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Metastatic disease from uveal melanoma:
treatment options and future prospects
Richard D Carvajal,1 Gary K Schwartz,1 Tongalp Tezel,2 Brian Marr,3
Jasmine H Francis,3 Paul D Nathan4
Division of Hematology/ ABSTRACT ocular melanocytosis and presence of germline
Oncology, Columbia University Uveal melanoma represents ∼85% of all ocular BRCA1-associated protein 1 (BAP1) mutations.8–13
Medical Center, New York,
USA melanomas and up to 50% of patients develop
Department of metastatic disease. Metastases are most frequently Epidemiology/tumour biology
Ophthalmology, Columbia localised to the liver and, as few patients are candidates The molecular profile of uveal melanoma is different
University Medical Center, for potentially curative surgery, this is associated with a from those of cutaneous or mucosal melanomas and
New York, USA
3 poor prognosis. There is currently little published is composed of a number of chromosomal abnormali-
Department of Surgery,
Memorial Sloan Kettering evidence for the optimal management and treatment of ties and somatic gene alterations (figure 1).
Cancer Center, New York, USA metastatic uveal melanoma and the lack of effective Monosomy 3, 1p loss, 1q gain, 6q loss, 6p gain,
Division of Cancer Services, therapies in this setting has led to the widespread use of 8p loss and 8q gain are common chromosomal
Mt Vernon Cancer Centre, systemic treatments for patients with cutaneous abnormalities in uveal melanoma.14 15 Ten-year
Northwood, UK
melanoma. Uveal and cutaneous melanomas are disease-specific mortality rate varies with
Correspondence to intrinsically different diseases and so dedicated abnormality.14 15 Monosomy 3 is observed in
Dr Richard D Carvajal, Division management strategies and therapies for uveal ∼50% of tumours and is associated with metastatic
of Hematology/Oncology, melanoma are much needed. This review explores the disease.16 Simultaneous monosomy 3 and chromo-
Columbia University Medical
biology of uveal melanoma and how this relates to some 8 alterations are associated with a worse
Center, New York,
NY 10032, USA; ongoing trials of targeted therapies in the metastatic prognosis, while the outcome is more promising in disease setting. In addition, we consider the options to patients with tumours harbouring partial mono-
optimise patient management and care. somy 3.16 17
Received 12 May 2016 Oncogenic mutations in genes associated with
Revised 1 August 2016
Accepted 8 August 2016 the G-protein-α subunits GNAQ or GNA11 are
Published Online First observed in ≥80% of primary uveal melanomas
29 August 2016 and are associated with constitutive activation of
Biology of uveal melanoma
signalling pathways including the central oncogenic
Uveal melanoma is the most common primary
RAS/RAF/MEK/ERK (RAS-ERK) pathway;18–20
intraocular malignancy in adults, representing
thereby driving cell proliferation, tumour growth
∼85% of ocular melanomas.1 Remaining ocular
and progression21 22 (figure 1).
melanomas arise from the conjunctiva (∼5%) or
Inactivating BAP1 mutations are found in ∼50%
other sites (∼10%).1 Uveal melanoma is considered
of all cases, most frequently in class 2 metastasising
a rare cancer, representing ∼3%–5% of recorded
disease.13 23 BAP1 encodes the catalytic subunit of
melanoma cases in the USA.1 2 Unlike cutaneous
a nuclear ubiquitin carboxy-terminal hydrolase,
melanoma, the most common subtype, which arises
with various substrates including BRCA1 and
from melanocytes located in the basal layer of the
histone H2A.24 25 Inactivating BAP1 mutations
epidermis,3 uveal melanoma arises from melano-
increase the prometastatic behaviour of uveal mel-
cytes located anywhere in the uveal tract.
