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The inhibitory role of microRNA-141-3p in human cutaneous melanoma growth and metastasis through the fibroblast growth factor 13-mediated mitogen-activated protein kinase axis. 微小RNA-141-3p通过成纤维细胞生长因子13介导的丝裂原活化蛋白激酶轴在人类皮肤黑色素瘤生长和转移中的抑制作用。
IF 2.2 4区 医学 Q3 DERMATOLOGY Pub Date : 2023-12-01 Epub Date: 2023-03-21 DOI: 10.1097/CMR.0000000000000873
Haojan Yang, Jiateng Zhou, Dongdong Li, Shengbo Zhou, Xinyi Dai, Xinchao Du, Hailei Mao, Bin Wang

Human cutaneous melanoma (CM) is a highly invasive malignancy arising from melanocytes, and accompanied by ever-increasing incidence and mortality rates worldwide. Interestingly, microRNAs (miRNAs) possess the ability to regulate CM cell biological functions, resulting in the aggressive progression of CM. Nevertheless, a comprehensive understanding of the underlying mechanism remains elusive. Accordingly, the current study sought to elicit the functional role of miR-141-3p in human CM cells in association with fibroblast growth factor 13 (FGF13) and the MAPK pathway. First, miR-141-3p expression patterns were detected in human CM tissues and cell lines, in addition to the validation of the targeting relationship between miR-141-3p and FGF13. Subsequently, loss- and gain-of-function studies of miR-141-3p were performed to elucidate the functional role of miR-141-3p in the malignant features of CM cells. Intriguingly, our findings revealed that FGF13 was highly expressed, whereas miR-141-3p was poorly expressed in the CM tissues and cells. Further analysis highlighted FGF13 as a target gene of miR-141-3p. Meanwhile, overexpression of miR-141-3p inhibited the proliferative, invasive, and migratory abilities of CM cells, while enhancing their apoptosis accompanied by downregulation of FGF13 and the MAPK pathway-related genes. Collectively, our findings highlighted the inhibitory effects of miR-141-3p on CM cell malignant properties via disruption of the FGF13-dependent MAPK pathway, suggesting a potential target for treating human CM.

人类皮肤黑色素瘤(CM)是一种由黑色素细胞引起的高度侵袭性恶性肿瘤,其发病率和死亡率在全球范围内不断上升。有趣的是,微小RNA(miRNA)具有调节CM细胞生物学功能的能力,导致CM的侵袭性进展。然而,对其潜在机制的全面理解仍然难以捉摸。因此,目前的研究试图引发miR-141-3p在人类CM细胞中与成纤维细胞生长因子13(FGF13)和MAPK途径相关的功能作用。首先,除了验证miR-141-3p和FGF13之间的靶向关系外,还在人类CM组织和细胞系中检测到miR-141-3p的表达模式。随后,对miR-141-3p进行了功能丧失和获得研究,以阐明miR-141-3p在CM细胞恶性特征中的功能作用。有趣的是,我们的研究结果显示,FGF13在CM组织和细胞中高表达,而miR-141-3p在CM组织或细胞中低表达。进一步的分析强调FGF13是miR-141-3p的靶基因。同时,miR-141-3p的过表达抑制了CM细胞的增殖、侵袭和迁移能力,同时增强了其凋亡,同时下调了FGF13和MAPK通路相关基因。总之,我们的研究结果强调了miR-141-3p通过破坏FGF13依赖性MAPK途径对CM细胞恶性特性的抑制作用,这表明它是治疗人类CM的潜在靶点。
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引用次数: 0
pSTAT5 is associated with improved survival in patients with thick or ulcerated primary cutaneous melanoma. pSTAT5与增厚或溃疡原发性皮肤黑色素瘤患者生存率的提高有关
IF 2.2 4区 医学 Q3 DERMATOLOGY Pub Date : 2023-12-01 Epub Date: 2023-08-10 DOI: 10.1097/CMR.0000000000000915
Samuel X Tan, Sharene Chong, Casey Rowe, Magdalena Claeson, James Dight, Chenhao Zhou, Mathieu P Rodero, Maryrose Malt, B Mark Smithers, Adele C Green, Kiarash Khosrotehrani

