Melanoma Schadendorf, Dirk; van Akkooi, Alexander C J; Berking, Carola ...
The Lancet (British edition),
09/2018, Letnik:
392, Številka:
10151
Journal Article
Recenzirano
Cutaneous melanoma causes 55 500 deaths annually. The incidence and mortality rates of the disease differ widely across the globe depending on access to early detection and primary care. Once ...melanoma has spread, this type of cancer rapidly becomes life-threatening. For more than 40 years, few treatment options were available, and clinical trials during that time were all unsuccessful. Over the past 10 years, increased biological understanding and access to innovative therapeutic substances have transformed advanced melanoma into a new oncological model for treating solid cancers. Treatments that target B-Raf proto-oncogene serine/threonine-kinase (BRAF)V600 (Val600) mutations using selected BRAF inhibitors combined with mitogen-activated protein kinase inhibitors have significantly improved response and overall survival. Furthermore, advanced cutaneous melanoma has developed into a prototype for testing checkpoint-modulating agents, which has increased hope for long-term tumour containment and a potential cure. These expectations have been sustained by clinical success with targeted agents and antibodies that block programmed cell-death protein 1 in locoregional disease, which induces prolongation of relapse-free, distant-metastasis-free, and overall survival times.
Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether ...adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations.
In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety.
At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval CI, 0.39 to 0.58; P<0.001). The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P=0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma.
Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 .).
Melanoma has one of the fastest rising incidence rates of any cancer. It accounts for a small percentage of skin cancer cases but is responsible for the majority of skin cancer deaths. Although ...history-taking and visual inspection of a suspicious lesion by a clinician are usually the first in a series of 'tests' to diagnose skin cancer, dermoscopy has become an important tool to assist diagnosis by specialist clinicians and is increasingly used in primary care settings. Dermoscopy is a magnification technique using visible light that allows more detailed examination of the skin compared to examination by the naked eye alone. Establishing the additive value of dermoscopy over and above visual inspection alone across a range of observers and settings is critical to understanding its contribution for the diagnosis of melanoma and to future understanding of the potential role of the growing number of other high-resolution image analysis techniques.
To determine the diagnostic accuracy of dermoscopy alone, or when added to visual inspection of a skin lesion, for the detection of cutaneous invasive melanoma and atypical intraepidermal melanocytic variants in adults. We separated studies according to whether the diagnosis was recorded face-to-face (in-person), or based on remote (image-based), assessment.
We undertook a comprehensive search of the following databases from inception up to August 2016: CENTRAL; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles.
Studies of any design that evaluated dermoscopy in adults with lesions suspicious for melanoma, compared with a reference standard of either histological confirmation or clinical follow-up. Data on the accuracy of visual inspection, to allow comparisons of tests, was included only if reported in the included studies of dermoscopy.
Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated accuracy using hierarchical summary receiver operating characteristic (SROC),methods. Analysis of studies allowing direct comparison between tests was undertaken. To facilitate interpretation of results, we computed values of sensitivity at the point on the SROC curve with 80% fixed specificity and values of specificity with 80% fixed sensitivity. We investigated the impact of in-person test interpretation; use of a purposely developed algorithm to assist diagnosis; observer expertise; and dermoscopy training.