anoma cells, although the mechanism by which this
Approximately 85%–90% of cases involve the
occurs remains unknown.24
choroid, while those remaining are localised to the
Mutations associated with a less aggressive behav-
iris or ciliary body.4 5 Cutaneous and uveal melano-
iour include those found in splicing factor 3B
mas are biologically distinct (figure 1) and differ in
subunit 1 (SF3B1) and eukaryotic translation initi-
terms of incidence by gender, race and geographical
ation factor 1A, X-linked (EIF1AX).26 27 These
mutations are mutually exclusive to one another in
19% and 24% of uveal melanomas, respectively.26 27
Incidence Despite this frequency, SF3B1 or EIF1AX mutations
By contrast to rates of cutaneous melanoma, which are found in just 3% of uveal melanomas with
have been steadily increasing since the 1970s,6 the monosomy 3.27 Furthermore, preliminary whole
incidence of uveal melanoma has remained stable genome single-nucleotide polymorphism microarray
for many years.2 7 In the USA, the mean data showed that amplification of CNKSR3, the
age-adjusted incidence is 5.1 per million,2 while product of which is thought to be involved in transe-
incidence in Europe varies with latitude being pithelial sodium transport, correlated with
greater in Northern (≥8 cases per million in improved survival of patients with primary uveal
Norway and Denmark) compared with Southern melanoma.28
To cite: Carvajal RD, (two cases per million in Spain and Italy) Europe.7
Schwartz GK, Tezel T, et al. Risk factors for the development of uveal melan- Prognostication
Br J Ophthalmol oma include Caucasian ethnicity, welding, light eye Survival prognostication takes into account clinical
2017;101:38–44. colour (green or blue), dysplastic naevus syndrome, predictors (basal tumour diameter, tumour
38 Carvajal RD, et al. Br J Ophthalmol 2017;101:38–44. doi:10.1136/bjophthalmol-2016-309034

29 Most histopathological indicators show good correl.48 49 by multiple factors.33–35 Ipilimumab.bmj.38 stage30 with pathological and genetic prognostic factors. Despite being at lower risk. GPCR.39 suggesting that surveillance of at least this dur- that patients find an uncertain prognosis more stressful than a ation should be undertaken. as classified by genomic profiling.51 However. Dacarbazine.29 Treatment options for metastatic disease For those patients who do develop metastatic disease. doi:10.94–101 (Adapted from Vidwans et al102).34 45 46 Review Figure 1 Representation showing the mutations associated with the RAS/RAF/MEK/ERK pathway observed in melanoma.32 temozolomide. thickness. et al.0– on May 17. G-protein coupled receptor. including a striking increase in been developed to combine the clinical tumour.37 with strated very limited clinical activity in treatment-naïve or Carvajal RD. ipilimumab demon- (low metastatic risk) or class 2 (high metastatic risk). patients can be classified as class 1 rates than previously reported. RTK. including tumour size.101:38–44. tic option for treatment of cutaneous melanoma.40 poor one and accurate prognostication allows special care to be targeted at high-risk patients. fotemustine and various One-year survival of patients with metastases is reported to be combinations have been investigated in uveal melanoma with 15%. early identification of patients.40–42 and activity has been adjuvant systemic therapy has been demonstrated to reduce the limited.Published by group. metastasis expression of preferentially expressed antigen in melanoma.47–50 but evidence of a median overall survival (OS) of may be of value and could allow for tailored management of 6. who are at high risk of metastasis noma. a chemotherapeu- Despite the development of effective local therapies. node.bmj. logical predictors (epithelioid melanoma cytomorphology.31 No effective these molecularly distinct diseases. as described experience metastatic disease are class 1. approximately 40% of patients falling into the latter group. The risk of developing metastatic disease is determined delayed and durable in only a minority of patients.41 Response rates of ∼5%–10% have metastatic disease. despite the inherent differences between and up to 50% of patients develop metastases. as recently reviewed by Triozzi and Singh. with reported median survival ranging from 4 to 15 disappointing results to date. receptor tyrosine kinase. a distinct molecular subgroup to those class 1 patients whose ation with metastatic mortality and mathematical methods have disease does not metastasise. Gene expression profiling tests are one way to determine treatment-naïve patients suggested more promising response a patient’s risk of progressing. Genotypic profiling using multiplex ligation-dependent probe Personalised prognostication is a matter of debate between phy. cisplatin. sence of extravascular matrix patterns.1136/bjophthalmol-2016-309034 39 . However. 5-year sur. is Surveillance to identify high-risk patients approved in the USA and Europe for the treatment of advanced.14 About 65% of patients defined as high risk relapse an unpreventable fatal outcome. these patients comprise above. there is as METASTATIC DISEASE yet no proven standard of care. Downloaded from http://bjo. a human monoclonal antibody that blocks the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). patho. has been used vival rates (∼80%) have not changed in the past three decades2 for uveal melanoma. ciliary body involvement. location36 and genetic Preliminary data from the phase II GEM-1 trial in profile. amplification has also proven useful for determining high-risk sicians as many believe that there is no advantage in predicting patients.7 months in these trials suggests that responses could be patients. extraocular spread). treosulfan. Given the poor prognosis associated with the development of unresectable melanoma. high mitotic count per approximately 15% of patients with uveal melanoma who 40 high-power fields) and genetic predictors. Br J Ophthalmol 2017. pre. following the been reported from evaluations in metastatic uveal mela- treatment of primary disease.41 43 44 Other chemotherapeutic regimens including risk of metastasis. 2017 . studies have shown within 5 years.