Identifying prognostic biomarkers to predict clinical outcomes in stage I and II cutaneous melanomas could guide the clinical application of adjuvant and neoadjuvant therapies. We aimed to investigate the prognostic value of phosphorylated signal transducer and activator of transcription 5 (pSTAT5) as a biomarker in early-stage melanoma. This study evaluated all initially staged Ib and II melanoma patients undergoing sentinel node biopsy at a tertiary centre in Brisbane, Australia between 1994 and 2007, with survival data collected from the Queensland Cancer Registry. Primary melanoma tissue from 189 patients was analysed for pSTAT5 level through immunohistochemistry. Cox regression modelling, with adjustment for sex, age, ulceration, anatomical location, and Breslow depth, was applied to determine the association between pSTAT5 detection and melanoma-specific survival. Median duration of follow-up was 7.4 years. High pSTAT5 detection was associated with ulceration and increased tumour thickness. However, multivariate analysis indicated that high pSTAT5 detection was associated with improved melanoma-specific survival (hazard ratio: 0.15, 95% confidence interval: 0.03-0.67) as compared to low pSTAT5 detection. This association persisted when pSTAT5 detection was limited to immune infiltrate or the vasculature, as well as when sentinel node positivity was accounted for. In this cohort, staining for high-pSTAT5 tumours identified a subset of melanoma patients with increased survival outcomes as compared to low-pSTAT5 tumours, despite the former having higher-risk clinicopathological characteristics at diagnosis. pSTAT5 is likely an indicator of local immune activation, and its detection could represent a useful tool to stratify the risk of melanoma progression.

确定预测I期和II期皮肤黑色素瘤临床结果的预后生物标志物可以指导辅助和新辅助治疗的临床应用。我们旨在研究磷酸化信号转导子和转录激活子5(pSTAT5)作为早期黑色素瘤的生物标志物的预后价值。这项研究评估了1994年至2007年间在澳大利亚布里斯班一家三级中心接受前哨淋巴结活检的所有初发Ib和II期黑色素瘤患者,存活数据收集自昆士兰癌症登记处。通过免疫组织化学分析189名患者的原发性黑色素瘤组织的pSTAT5水平。Cox回归模型,对性别、年龄、溃疡、解剖位置和Breslow深度进行了调整,用于确定pSTAT5检测与黑色素瘤特异性生存率之间的关系。中位随访时间为7.4年。高pSTAT5检测与溃疡和肿瘤厚度增加有关。然而,多变量分析表明,与低pSTAT5检测相比,高pSTAT5的检测与黑色素瘤特异性生存率的提高有关(风险比:0.15,95%置信区间:0.03–0.67)。当pSTAT5检测仅限于免疫浸润或血管系统时,以及当前哨淋巴结阳性被考虑时,这种关联持续存在。在该队列中,高pSTAT5肿瘤的染色确定了一组黑色素瘤患者,与低pSTAT5瘤相比,其生存结果增加,尽管前者在诊断时具有更高的风险临床病理特征。pSTAT5可能是局部免疫激活的指标,其检测可能是对黑色素瘤进展风险进行分层的有用工具。
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引用次数: 0
Cost-effectiveness analysis of an orphan drug tebentafusp in patients with metastatic uveal melanoma and a call for value-based pricing. 孤儿药物tebentafusp治疗转移性葡萄膜黑色素瘤患者的成本效益分析和基于价值的定价呼吁。
IF 2.2 4区 医学 Q3 DERMATOLOGY Pub Date : 2023-12-01 Epub Date: 2023-08-25 DOI: 10.1097/CMR.0000000000000919
Shaohong Luo, Chen Xie, Ningning Lin, Dong Lin, Dian Gu, Shen Lin, Xiaoting Huang, Xiongwei Xu, Xiuhua Weng

The normative regimens recommendations for treating metastatic uveal melanoma (mUM) are absent in the US. Recently, a phase III randomized clinical trial revealed that tebentafusp yielded a conspicuously longer overall survival than the control group. Based on the prominent efficacy, this study aimed to assess whether tebentafusp is cost-effective compared to the control group in patients with untreated mUM. A three-state partitioned survival model was developed to assess the costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) from the perspective of US payers. Scenario analyses and sensitivity analyses were conducted to explore the conclusion uncertainty. Compared with control group, tebentafusp therapy yielded an additional 0.47 QALYs (1.19 vs. 0.72 QALYs) and an incremental cost of $444 280 ($633 822 vs. $189 542). The resultant ICER of $953 230/QALY far outweighed the willingness-to-pay threshold of $200 000/QALY. The ICER was always more than $750 000/QALY in all the univariable and probabilistic sensitivity analyses. Scenario analyses indicated that reducing the unit price of tebentafusp to $33.768/µg was associated with a favorable result of tebentafusp being cost-effective. For treatment-naive patients with mUM, the cost of tebentafusp therapy was not worth the improvement in survival benefits at the current price compared to the investigator's choice of therapy. The cost-effectiveness of tebentafusp could be promoted using value-based pricing.

