Genetic prognostication in uveal melanoma Dogrusöz, Mehmet; Jager, Martine J.
Acta ophthalmologica (Oxford, England),
June 2018, 2018-Jun, 2018-06-00, 20180601, Letnik:
96, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Uveal melanoma (UM) is a rare tumour with a high propensity to metastasize. Although no effective treatment for metastases yet exists, prognostication in UM is relevant for patient counselling, ...planning of follow‐up and stratification in clinical trials. Besides conventional clinicopathologic characteristics, genetic tumour features with prognostic significance have been identified. Non‐random chromosome aberrations such as monosomy 3 and gain of chromosome 8q are strongly correlated with metastatic risk, while gain of chromosome 6p indicates a low risk. Recently, mutations in genes such as BAP1, SF3B1 and EIF1AX have been shown to be related to patient outcome. Genetics of UM is a rapidly advancing field, which not only contributes to the understanding of the pathogenesis of this cancer, but also results in further refinement of prognostication. Concomitantly, advances have been made in the use of genetic tests. New methods for genetic typing of UM have been developed. Despite the considerable progress made recently, many questions remain, such as those relating to the reliability of prognostic genetic tests, and the use of biopsied or previously irradiated tumour tissue for prognostication by genetic testing. In this article, we review genetic prognostic indicators in UM, also comparing available genetic tests, addressing the clinical application of genetic prognostication and discussing future perspectives for improving genetic prognostication in UM.
Updates in Melanoma Tracey, Elisabeth Hamelin; Vij, Alok
Dermatologic clinics,
01/2019, Letnik:
37, Številka:
1
Journal Article
Recenzirano
Skin cancer is reaching epidemic levels in the United States. Recent advances in the understanding of the pathophysiology of melanoma have allowed improved risk stratification in the revised American ...Joint Committee on Cancer (AJCC) criteria, new tests to capture patients at higher risk than their stage may indicate, and new treatments to offer hope and cures to patients with advanced disease.
•Indocyanine green is a photosensitizer approved for clinical use.•Anionic indocyanine green is unstable and hardly permeates through skin.•Topical photodynamic therapy is noninvasive strategy for ...melanoma treatment.•Chitosan-coating of liposomes can protect indocyanine green from degradation.•Chitosan-coated liposomes enhances skin permeation of indocyanine green.
Indocyanine green (ICG) has been used clinically and noticed as a promising candidate for the topical melanoma photodynamic therapy (PDT). Despite its high potentials in topical PDT, the use of ICG has been hampered by the instability in aqueous solution. In the present study, chitosan-coated liposomes were adopted as a formulation strategy which could stabilize and enhance skin permeation of ICG. Chitosan-coating was verified by the significantly increased liposomal size and reversed zeta potential from negative to positive value by positive chitosan coating. Chitosan-coating liposomes protected ICG from degradation while uncoated liposomes did not. Moreover, they significantly increased cellular uptake and photocytotoxicity of ICG in B16-F10 melanoma cells in a chitosan-dependent manner. The skin permeation of ICG was also drastically improved by chitosan-coated liposomes. These findings emphasize the promising potential of ICG-loaded chitosan-coated liposomes for topical PDT of melanoma.
Background
Counterintuitively, more deaths from melanoma occur among patients with thin (T1) primary melanomas (≤ 1 mm) than among those with thick primary melanoma because the great majority present ...with T1 tumors. Therefore, it is important to stratify their risk as accurately as possible to guide their management and follow-up. This study sought to explore the relationship between tumor thickness and prognosis for patients with thin primary melanomas.
Methods
A retrospective, single-institution study investigated 6263 patients with cutaneous melanoma (including 2117 T1 cases) who had a minimum follow-up period of 10 years.
Results
For the entire patient cohort, the 10-year melanoma-specific survival (MSS) rate ranged between 92% for the patients with primary melanomas up to 0.3 mm thick and 32% for those with melanomas thicker than 8 mm. When divided into 25-quantile-thickness groups there was a significant difference in 10-year MSS between the two consecutive groups 0.8 and 0.9 mm; the differences in survival were not significantly different for any other consecutive cut points within the less than or equal to 1 mm thickness range, indicating a biologically-relevant difference in outcome above and below 0.8 mm. For the patients treated initially at the authors’ institution, the 10- and 20-year MSS rates for those with tumors up to 0.8 mm thick were respectively 93.4 and 85.7%, and for tumors 0.9 to 1.0 mm, the rates were respectively 81.1 and 71.4%. Only 29.3% of the T1 patients who died of melanoma were deceased within 5 years.
Conclusions
A naturally occurring thickness cut point of 0.8 mm predicts higher or lower risk for patients with thin primary cutaneous melanomas. Long-term follow-up assessment of patients with T1 melanoma is important because late mortality due to melanoma is more common than early mortality.
