免疫检查点抑制剂和靶向药物辅助治疗可切除黑素瘤疗效的网状Meta分析

目的通过贝叶斯网状Meta分析评估免疫检查点抑制剂和靶向药物对可切除黑素瘤的治疗效果。方法通过PubMed、Embase和Cochrane数据库检索可切除黑素瘤辅助治疗的随机对照试验。基于风险比, 应用贝叶斯固定效应模型对无复发生存期进行网状Meta分析来评估相对治疗效果。通过StataSE 15和OpenBUGS 3.2.3软件对数据进行综合分析。结果共纳入6篇文章, 包括5 587例患者和7种治疗方法。其中Ⅲ期亚组5 019例, 存在溃疡亚组2 085例, 不存在溃疡亚组2 629例, BRAF突变亚组2 054例;7种治疗分别为手术 + 观察或安慰剂、手术 + dabrafenib联合trametinib辅助治疗、手术 + nivolumab辅助治疗、手术 + ipilimumab辅助治疗、手术 + pembrolizumab辅助治疗、手术 + bevacizumab辅助治疗以及手术 + vemurafenib辅助治疗。在网状Meta分析中, dabrafenib联合trametinib(HR 0.47, 95%CI 0.39 ～ 0.57)、nivolumab(HR 0.49,...     

106例恶性黑素瘤患者应用免疫检查点抑制剂的免疫相关皮肤毒性及护理对策

<正>恶性黑素瘤是临床上常见的恶性肿瘤,发病率呈逐年上升的趋势^[1]。早期病变主要以手术治疗为主,患者可获得满意的临床预后,但对于晚期病变的患者,治疗手段有限,且效果不如人意^[2]。2011年细胞毒T淋巴细胞相关抗原4(cytotoxic T lymphocyte-associated antigen-4,CTLA-4)抑制剂伊匹木单抗(ipilimumab)获批用于治疗晚期恶性肿瘤患者,成为首个可延长转移性恶性黑素瘤患者生存的免疫治疗药物^[3]。     

酪氨酸激酶抑制剂在恶性黑素瘤分子靶向治疗中的进展

恶性黑素瘤是一种异质性肿瘤,不同发病部位或不同组织学类型,可能存在不同的基因和信号转导途径的异常.因此,针对异常基因、信号通路的靶向治疗药物的发明和临床应用为晚期黑素瘤患者的个性化治疗提供了新的选择.中国人最常见的黑素瘤是肢端型,该型黑素瘤中最常见的异常基因是c-kit基因.针对c-kit基因的靶向药物酪氨酸激酶抑制剂在治疗晚期黑素瘤方面已有较多体外研究及临床观察.主要介绍酪氨酸激酶抑制剂中的受体酪氨酸激酶抑制剂、多靶点酪氨酸激酶抑制剂和非受体酪氨酸激酶抑制剂3类药物的药理作用机制及国内外治疗黑素瘤的研究进展,以及酪氨酸激酶抑制剂的常见不良反应.     

黑素瘤的自噬靶向治疗

皮肤恶性黑素瘤是一种起源于黑素细胞且恶性程度很高的肿瘤,对传统的放疗化疗均不敏感.大部分化疗药物是通过诱导凋亡发挥细胞毒作用,但对癌细胞的作用是不足的,因此,人们尝试调控细胞活力,进行其他途径的靶向治疗.虽然自噬对癌症具有促进和抑制的双重作用,但利用自噬进行癌症治疗具有广泛的应用前景.概述自噬在黑素瘤的化疗和免疫疗法中的作用,以期对皮肤恶性黑素瘤的临床诊治提供帮助.     