美国缺乏治疗转移性葡萄膜黑色素瘤(mUM)的规范方案建议。最近,一项III期随机临床试验显示,tebentafusp的总生存期明显长于对照组。基于显著的疗效,本研究旨在评估在未经治疗的mUM患者中,与对照组相比,tebentafusp是否具有成本效益。开发了一个三州分割生存模型,从美国支付者的角度评估成本、质量调整寿命(QALYs)和增量成本效益比(ICER)。对结论的不确定性进行了情景分析和敏感性分析。与对照组相比,tebentafusp治疗产生了0.47个额外的QALYs(1.19对0.72个QALYs)和444美元的增量成本 280(633美元 822美元对189美元 542)。由此产生的953美元的ICER 230/QALY远远超过了200美元的支付门槛 000/QALY。ICER总是超过750美元 000/QALY。情景分析表明,将tebentafusp的单价降至33.768/µg与tebentausp具有成本效益的有利结果有关。对于未接受治疗的mUM患者,与研究者的治疗选择相比,以目前的价格计算,替本他福普治疗的成本不值得提高生存效益。可以使用基于价值的定价来提高tebentafusp的成本效益。
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引用次数: 0
The combination of PAC-1 and entrectinib for the treatment of metastatic uveal melanoma. PAC-1和恩特替尼联合治疗转移性葡萄膜黑色素瘤。
IF 2.2 4区 医学 Q3 DERMATOLOGY Pub Date : 2023-12-01 Epub Date: 2023-09-22 DOI: 10.1097/CMR.0000000000000927
Matthew W Boudreau, Emily J Tonogai, Claire P Schane, Min X Xi, James H Fischer, Jayanthi Vijayakumar, Yan Ji, Theodore M Tarasow, Timothy M Fan, Paul J Hergenrother, Arkadiusz Z Dudek

The treatment of metastatic uveal melanoma remains a major clinical challenge. Procaspase-3, a proapoptotic protein and precursor to the key apoptotic executioner caspase-3, is overexpressed in a wide range of malignancies, and the drug PAC-1 leverages this overexpression to selectively kill cancer cells. Herein, we investigate the efficacy of PAC-1 against uveal melanoma cell lines and report the synergistic combination of PAC-1 and entrectinib. This preclinical activity, tolerability data in mice, and the known clinical effectiveness of these drugs in human cancer patients led to a small Phase 1b study in patients with metastatic uveal melanoma. The combination of PAC-1 and entrectinib was tolerated with no treatment-related grade ≥3 toxicities in these patients. The pharmacokinetics of entrectinib were not affected by PAC-1 treatment. In this small and heavily pretreated initial cohort, stable disease was observed in four out of six patients, with a median progression-free survival of 3.38 months (95% CI 1.6-6.5 months). This study is an initial demonstration that the combination of PAC-1 and entrectinib may warrant further clinical investigation. Clinical trial registration: Clinical Trials.gov: NCT04589832.

转移性葡萄膜黑色素瘤的治疗仍然是一个主要的临床挑战。原凋亡蛋白酶-3是一种促凋亡蛋白,也是关键凋亡执行子胱天蛋白酶-3的前体,在多种恶性肿瘤中过表达,药物PAC-1利用这种过表达选择性杀死癌症细胞。在此,我们研究了PAC-1对葡萄膜黑色素瘤细胞系的疗效,并报道了PAC-1和恩特替尼的协同组合。这种临床前活性、小鼠耐受性数据以及这些药物在人类癌症患者中的已知临床有效性导致了对转移性葡萄膜黑色素瘤患者的小型1b期研究。PAC-1和恩曲替尼的联合用药在这些患者中具有耐受性,且无治疗相关等级≥3的毒性。恩曲替尼的药代动力学不受PAC-1治疗的影响。在这个经过大量预处理的小型初始队列中,六分之四的患者病情稳定,中位无进展生存期为3.38个月(95%CI 1.6-6.5个月)。这项研究初步证明,PAC-1和恩特替尼的组合可能需要进一步的临床研究。临床试验注册:Clinical Trials.gov:NCT04589832。
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引用次数: 0
Estimating survival in patients with melanoma brain metastases: prognostic value of lactate dehydrogenase. 评估黑色素瘤脑转移患者的生存率:乳酸脱氢酶的预后价值。
IF 2.2 4区 医学 Q3 DERMATOLOGY Pub Date : 2023-10-01 Epub Date: 2023-07-03 DOI: 10.1097/CMR.0000000000000907
Giacomo Pelizzari, Elisa Bertoli, Silvia Buriolla, Maria Grazia Vitale, Debora Basile, Lorenza Palmero, Diego Zara, Donatella Iacono, Freschi Andrea, Gaetano Pascoletti, Silvia Bolzonello, Mattia Garutti, Gianpiero Fasola, Fabio Puglisi, Alessandro Marco Minisini