Preclinical modeling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAF
in melanoma
. We conducted S1320, a randomized, open-label, phase 2 ...clinical trial (NCT02196181) evaluating whether intermittent dosing of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib improves progression-free survival in patients with metastatic and unresectable BRAF
melanoma. Patients were enrolled at 68 academic and community sites nationally. All patients received continuous dabrafenib and trametinib during an 8-week lead-in period, after which patients with non-progressing tumors were randomized to either continuous or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. The trial has completed accrual and 206 patients with similar baseline characteristics were randomized 1:1 to the two study arms (105 to continuous dosing, 101 to intermittent dosing). Continuous dosing yielded a statistically significant improvement in post-randomization progression-free survival compared with intermittent dosing (median 9.0 months versus 5.5 months, P = 0.064, pre-specified two-sided α = 0.2). Therefore, contrary to the initial hypothesis, intermittent dosing did not improve progression-free survival in patients. There were no differences in the secondary outcomes, including overall survival and the overall incidence of treatment-associated toxicity, between the two groups.
Sentinel-node biopsy, a minimally invasive procedure for regional melanoma staging, was evaluated in a phase 3 trial.
We evaluated outcomes in 2001 patients with primary cutaneous melanomas randomly ...assigned to undergo wide excision and nodal observation, with lymphadenectomy for nodal relapse (observation group), or wide excision and sentinel-node biopsy, with immediate lymphadenectomy for nodal metastases detected on biopsy (biopsy group). Results No significant treatment-related difference in the 10-year melanoma-specific survival rate was seen in the overall study population (20.8% with and 79.2% without nodal metastases). Mean (± SE) 10-year disease-free survival rates were significantly improved in the biopsy group, as compared with the observation group, among patients with intermediate-thickness melanomas, defined as 1.20 to 3.50 mm (71.3 ± 1.8% vs. 64.7 ± 2.3%; hazard ratio for recurrence or metastasis, 0.76; P=0.01), and those with thick melanomas, defined as >3.50 mm (50.7 ± 4.0% vs. 40.5 ± 4.7%; hazard ratio, 0.70; P=0.03). Among patients with intermediate-thickness melanomas, the 10-year melanoma-specific survival rate was 62.1 ± 4.8% among those with metastasis versus 85.1 ± 1.5% for those without metastasis (hazard ratio for death from melanoma, 3.09; P<0.001); among patients with thick melanomas, the respective rates were 48.0 ± 7.0% and 64.6 ± 4.9% (hazard ratio, 1.75; P=0.03). Biopsy-based management improved the 10-year rate of distant disease-free survival (hazard ratio for distant metastasis, 0.62; P=0.02) and the 10-year rate of melanoma-specific survival (hazard ratio for death from melanoma, 0.56; P=0.006) for patients with intermediate-thickness melanomas and nodal metastases. Accelerated-failure-time latent-subgroup analysis was performed to account for the fact that nodal status was initially known only in the biopsy group, and a significant treatment benefit persisted.
Biopsy-based staging of intermediate-thickness or thick primary melanomas provides important prognostic information and identifies patients with nodal metastases who may benefit from immediate complete lymphadenectomy. Biopsy-based management prolongs disease-free survival for all patients and prolongs distant disease-free survival and melanoma-specific survival for patients with nodal metastases from intermediate-thickness melanomas. (Funded by the National Cancer Institute, National Institutes of Health, and the Australia and New Zealand Melanoma Trials Group; ClinicalTrials.gov number, NCT00275496.).
Immunotherapy with PD-1 antibodies has greatly increased prognosis of patients with advanced melanoma. Identifying biomarkers that predict overall survival (OS) and response to immunotherapy is ...important.
OS and best overall response according to RECIST version 1.1 were analysed, and S100B and lactate dehydrogenase (LDH) serum levels were assessed retrospectively in 152 patients treated with anti-PD-1, and in 86 patients treated with anti-PD-1 plus anti-CTLA-4 antibodies at University Hospital Tuebingen, Germany.
In the pembrolizumab group, patients with elevated baseline S100B or LDH exhibited significantly impaired OS compared with patients with normal S100B (1-year OS: 51.1% vs 83.1%, log-rank P < .0001) and normal LDH (1-year OS: 44.4% vs 80.8%, P = .00022), respectively. LDH increases of >25% and S100B increases of >145% compared to baseline were significantly associated with impaired OS (both P < .0001). In patients treated with ipilimumab and nivolumab, baseline S100B and increasing S100B levels of >145% as well as baseline LDH were associated with impaired OS (P < .0001, P = .00060, and P = .0050, respectively), whereas increasing LDH of >25% was not (P = .64).
S100B could serve as a strong baseline marker for OS in melanoma patients receiving anti-PD-1 therapy. Rising S100B levels during the first weeks of therapy could help guide treatment decisions.
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