96)) were not improved with sunitinib over p=0. A second phase I been designed based on our increased understanding of the trial is being developed in which selumetinib will be escalated biology of this disease. OS data were immature at the time oma. There was a numerical phase II DeCOG trial. As selumetinib in combination with the AKT inhibitor patients with metastatic uveal melanoma. Initial assessment of on trial assumptions.43 uveal melanoma (NCT01801358).57 which melanoma.56 a phase II trial in patients with metastatic uveal with selumetinib monotherapy in the phase II trial43 may have melanoma is currently recruiting (NCT02359851). 1. inhibits This was the first clinical trial in uveal melanoma designed with driver mutations in the receptor tyrosine kinase. intent to register a drug product with regulatory bodies. MK2206 reduced cell viability by >50% in multiple metinib resulted in improvements in efficacy outcomes com. assessment of OS was confounded proliferation and induction of apoptosis. SUMIT did not meet its primary end point of PFS by in ≥63% of surgical primary uveal melanoma specimens. dacarbazine in a phase II trial of 74 patients with metastatic 40 Carvajal RD.8 months and median OS was 6.62 to 1. two-sided 95% CI 0.8 months and an uncon- profile of uveal melanoma. potent and highly Review pre-treated patients with metastatic uveal melanoma in the respectively (two-sided p=0. Immunohistochemistry analysis found that c-Kit was expressed However.27). Other trials in the metastatic setting static uveal melanoma was initiated (SUMIT. ARRY-142886).86 to 2. associated with halting of CI 0. HR 0.Published by group.30 to 0. et al. including MEK and protein kinase C and 8 achieved stable disease. respectively (HR. another potent MEK1/2 inhibitor. selumetinib 75 mg twice daily with 2 days off prior to each efforts have been placed on conducting clinical trials that have paclitaxel bolus (EudraCT: 2014-004437-22).61 66 In a phase I trial in advanced oncogenic aberrations of this pathway such as BRAF.58 59 Given the molecular corresponding to a median PFS of 1.35 vs 8. HR.06)).70 metinib compared with 0% with chemotherapy. rafenib in cutaneous melanoma.8 months.61 62 was mas and is associated with a higher risk of metastatic disease.88 months (HR. There is a real need for specifically approved treatments and Further assessment of selumetinib for the treatment of uveal dedicated management strategies in order to improve outcomes melanoma is ongoing in a trial comparing weekly intravenous for patients affected by this difficult-to-manage disease. study design and notably oma who had progressed on ipilimumab reported a median PFS the addition of dacarbazine to selumetinib in SUMIT.09.32). is characterised GNAQ/GNA11 mutations drive the constitutive activation of by different pharmacokinetic properties than selumetinib. The combination also by the crossover of 86% of patients from the chemotherapy arm significantly reduced tumour size in a GNAQ-mutant mouse xeno- to selumetinib. treatment with selu. c-Kit. a phase III trial (n=129) to assess the efficacy of selumetinib in combination with dacarbazine in patients with systemic treatment-naïve meta. Downloaded from http://bjo. doi:10.46 (95% CI 0.65 months (HR.67 No radiographic responses that target downstream components of the molecular pathways were observed.76 vs 3.9 and AKT inhibition is a treatment strategy of interest.49 (95% Nivolumab and pembrolizumab.65 Median PFS was gesting that c-Kit may be important in uveal melanoma tumour not significantly improved in the selumetinib+dacarbazine arm growth. above 75 mg twice daily using an intermittent dosing schedule of 3 days on followed by 4 days off. the corresponding response rates were 3. fully human monoclonal CI 0.1 months treatment with the MEK inhibitor binimetinib (MEK162) and the for selumetinib and chemotherapy. 