Patients with melanoma brain metastases (MBM) have poor prognosis, albeit advances in locoregional and systemic treatments. The melanoma-specific Graded Prognostic Assessment (GPA) effectively stratifies survival for patients with MBM. Nevertheless, lactate dehydrogenase (LDH), a well known prognostic factor for patients with melanoma, is not represented in the GPA scores and might add prognostic information for patients with MBM. In this study, 150 consecutive patients with MBM were retrospectively analyzed with the aim of evaluating independent prognostic factors for MBM patients, including LDH. Furthermore, we implemented a disease-specific prognostic score and estimated survival according to treatment modalities. On the basis of multivariable Cox regression analyses, six prognostic factors (age, BRAF status, number of MBM, number of extracranial metastatic sites, performance status, and LDH level) resulted statistically significant in terms of survival and were combined in a prognostic score to stratify patients in distinct prognostic groups ( P  < 0.0001). Among treatment modalities, a multimodal approach with stereotactic radiosurgery or neurosurgery associated with systemic therapy showed the best outcome (median overall survival: 12.32 months, 95% confidence interval, 7.92-25.30). This is the first study to demonstrate that LDH has independent prognostic value for patients with MBM and might be used to improve prognostic stratification, albeit external validation is mandatory. Survival of patients with MBM is affected by both disease-specific risk factors and treatment modalities, with locoregional treatments associated with better outcomes.

黑色素瘤脑转移(MBM)患者预后不佳,尽管局部和全身治疗取得了进展。黑色素瘤特异性分级预后评估(GPA)有效地对MBM患者的生存率进行了分层。然而,乳酸脱氢酶(LDH)是黑色素瘤患者的一个众所周知的预后因素,在GPA评分中没有表现出来,可能会增加MBM患者的预后信息。在本研究中,对150例连续的MBM患者进行了回顾性分析,目的是评估MBM患者的独立预后因素,包括LDH。此外,我们根据治疗方式进行了疾病特异性预后评分和估计生存率。在多变量Cox回归分析的基础上,六个预后因素(年龄、BRAF状态、MBM数量、颅外转移部位数量、表现状态和LDH水平)在生存率方面具有统计学意义,并结合预后评分将患者分为不同的预后组(P
{"title":"Estimating survival in patients with melanoma brain metastases: prognostic value of lactate dehydrogenase.","authors":"Giacomo Pelizzari,&nbsp;Elisa Bertoli,&nbsp;Silvia Buriolla,&nbsp;Maria Grazia Vitale,&nbsp;Debora Basile,&nbsp;Lorenza Palmero,&nbsp;Diego Zara,&nbsp;Donatella Iacono,&nbsp;Freschi Andrea,&nbsp;Gaetano Pascoletti,&nbsp;Silvia Bolzonello,&nbsp;Mattia Garutti,&nbsp;Gianpiero Fasola,&nbsp;Fabio Puglisi,&nbsp;Alessandro Marco Minisini","doi":"10.1097/CMR.0000000000000907","DOIUrl":"10.1097/CMR.0000000000000907","url":null,"abstract":"<p><p>Patients with melanoma brain metastases (MBM) have poor prognosis, albeit advances in locoregional and systemic treatments. The melanoma-specific Graded Prognostic Assessment (GPA) effectively stratifies survival for patients with MBM. Nevertheless, lactate dehydrogenase (LDH), a well known prognostic factor for patients with melanoma, is not represented in the GPA scores and might add prognostic information for patients with MBM. In this study, 150 consecutive patients with MBM were retrospectively analyzed with the aim of evaluating independent prognostic factors for MBM patients, including LDH. Furthermore, we implemented a disease-specific prognostic score and estimated survival according to treatment modalities. On the basis of multivariable Cox regression analyses, six prognostic factors (age, BRAF status, number of MBM, number of extracranial metastatic sites, performance status, and LDH level) resulted statistically significant in terms of survival and were combined in a prognostic score to stratify patients in distinct prognostic groups ( P  < 0.0001). Among treatment modalities, a multimodal approach with stereotactic radiosurgery or neurosurgery associated with systemic therapy showed the best outcome (median overall survival: 12.32 months, 95% confidence interval, 7.92-25.30). This is the first study to demonstrate that LDH has independent prognostic value for patients with MBM and might be used to improve prognostic stratification, albeit external validation is mandatory. Survival of patients with MBM is affected by both disease-specific risk factors and treatment modalities, with locoregional treatments associated with better outcomes.</p>","PeriodicalId":18550,"journal":{"name":"Melanoma Research","volume":"33 5","pages":"398-405"},"PeriodicalIF":2.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10176585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A glimpse at locally advanced melanomas in the settings of poverty: pathologist's viewpoint. 贫困环境下局部晚期黑色素瘤的一瞥:病理学家的观点。
IF 2.2 4区 医学 Q3 DERMATOLOGY Pub Date : 2023-10-01 Epub Date: 2023-06-13 DOI: 10.1097/CMR.0000000000000909
Wubshet Assefa, Serkadis Muluye, Andualem Assefa, Yacob Alemu