We included a total of 104 study publications reporting on 103 study cohorts with 42,788 lesions (including 5700 cases), providing 354 datasets for dermoscopy. The risk of bias was mainly low for the index test and reference standard domains and mainly high or unclear for participant selection and participant flow. Concerns regarding the applicability of study findings were largely scored as 'high' concern in three of four domains assessed. Selective participant recruitment, lack of reproducibility of diagnostic thresholds and lack of detail on observer expertise were particularly problematic.The accuracy of dermoscopy for the detection of invasive melanoma or atypical intraepidermal melanocytic variants was reported in 86 datasets; 26 for evaluations conducted in person (dermoscopy added to visual inspection), and 60 for image-based evaluations (diagnosis based on interpretation of dermoscopic images). Analyses of studies by prior testing revealed no obvious effect on accuracy; analyses were hampered by the lack of studies in primary care, lack of relevant information and the restricted inclusion of lesions selected for biopsy or excision. Accuracy was higher for in-person diagnosis compared to image-based evaluations (relative diagnostic odds ratio (RDOR) 4.6, 95% confidence interval (CI) 2.4 to 9.0; P < 0.001).We compared accuracy for (a), in-person evaluations of dermoscopy (26 evaluations; 23,169 lesions and 1664 melanomas),versus visual inspection alone (13 evaluations; 6740 lesions and 459 melanomas), and for (b), image-based evaluations of dermoscopy (60 evaluations; 13,475 lesions and 2851 melanomas),versus image-based visual inspection (11 evaluations; 1740 lesions and 305 melanomas). For both comparisons, meta-analysis found dermoscopy to be more accurate than visual inspection alone, with RDORs of (a), 4.7 (95% CI 3.0 to 7.5; P < 0.001), and (b), 5.6 (95% CI 3.7 to 8.5; P < 0.001). For a), the predicted difference in sensitivity at a fixed specificity of 80% was 16% (95% CI 8% to 23%; 92% for dermoscopy + visual inspection versus 76% for visual inspection), and predicted difference in specificity at a fixed sensitivity of 80% was 20% (95% CI 7% to 33%; 95% for dermoscopy + visual inspection versus 75% for visual inspection). For b) the predicted differences in sensitivity was 34% (95% CI 24% to 46%; 81% for dermoscopy versus 47% for visual inspection), at a fixed specificity of 80%, and predicted difference in specificity was 40% (95% CI 27% to 57%; 82% for dermoscopy versus 42% for visual inspection), at a fixed sensitivity of 80%.Using the median prevalence of disease in each set of studies ((a), 12% for in-person and (b), 24% for image-based), for a hypothetical population of 1000 lesions, an increase in sensitivity of (a), 16% (in-person), and (b), 34% (image-based), from using dermoscopy at a fixed specificity of 80% equates to a reduction in the number of melanomas missed of (a), 19 and (b), 81 with (a), 176 and (b), 152 false positive results. An increase in specificity of (a), 20% (in-person), and (b), 40% (image-based), at a fixed sensitivity of 80% equates to a reduction in the number of unnecessary excisions from using dermoscopy of (a), 176 and (b), 304 with (a), 24 and (b), 48 melanomas missed.The use of a named or published algorithm to assist dermoscopy interpretation (as opposed to no reported algorithm or reported use of pattern analysis), had no significant impact on accuracy either for in-person (RDOR 1.4, 95% CI 0.34 to 5.6; P = 0.17), or image-based (RDOR 1.4, 95% CI 0.60 to 3.3; P = 0.22), evaluations. This result was supported by subgroup analysis according to algorithm used. We observed higher accuracy for observers reported as having high experience and for those classed as 'expert consultants' in comparison to those considered to have less experience in dermoscopy, particularly for image-based evaluations. Evidence for the effect of dermoscopy training on test accuracy was very limited but suggested associated improvements in sensitivity.
Despite the observed limitations in the evidence base, dermoscopy is a valuable tool to support the visual inspection of a suspicious skin lesion for the detection of melanoma and atypical intraepidermal melanocytic variants, particularly in referred populations and in the hands of experienced users. Data to support its use in primary care are limited, however, it may assist in triaging suspicious lesions for urgent referral when employed by suitably trained clinicians. Formal algorithms may be of most use for dermoscopy training purposes and for less expert observers, however reliable data comparing approaches using dermoscopy in person are lacking.
Cytotoxic CD8+ T cells are central to the antitumor immune response by releasing cytotoxic granules that kill tumor cells. They are activated by antigen-presenting cells, which become activated by ...DAMPs (damage associated molecular patterns) through MyD88. However, the suppressive tumor microenvironment promotes T-cell tolerance to tumor antigens, in part by enhancing the activity of immune checkpoint molecules that prevent CD8+ T-cell activation and cytotoxicity. MyD88 limits CD4+ T-cell activation during cardiac adaptation to stress. A similar mechanism is hypothesized to exist in CD8+ T cells that could be modulated to improve antitumor immunity. Herein, adoptive transfer of MyD88−/− CD8+ T cells in melanoma-bearing T-cell–deficient mice resulted in slower tumor growth, greater intratumoral T-cell accumulation, and higher melanoma cell death compared with transfer of wild-type CD8+ T cells. These findings were also observed in T-cell–specific MyD88−/− mice compared with wild-type littermates implanted with melanoma. Mechanistically, deletion of MyD88 enhanced CD8+ T-cell activation and survival, and T-cell receptor induced degranulation of cytotoxic molecules, overall improving the killing of melanoma cells. This enhanced cytotoxicity was retained in mice bearing tumors expressing the specific antigen for which cytotoxic T-cells were restricted. This study’s results demonstrate a conserved mechanism for MyD88 in modulating CD8+ T-cell activation and represent a novel target in improving cancer immunotherapy.