0.68 correlated with a MEK-dependent gene signature and found to A phase II trial prospectively evaluating the efficacy of trameti- be greater in tumour cells with GNAQ or BRAF mutations than nib with or without the AKT inhibitor GSK2141795 in patients in wild-type cells. uveal melanomas lack the including a longer half-life. vs 7 weeks.The corresponding response rate was 14% with selu.52 metinib+dacarbazine arm (3. HR 0. an oral. MEK inhibitor trials in the metastatic setting Trametinib.59. 2017 .71 The combination of binimetinib and AEB071 is temozolomide or dacarbazine may affect the efficacy of being investigated in a phase Ib/II trial in patients with metastatic selumetinib.78 (95% CI 0.1 months. one-sided Activating somatic mutations in GNAQ led to the constitutive p<0. Based on these promising observations. compared of ∼3 months.1136/bjophthalmol-2016-309034 . two patients achieved 24% tumour reduction driving tumour growth.84)).8 vs CI 0. 1. the RAS-ERK pathway.67 (AZD6244. activation of the downstream PKC pathway PLCβ/PKC/ERK1/2. on May 17. Phosphorylated AKT is observed in >50% of uveal melano- allosteric MEK1/2 inhibitor60 with a short half-life. the activity of PD-1 inhibition in uveal of primary analysis and no further analyses are foreseen based melanoma has not yet been well described. median progression-free survival (PFS) improvement in investigator-determined median PFS in the selu- was 2.001). as it was observed that prior treatment with graft model. Further evaluation of the discrepancies antibodies targeting the programmed cell death 1 (PD-1) recep. No significant Preclinical in vitro models showed a strong sensitivity to synergistic improvement in median OS was observed (11. In a phase II trial in 101 treatment-naïve or pre-treated table 1). led to the differences observed in PFS between the two trials.41 to 1.63 with metastatic uveal melanoma is ongoing (NCT01979523. there is a rationale for treatments firmed overall response rate of 0%. However. of biomarkers are ongoing. GNAQ-mutant uveal melanoma cell lines and reduced tumour pared with chemotherapy (temozolomide or dacarbazine).1% and 0%.69 the combination of MEK Median PFS was significantly improved with selumetinib (15.72 Median PFS (2.However. 95% PKC inhibitor AEB071 (sotrastaurin). trametinib demonstrated limited clinical activity in mediate sensitivity to the BRAF inhibitors vemurafenib and dab. 1. between BICR and investigator-determined PFS and assessment tor are approved in the USA and Europe for advanced melan.bmj. Four patients received treatment (PKC). 16 heavily pre-treated patients with metastatic uveal melanoma.92)) and OS (6.71).64 The multi-targeted tyrosine kinase inhibitor.8 vs 9.36). Br J Ophthalmol 2017.8 vs 2.66.28 to 0. NCT01974752). Given paclitaxel 80 mg/m2 in combination with selumetinib 75 mg and the limited activity of currently approved agents for advanced weekly intravenous paclitaxel 80 mg/m2 in combination with melanoma in the treatment of metastatic uveal melanoma.101:38–44.8 months.53–55 However.48 to 1.bmj. pembrolizumab in seven patients with metastatic uveal melan. Differences in patient population. sug- blinded independent central review (BICR). 95% compared with the placebo+dacarbazine arm (2. sunitinib. two patients received treatment for Reduction of uveal melanoma cell viability with selumetinib ≥40 weeks. for ≥16 weeks.43 volume in mouse xenograft models.