Cutaneous melanoma is the most aggressive cancer of the skin arising from pigment-producing cells, known as melanocytes. It is notorious for spreading early to distant locations. Survival of patients with melanoma largely depends on the thickness of the lesion at the primary site thus spotting it early is crucial. Early diagnosis of melanoma, with an improved quality of life and treatment outcomes, is being achieved in some developed nations through screening and health education. On the contrary, as practicing pathologists in a resource-scarce country, we frequently encounter patients with locally advanced melanoma manifesting as ulceration, bleeding, fungation, and bone erosion. Several factors, including low socioeconomic status, medical mistrust, inaccessibility of health facilities, and absent screening and surveillance services can be attributed to the delayed diagnosis. Therefore to alleviate the burden and complications caused by the late presentation of cutaneous melanoma, an urgent massive community mobilization, information campaigning, and the provision of accessible basic primary health care are urgently needed.

皮肤黑色素瘤是最具侵袭性的皮肤癌症,由产生色素的细胞,即黑色素细胞引起。它因早期传播到遥远的地方而臭名昭著。黑色素瘤患者的生存在很大程度上取决于原发部位病变的厚度,因此尽早发现病变至关重要。一些发达国家正在通过筛查和健康教育实现黑色素瘤的早期诊断,从而提高生活质量和治疗效果。相反,作为一个资源匮乏的国家的执业病理学家,我们经常遇到局部晚期黑色素瘤患者,表现为溃疡、出血、真菌和骨质侵蚀。一些因素,包括社会经济地位低、医疗不信任、无法获得卫生设施以及缺乏筛查和监测服务,都可归因于诊断延迟。因此,为了减轻皮肤黑色素瘤晚期发病造成的负担和并发症,迫切需要大规模的社区动员、信息宣传和提供可获得的基本初级卫生保健。
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引用次数: 0
Analysis of circulating tumor DNA during checkpoint inhibition in metastatic melanoma using a tumor-agnostic panel. 使用肿瘤不可知小组分析转移性黑色素瘤检查点抑制期间的循环肿瘤DNA。
IF 2.2 4区 医学 Q3 DERMATOLOGY Pub Date : 2023-10-01 Epub Date: 2023-06-12 DOI: 10.1097/CMR.0000000000000903
Judit Kisistók, Ditte Sigaard Christensen, Mads Heilskov Rasmussen, Lone Duval, Ninna Aggerholm-Pedersen, Adam Andrzej Luczak, Boe Sandahl Sorensen, Martin Roelsgaard Jakobsen, Trine Heide Oellegaard, Nicolai Juul Birkbak