Display omitted
Introduction
Melanoma is the most serious form of skin cancer causing most of the skin cancer-related deaths. The incidence of melanoma has risen so dramatically over past few years that no other ...solid or blood malignancy comes close to it in terms of increased incidence. The main problem associated with the treatment of melanoma is low response rate to the existing treatment modalities, which in turn is due to the incomplete response by chemotherapeutic agents and inherent resistance of melanoma cells.
Materials and Methods
Conventional therapeutic strategies, as well as, recent literature on melanoma have been thoroughly studied. This review summarizes the base of anti-melanoma treatment with conventional chemotherapeutic drugs, followed by an account of recent studies which explored the potential of nanotechnology and newer strategies and agents in melanoma treatment.
Conclusion
Although melanoma is curable if detected in its early localized form, metastatic melanoma continues to be a therapeutic challenge. Metastatic melanoma has a very poor prognosis and conventional therapies have not improved the outcomes of the treatment so far. For this reason, newer combinations of anti-melanoma drugs and newer strategies utilizing nanotechnology have been constantly explored.
For many solid tumors, immune checkpoint blockade therapy has become first line treatment, yet a large proportion of patients with immunologically cold tumors do not benefit due to the paucity of ...tumor infiltrating lymphocytes. Here we show that the orphan G Protein-Coupled Receptor 182 (GPR182) contributes to immunotherapy resistance in cancer via scavenging chemokines that are important for lymphocyte recruitment to tumors. GPR182 is primarily upregulated in melanoma-associated lymphatic endothelial cells (LECs) during tumorigenesis, and this atypical chemokine receptor endocytoses chemokines promiscuously. In GPR182-deficient mice, T cell infiltration into transplanted melanomas increases, leading to enhanced effector T cell function and improved antitumor immunity. Ablation of GPR182 leads to increased intratumoral concentrations of multiple chemokines and thereby sensitizes poorly immunogenic tumors to immune checkpoint blockade and adoptive cellular therapies. CXCR3 blockade reverses the improved antitumor immunity and T cell infiltration characteristic of GPR182-deficient mice. Our study thus identifies GPR182 as an upstream regulator of the CXCL9/CXCL10/CXCR3 axis that limits antitumor immunity and as a potential therapeutic target in immunologically cold tumors.
The recognition and diagnosis of clinically amelanotic or hypomelanotic melanoma is a challenge.
This study aimed to examine the anatomic distribution and risk factors associated with clinically ...amelanotic or hypomelanotic melanoma and compare the survival of patients with clinically amelanotic or hypomelanotic melanoma with that of patients with pigmented melanoma.
A prospective cohort study of all cases of primary invasive melanoma managed at a tertiary referral center was performed.
There were a total of 3913 invasive melanomas, and 384 (9.8%) were clinically amelanotic or hypomelanotic. Skin phototype I; red as well as blonde hair color; actinic keratoses; nodular, desmoplastic, and lentigo maligna subtype; increased Breslow thickness; and mitoses were independently associated with amelanotic or hypomelanotic melanoma (P < .05). After adjustment for subtype and thickness, the face, ears, lateral aspect of the neck, upper portion of the arm, posterior aspect of the forearm, dorsal aspect of the hand, and anterior aspect of the lower portion of the leg were associated with increased odds of amelanotic or hypomelanotic melanoma when compared with the upper portion of the back (P < .05). Mortality risk from melanoma appeared greater for amelanotic or hypomelanotic melanoma than for pigmented melanoma (hazard ratio, 1.5; 95% confidence interval, 1.1-2.1) but was similar once Breslow thickness was taken into account.
Single tertiary referral center.
Although clinically amelanotic or hypomelanotic melanoma can occur on all body sites, it is more common on chronically sun-exposed areas. Clinicians should have an increased index of suspicion in patients with a sun-sensitive skin phenotype, red hair, and associated actinic keratoses.
PDF