improvements in PFS (4.87 88 A single trial has compared the efficacy cizumab inhibited VEGF activity.83 adjuvant setting has been discussed in excellent prior publica- Although evidence is limited.44 chemotherapy85 and hepatic arterial chemoembolisation. median PFS and OS were 3 the blood supply to the liver to allow direct delivery of high- and 12 months. offered a median OS of 12. et al.6 months for HIA vs 13. phase III trial of PHP with melphalan compared with best respectively.80 stable disease were observed in eight and two patients.86 Bevacizumab is an antiangiogenic agent that targets all iso. PFS and overall response rate with PHP therapy. a uveal alternative care in 93 patients with ocular (88%) or cutaneous melanoma-specific phase II trial comparing cabozantinib with (12%) melanoma demonstrated significantly improved hepatic temozolomide has been initiated (NCT01835145).77 dose chemotherapy.5 months) and response rate (10. disease who had received no prior systemic therapy for regional chemotherapy such as hepatic intra-arterial (HIA) advanced disease. PD-1. In a small trial of 13 patients.101:38–44. intravenous fotemustine).5 vs oma treatments. respectively. reducing primary ocular Review Table 1 Ongoing clinical trials in metastatic uveal melanoma Therapy Mechanism of action Phase Identifier Trial status Selumetinib+paclitaxel MEK1/2 inhibitor+chemotherapy II EudraCT: 2014-004437-22 Recruiting Trametinib+GSK2141795 MEK inhibitor+AKT inhibitor II NCT01979523 Recruiting Binimetinib+AEB071 MEK inhibitor+PKC inhibitor I/II NCT01801358 Recruitment held Cabozantinib MET inhibitor II NCT01835145 Recruiting Vorinostat Histone deacetylase inhibitor II NCT01587352 Recruiting Sorafenib Multi-kinase inhibitor II NCT01377025 Recruitment complete Ganetespib HSP90 inhibitor II NCT01200238 Recruitment held Adoptive T-cell transfer Tumour-infiltrating lymphocytes II NCT01814046 Recruiting AEB071+BYL719 PKC inhibitor+PI3K inhibitor Ib NCT02273219 Recruiting AEB071 PKC inhibitor I NCT01430416 Recruitment complete Pembrolizumab Anti-PD-1 II NCT02359851 Recruiting HSP90.76 No objective responses with HIA versus intravenous chemotherapy. protein kinase C. including rational use of existing cytotoxic disease. corre- hepatocyte growth factor. overex. Although there was anoma growth and suppressing the formation of hepatic no OS benefit (median 14. between HIA and intravenous fotemustine.81 82 A phase II study (NCT01814046) is combination with ipilimumab is being assessed in a phase 0 investigating the use of chemotherapy followed by autologous study (NCT01730157). a fully human monoclonal anti.8 months by crossover.89 A phase III with uveal melanoma has been achieved with cabozantinib.84 information. A non-surgical alter- of 23 patients with uveal melanoma treated as part of a phase II native to IHP is percutaneous hepatic perfusion (PHP).32 Carvajal RD.85 were observed in a phase II trial of the combination of bevaci. beva.1136/bjophthalmol-2016-309034 41 . 50% of patients appear to have to identify patients at risk. At the time of death.bmj.9 months. A trial revealed a median PFS and OS of 4.73 74 In preclinical models. 2017 . tumour-infiltrating lymphocytes with or without high doses of the growth factor interleukin-2 in patients with metastatic Systemic adjuvant therapy ocular melanoma.8 months for micrometastases. MET. however. which is implicated in the sponding to a potential survival benefit of 14 months com- metastasis of uveal melanoma.4%) were observed patients treated with bevacizumab. Adjuvant therapy has not been widely studied in uveal melan- oma and there is little evidence that any approach improves Liver-targeted treatment options patient outcome.78 Clinical activity in patients pared with retrospective controls ( p=0. curative. programmed cell death 1. however. tremelimumab.75 In a retrospective review of uveal melan. partial responses and being stopped early because of futility. the median PFS of 2. Retrospective case studies suggest that surgical resection may be forms of vascular endothelial growth factor (VEGF). preliminary data suggest tions and the readers are referred to these reviews for additional improvements in patient outcomes following hepatic resection.90 in a phase II trial of 11 patients with advanced uveal melanoma.8 and 12. corresponding to a microspheres has also shown benefit for patients with liver 6-month PFS rate of 9. these studies report on highly selected patient pression of VEGF in uveal melanoma results in increased populations and surgery is not suitable for >90% of patients tumour size and angiogenesis. Isolated hepatic perfusion (IHP) involves surgically isolating zumab and temozolomide (n=35). Localised radioembolisation using yttrium-90 (90Y)-labelled However. In a trial of 34 patients with isolated liver Activating mutations of GNAQ and GNA11 upregulate the metastases. Downloaded from http://bjo.029). similar between the two arms. new approaches to adjuvant therapy The liver is the organ most commonly affected by metastatic are being developed. this was confounded body that inhibits CTLA-4. no significant survival benefit was seen in 3.6 months.5% vs 2. OS was More recently.bmj. respect- Adoptive T-cell therapy has shown promise in the treatment ively. the median OS with IHP was 24 months. with liver metastases. a trial comparing IHP with the best alternative care in uveal non-selective dual MET and VEGF inhibitor. fenib is being studied in a phase I trial (NCT01893099) and clinical mouse model. The use of systemic therapy in the metastases exclusively in the liver. approximately 90% of patients and immunotherapeutic regimens using tumour genetic criteria have liver on May 17. However.78 On the basis of these encouraging data. of these. heat shock protein 90. doi:10. PKC. Br J Ophthalmol 2017. and lack of responses led to the trial metastases.1%.79 Subset analysis melanoma is underway (NCT01785316).Published by group.91 The combination of 90Y-labelled microspheres with sora- of metastatic solid cancers and activity in a uveal melanoma pre.

