasmic BAP1 protein (cBAP1) expression was also observed in UM: although appearing 'predominantly diffuse' in most nBAP1-negative UM, a distinct 'focal perinuclear' expression pattern - localized immediately adjacent to the cis Golgi - was seen in 31% (18/59). These tumours tended to carry loss-of-function BAP1 mutations. Our study demonstrates loss of nBAP1 expression to be the strongest prognostic marker in UM, confirming its importance in UM progression. Our data suggest that non-genetic mechanisms account for nBAP1 loss in a small number of UMs. In addition, we describe a subset of nBAP1-negative UM, in which BAP1 is sequestered in perinuclear bodies, most likely within Golgi, warranting further mechanistic investigation.

Prognostic biopsy of choroidal melanoma: an optimised surgical and laboratory approach.

BACKGROUND: Accurate survival prognostication for patients with uveal melanoma (UM) enables effective patient counselling and permits personalised systemic surveillance for the early detection of metastases and, in high-risk patients, enrolment in any trials of systemic adjuvant therapy. The aim of this work is to determine the success of prognostic UM tumour biopsy using an improved surgical approach and optimised sample handling workflow. METHODS: Patients with UM treated by primary radiotherapy between 2011 and 2013 and who underwent a prognostic biopsy with cytology, multiplex ligation-dependent probe amplification and/or microsatellite analysis were included. The main outcomes and measures were success of cytology and genetic studies, and surgical complications. RESULTS: The cohort comprised 232 patients with UM having a median age of 59 years (range, 25-82) at treatment. The median largest basal diameter was 11.4 mm (range, 4.1-20.8) and tumour height was 3.4 mm (range, 0.7-10.3). Ciliary body involvement was noted in 42 cases. Treatment consisted of Ru-106 brachytherapy in 151 cases (65%) and proton beam radiotherapy in 81 cases (35%). With improvements in surgical techniques and laboratory methods over time, cytology success increased from 92% (131/142) to 99% (89/90) and the numbers of samples with sufficient DNA for genetic testing increased from 79% (104/131) to 93% (83/89). Overall, chromosome 3 loss was noted in 64/187 (34%) cases. Surgical complications, including transient localised bleeding, vitreous haemorrhage and retinal perforation, decreased over time. Eight patients required additional surgery. CONCLUSIONS: Improved surgical techniques and laboratory methods yielded successful cytology and genetic information in the majority of cases. PRECIS: Analysis of data from 232 patients with uveal melanoma undergoing prognostic tumour biopsy demonstrated that improved surgical techniques and laboratory methods yielded successful cytology and genetic information in 99% and 89% of cases, respectively.

Variations in the anatomy of the vertebral artery cervical loop segment - a potential predisposing factor for traumatic basal subarachnoid hemorrhage?

Fatal traumatic basal subarachnoid hemorrhage (TBSAH) is a characteristic forensic pathological entity, the investigation of which requires special techniques. In Liverpool, post-mortem room angiography is undertaken, followed by complete removal of the vertebral arteries and histological examination. It has been observed that the arterial anatomy can be highly variable, particularly the length and course of the loop segments located between the C2 vertebra and the dura. In a number of cases of TBSAH the loop segments of torn vessels have appeared relatively short. Having observed this phenomenon subjectively in our case work, a radiological study was undertaken with the aim of quantifying vertebral artery loop anatomy variation in a 'normal' population. Multiphase post-mortem computed tomography angiography (MPMCTA) scans of 98 subjects were reviewed and the lengths of the different portions of the loop segments (foramen magnum to the upper border of C1, between C1 and C2, and the bony foramina themselves) of each vertebral artery were measured using semi-automated vessel analysis software. The measurements obtained provide objective evidence of marked anatomical variation, with some loop segments more than twice the length of others. These results are important because a short vertebral artery loop segment might be a significant factor in predisposing an individual to TBSAH following a blow to the head or neck.

External Validation of the Liverpool Uveal Melanoma Prognosticator Online.

PURPOSE: To validate the Liverpool Uveal Melanoma Prognosticator Online (LUMPO) in a cohort of patients treated at the University of California-San Francisco (UCSF). METHODS: A retrospective chart review was performed of 390 patients treated between 2002 and 2007 for choroidal melanoma at UCSF. Similar patients (n = 1175) treated at the Liverpool Ocular Oncology Centre (LOOC) were included in the study. The data were analyzed using the model previously developed for LUMPO, an online prognostication tool combining multiple prognostic factors. Main outcome measures included all-cause mortality and melanoma-specific mortality. Reliability of the survival estimates in each group of patients was indicated by the C-indices of discrimination and Hosmer-Lemeshow test. RESULTS: Patients treated at UCSF tended to be younger with thicker tumors, and were more likely to receive proton beam radiotherapy as primary treatment compared to patients at LOOC. There were no significance differences with respect to ciliary body involvement, melanoma cytomorphology, and mitotic counts between the two groups. Death occurred in 140/390 (35%) patients from UCSF and 409/1175 (34%) patients from LOOC, with no difference in overall mortality by Kaplan-Meier analysis (log rank test, P = 0.503). For all-cause mortality and melanoma-specific mortality, the C-index of discrimination and Hosmer-Lemeshow test at 5 years after treatment indicated good discrimination performance of the model, with no statistically significant difference between observed and predicted survival. CONCLUSIONS: Despite differences between the two cohorts, external validation in patients treated at UCSF indicates that LUMPO estimated the all-cause and melanoma-specific mortality well.