Immunotherapy has revolutionized treatment of patients diagnosed with metastatic melanoma, where nearly half of patients receive clinical benefit. However, immunotherapy is also associated with immune-related adverse events, which may be severe and persistent. It is therefore important to identify patients that do not benefit from therapy early. Currently, regularly scheduled CT scans are used to investigate size changes in target lesions to evaluate progression and therapy response. This study aims to explore if panel-based analysis of circulating tumor DNA (ctDNA) taken at 3-week intervals may provide a window into the growing cancer, can be used to identify nonresponding patients early, and determine genomic alterations associated with acquired resistance to checkpoint immunotherapy without analysis of tumor tissue biopsies. We designed a gene panel for ctDNA analysis and sequenced 4-6 serial plasma samples from 24 patients with unresectable stage III or IV melanoma and treated with first-line checkpoint inhibitors enrolled at the Department of Oncology at Aarhus University Hospital, Denmark. TERT was the most mutated gene found in ctDNA and associated with a poor prognosis. We detected more ctDNA in patients with high metastatic load, which indicates that more aggressive tumors release more ctDNA into the bloodstream. Although we did not find evidence of specific mutations associated with acquired resistance, we did demonstrate in this limited cohort of 24 patients that untargeted, panel-based ctDNA analysis has the potential to be used as a minimally invasive tool in clinical practice to identify patients where the benefits of immunotherapy outweigh the drawbacks.

免疫疗法彻底改变了被诊断为转移性黑色素瘤患者的治疗,近一半的患者从中受益。然而,免疫疗法也与免疫相关的不良事件有关,这些不良事件可能是严重和持续的。因此,尽早识别那些没有从治疗中受益的患者是很重要的。目前,定期安排的CT扫描用于研究靶病变的大小变化,以评估进展和治疗反应。本研究旨在探索以3周为间隔对循环肿瘤DNA(ctDNA)进行的基于面板的分析是否可以提供一个了解癌症生长的窗口,是否可以用于早期识别无反应的患者,并在不分析肿瘤组织活组织检查的情况下确定与检查点免疫疗法获得性耐药性相关的基因组改变。我们设计了一个用于ctDNA分析的基因小组,并对来自丹麦奥胡斯大学医院肿瘤科的24名不可切除的III期或IV期黑色素瘤患者的4-6个系列血浆样本进行了测序,这些患者接受了一线检查点抑制剂的治疗。TERT是ctDNA中发现的突变最多的基因,与预后不良有关。我们在高转移负荷的患者中检测到更多的ctDNA,这表明更具侵袭性的肿瘤会向血液中释放更多的ctDNA。尽管我们没有发现与获得性耐药性相关的特定突变的证据,但我们确实在这个由24名患者组成的有限队列中证明,非靶向的、基于面板的ctDNA分析有潜力在临床实践中用作微创工具,以识别免疫疗法利大于弊的患者。
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引用次数: 0
Combined Mcl-1 and YAP1/TAZ inhibition for treatment of metastatic uveal melanoma. Mcl-1和YAP1/TAZ联合抑制治疗转移性葡萄膜黑色素瘤。
IF 2.2 4区 医学 Q3 DERMATOLOGY Pub Date : 2023-10-01 Epub Date: 2023-07-18 DOI: 10.1097/CMR.0000000000000911
Kseniya A Glinkina, Amina F A S Teunisse, Maria Chiara Gelmi, Jelle de Vries, Martine J Jager, Aart G Jochemsen

Uveal melanoma is the most common intraocular tumor in adults, representing approximately 5% of all melanoma cases. Up to 50% of uveal melanoma patients develop metastases that are resistant to most of the commonly used antineoplastic treatments. Virtually all uveal melanoma tumors harbor activating mutations in GNAQ or GNA11 , encoding Gαq and Gα11, respectively. Constant activity of these proteins causes deregulation of multiple downstream signaling pathways including PKC, MAPK and YAP1/TAZ. While the importance of YAP1 signaling for the proliferation of uveal melanoma has recently been demonstrated, much less is known about the paralog of YAP1 transcriptional coactivator, named TAZ; however, similar to YAP1, TAZ is expected to be a therapeutic target in uveal melanoma. We performed a small-scale drug screen to discover a compound synergistically inhibiting uveal melanoma proliferation/survival in combination with YAP1/TAZ inhibition. We found that the combination of genetic depletion of YAP1/TAZ together with Mcl-1 inhibition demonstrates a synergistic inhibitory effect on the viability of uveal melanoma cell lines. Similarly, indirect attenuation of the YAP1/TAZ signaling pathway with an inhibitor of the mevalonate pathway, that is, the geranyl-geranyl transferase inhibitor GGTI-298, synergizes with Mcl-1 inhibition. This combination could be potentially used as a treatment for metastatic uveal melanoma.