as well as patients eligible for clinical trials. a histopathologist. but is in fact the most UK who experienced delays. a greater percentage of patients in the Uveal melanoma is considered rare. personal fees from treatment surveillance. For example. doi:10. grants from Melanoma Research Foundation. Acknowledgements The authors thank Jon Moran. Br J Ophthalmol 2017. Metastatic disease is of active surveillance and management of patients following associated with a poor prognosis and as such the early identifi- adjuvant therapy has been recommended within the UK Uveal cation of patients at high risk of metastases by genetic analysis Melanoma National Guidelines. 2017 . made up PDN reports personal fees from AstraZeneca. PhD. team with experience in uveal melanoma treatment. multidisciplinary team care will be central to patient oligometastatic disease amenable to surgery or other local ther. grants from Melanoma sultation process should be coordinated by a multidisciplinary Research Alliance. As as a result of the early detection of asymptomatic disease has our understanding of the biology and treatment of this disease been documented. Drafting and critical revision: RDC. apies.14 37 40 TT. BM. personal fees from Janssen. JHF and PDN. personal fees and non-financial life implications throughout their treatment and post.40 Although no survival benefit may allow for personalised management and surveillance.40 Management and surveillance for metastatic uveal melanoma of a medical or clinical oncologist.Published by group.101:38–44. with subsequent referral to a (figure 2). from iMed Comms. The UK guidelines emphasise the importance of consulting Funding AstraZeneca. surveillance allows for the identification of develops. GKS. personal fees from Merck. there are a number of may arise from slow referral times. personal fees from Biogen Idec. or who reported their tumour as common primary intraocular malignancy in adults. management to help optimise outcomes.40 93 They recommend that this con. RDC has received grants. 42 Carvajal RD. expression profiling can be used to identify patients at high risk of developing metastases and guide surveillance decisions Contributors Defining the concept: RDC. ultimately required enucleation. who cation by clinical criteria. the patient at all stages of their treatment. Competing interests RDC received non-financial support from AstraZeneca. outside the submitted work. misdiagnosis or failed detec.40 optometrist or ophthalmologist. personal fees from Thompson Reuters. which are currently being tar- Given the frequent development of metastases. outside the submitted work.1136/bjophthalmol-2016-309034 . a liver surgeon and a clinical nurse. et al.bmj. consideration geted in clinical drug development. Aura Biosciences. support from AstraZeneca. cytogenetic studies and gene provided medical writing support funded by AstraZeneca. benefits and quality of the conduct of this work.39 Risk stratifi. accordingly.5 92 ciated with a variable prognosis. delays in imaging and administrative delays.5 Delays distinct from cutaneous melanoma. ensuring on May 17. underlying somatic gene alterations in uveal melanoma asso- tion of tumours. Delays in treatment at this stage can have implications on preventable morbidity and overall patient SUMMARY outcomes. grants from NIH and grants from ASCO. Downloaded from Review Figure 2 Summary of key points relevant to multidisciplinary team management of uveal melanoma from the UK Uveal Melanoma National Guidelines. an interventional radiolo- In most cases of uveal melanoma. Biologically being misdiagnosed. during duals are fully informed of any risks. specialist ocular oncologist. patients are diagnosed by an gist.

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