葡萄膜黑色素瘤是成人最常见的眼内肿瘤,约占所有黑色素瘤病例的5%。高达50%的葡萄膜黑色素瘤患者发生转移,对大多数常用的抗肿瘤治疗具有耐药性。事实上,所有葡萄膜黑色素瘤肿瘤都有GNAQ或GNA11的激活突变,分别编码Gαq和Gα11。这些蛋白质的持续活性导致包括PKC、MAPK和YAP1/TAZ在内的多种下游信号通路的失调。虽然YAP1信号传导对葡萄膜黑色素瘤增殖的重要性最近已经得到证实,但对YAP1转录辅激活因子TAZ的旁系知之甚少;然而,与YAP1类似,TAZ有望成为葡萄膜黑色素瘤的治疗靶点。我们进行了小规模的药物筛选,发现了一种与YAP1/TAZ抑制联合协同抑制葡萄膜黑色素瘤增殖/存活的化合物。我们发现,YAP1/TAZ的基因缺失与Mcl-1抑制相结合,对葡萄膜黑色素瘤细胞系的生存能力表现出协同抑制作用。类似地,用甲羟戊酸途径的抑制剂,即香叶基-香叶基转移酶抑制剂GGTI-298间接减弱YAP1/TAZ信号通路,与Mcl-1抑制协同作用。这种组合有可能用于治疗转移性葡萄膜黑色素瘤。
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引用次数: 0
Treatment experience with encorafenib plus binimetinib for BRAF V600-mutant metastatic melanoma: management insights for clinical practice. 安可非尼联合二甲替尼治疗BRAF V600突变转移性黑色素瘤的经验:临床实践的管理见解。
IF 1.5 4区 医学 Q3 DERMATOLOGY Pub Date : 2023-10-01 Epub Date: 2023-08-03 DOI: 10.1097/CMR.0000000000000891
Kourtney Augustyn, Jocelyn Joseph, Anisha B Patel, Azadeh Razmandi, Amatul Noor Ali, Hussein A Tawbi

For patients with locally advanced or metastatic melanoma who have BRAF V600 activating mutations, combination therapy with BRAF and MEK inhibitors is now the standard of care. The combination of encorafenib, a highly selective adenosine triphosphate-competitive BRAF inhibitor, plus binimetinib, a potent, selective, allosteric, non-adenosine triphosphate-competitive MEK1/2 inhibitor, was approved by the US Food and Drug Administration for unresectable or metastatic melanoma with BRAF V600E or V600K mutations based on data from the phase III COLUMBUS study (NCT01909453). Clinical data evaluating BRAF and MEK inhibitor combinations in advanced melanoma indicate a specific profile of adverse events that includes serious retinopathy, skin disorders, and cardiovascular toxicities. Here we provide an overview of the rationale for combining BRAF and MEK inhibitors for the treatment of melanoma, long-term safety results from COLUMBUS, and guidance on managing the most common adverse events associated with this combination based on clinical experience. Proactive and appropriate management of adverse events can allow for longer treatment durations and may result in better treatment outcomes.

对于患有BRAF V600激活突变的局部晚期或转移性黑色素瘤患者,BRAF和MEK抑制剂的联合治疗现在是标准的治疗方法。高选择性三磷酸腺苷竞争性BRAF抑制剂安可非尼与强效、选择性、变构、非三磷酸腺苷竞争力MEK1/2抑制剂二甲替尼的组合,根据COLUMBUS III期研究(NCT01909453)的数据,被美国食品和药物管理局批准用于BRAF V600E或V600K突变的不可切除或转移性黑色素瘤。评估晚期黑色素瘤BRAF和MEK抑制剂组合的临床数据表明,不良事件的具体情况包括严重的视网膜病变、皮肤病和心血管毒性。在此,我们概述了BRAF和MEK抑制剂联合治疗黑色素瘤的基本原理、COLUMBUS的长期安全性结果,以及基于临床经验管理与该联合治疗相关的最常见不良事件的指导。对不良事件进行积极和适当的管理可以延长治疗时间,并可能带来更好的治疗结果。
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引用次数: 0
Adjuvant dabrafenib and trametinib for patients with resected BRAF -mutated melanoma: DESCRIBE-AD real-world retrospective observational study. 达非尼和曲美替尼佐剂治疗BRAF突变黑色素瘤切除患者:DESCRIBE-AD真实世界回顾性观察研究。
IF 1.5 4区 医学 Q3 DERMATOLOGY Pub Date : 2023-10-01 Epub Date: 2023-03-28 DOI: 10.1097/CMR.0000000000000888
José L Manzano, Juan Martin-Liberal, Luis A Fernández-Morales, Gretel Benítez, Javier Medina Martínez, María Quindós, Almudena García-Castaño, Ovidio Fernández, Rocío V Simo, Margarita Majem, Lorena Bellido, Pablo Ayala de Miguel, Begoña Campos, Enrique Espinosa, José A Macías Cerrolaza, Irene Gil-Arnaiz, David Lorente, Alvaro Rodriguez-Lescure, Victor N Perez, Rafael López Castro, María G Gramaje, Teresa Puértolas, Juan F Rodriguez Moreno, Laia Espasa Font, Guillermo Belaustegui Ferrández, Pablo Cerezuela-Fuentes

BRAF and MEK inhibitor, dabrafenib plus trametinib, adjuvant therapy is effective for high-risk resected melanoma patients with BRAF - V600 mutations. However, real-world evidence is limited. We aimed to determine the feasibility of this therapy in routine clinical practice. DESCRIBE-AD, a retrospective observational study, collected real-world data from 25 hospitals in Spain. Histologically confirmed and resected BRAF -mutated melanoma patients aged ≥18 years who were previously treated with dabrafenib plus trametinib adjuvant therapy, were included. The primary objectives were treatment discontinuation rate and time to discontinuation. The secondary objectives included safety and efficacy. From October 2020 to March 2021, 65 patients were included. Dabrafenib and trametinib discontinuation rate due to treatment-related adverse events (TRAEs) of any grade was 9%. Other reasons for discontinuation included patients' decisions (6%), physician decisions (6%), unrelated adverse events (3%), disease progression (5%), and others (5%). The median time to treatment discontinuation was 9 months [95% confidence interval (CI), 5-11]. G3-4 TRAEs occurred in 21.5% of patients, the most common being pyrexia (3%), asthenia (3%), and diarrhoea (3%). Unscheduled hospitalisations and clinical tests occurred in 6 and 22% of patients, respectively. After 20-month median follow-up (95% CI, 18-22), 9% of patients had exitus due to disease progression, with a 12-month relapse-free survival and overall survival rates of 95.3% and 100%, respectively. Dabrafenib and trametinib adjuvant therapy proved effective for melanoma patients in a real-world setting, with a manageable toxicity profile. Toxicity frequencies were low leading to low incidence of unscheduled medical visits, tests, and treatment discontinuations.

BRAF和MEK抑制剂,达非尼加曲美替尼,辅助治疗对BRAF-V600突变的高危切除黑色素瘤患者有效。然而,现实世界的证据是有限的。我们旨在确定这种疗法在常规临床实践中的可行性。DESCRIBE-AD是一项回顾性观察性研究,收集了西班牙25家医院的真实世界数据。年龄≥18岁经组织学证实并切除BRAF突变黑色素瘤患者 包括既往接受达非尼加曲美替尼辅助治疗的患者。主要目标是停药率和停药时间。次要目标包括安全性和有效性。从2020年10月到2021年3月,纳入了65名患者。任何级别的治疗相关不良事件(TRAE)引起的达非尼和曲美替尼停药率为9%。停药的其他原因包括患者的决定(6%)、医生的决定(60%)、无关不良事件(3%)、疾病进展(5%)和其他(5%)。中断治疗的中位时间为9 月[95%置信区间(CI),5-11]。G3-4 TRAE发生在21.5%的患者中,最常见的是发热(3%)、乏力(3%)和腹泻(3%)。非计划住院和临床检查分别发生在6%和22%的患者中。经过20个月的中位随访(95%CI,18-22),9%的患者因疾病进展而退出,12个月无复发生存率和总生存率分别为95.3%和100%。Dabrafenib和trametinib辅助治疗在现实世界中被证明对黑色素瘤患者有效,毒性可控。毒性频率较低,导致计划外就诊、检查和中断治疗的发生率较低。
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Melanoma Research
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