恶性黑素瘤免疫检查点抑制疗法研究进展

【摘要】 免疫检查点抑制剂在过去几年中已成为许多恶性黑素瘤患者的重要治疗选择,其旨在恢复并促进效应T细胞特异性识别和杀伤肿瘤细胞的功能,系统性增强全身的抗肿瘤免疫反应,对于手术切除后具有高复发风险或处于疾病晚期（不可切除或存在转移）的患者都是较好的治疗选择。目前免疫检查点抑制的主要目标是程序性死亡受体 1与细胞毒性T淋巴细胞相关抗原4,它们分别是中枢和外周免疫耐受的两个关键受体。本文主要讨论不同免疫检查点抑制剂的临床效应、可能存在的药物反应性预测标志物与相关不良反应。     

免疫检查点抑制剂相关的皮肤不良反应

免疫检查点抑制剂是治疗恶性肿瘤的突破,伴随而来的不良事件发生几率也愈来愈多,其中皮肤不良反应是最常见的不良事件之一,常见有非特异性斑丘疹、白癜风和苔藓样皮炎,少见的有大疱性皮肤病和银屑病样皮炎,严重的可以有伴嗜酸性粒细胞增多和系统症状的药疹(DRESS)、Stevens-Johnson综合征(SJS)和中毒性表皮坏死松解症(TEN)等。免疫相关的皮肤不良反应虽然发生率高,但多数为轻度的皮肤不良反应,只有极少数会危及生命。为了限制免疫检查点抑制剂的剂量减量或治疗中断,并防止对患者生活质量造成不良影响,医护人员需要早期认识并正确处置这些不良反应,对于合理调整免疫检查点抑制剂的治疗方案,改善肿瘤患者预后和防范药物不良反应风险有重要的意义。本文就目前免疫相关皮肤不良反应进行综述。     

中国黑素瘤研究进展与新治疗策略

【摘要】 尽管黑素瘤发病率正快速增长,但其在中国所占比例低,肿瘤科医生关注少。黑素瘤患者首诊科室主要是皮肤科,皮肤科医生能综合分析临床诊断、病理诊断、外科治疗和药物治疗,对黑素瘤的诊治具有独特优势。中国学者近年在黑素瘤的细胞死亡调控、表观遗传学修饰、靶向药物耐药、肿瘤微环境和肿瘤免疫调控等方面已获得很大进展。中国独有的一类新药干扰素α-1b不仅可用于Ⅱ、Ⅲ期高危黑素瘤的辅助治疗,对Ⅳ期黑素瘤也有很好的疗效,不良反应远低于干扰素α-2b。与白色人种不同,亚洲人皮肤黑素瘤以肢端型及黏膜型为主。以干扰素α-1b为基础制定联合治疗策略,探索其与程序性死亡受体-配体1抑制剂、靶向药物或血管生成抑制剂等的联合治疗方案,正在为挽救Ⅳ期黑素瘤患者带来希望。     

儿童黑素瘤临床研究进展

儿童黑素瘤较为罕见, 不同亚型的肿瘤存在发病机制的差异。部分肿瘤临床表现并不典型, 成人黑素瘤诊断标准可能不完全适用于儿童。手术是一线治疗手段, 具体切缘范围可小于成人。近年来黑素瘤的免疫治疗、靶向治疗等治疗手段迅速发展, 但相关药物很少获批儿童适应证。儿童黑素瘤治疗的大样本研究也较少, 但有文献报道相关药物的应用。本文综述儿童黑素瘤发病机制、临床表现和治疗的相关进展, 以期为儿童黑素瘤的诊治提供参考。     

肠道菌群与黑素瘤免疫检查点抑制剂治疗的研究进展

越来越多的研究表明, 肠道菌群通过多种机制影响黑素瘤的发展, 且在黑素瘤治疗过程中扮演重要的角色。本文就肠道菌群与黑素瘤发展的关系, 肠道菌群对黑素瘤免疫检查点抑制剂治疗及相关不良反应的影响作一综述。     

黑素瘤的分子发病机制和靶向治疗新进展

黑素瘤是一种皮肤恶性肿瘤,晚期患者预后不良,目前尚无有效的治疗方法。在黑素瘤中可以通过多种途径激活RAS/RAF/MEK/ERK(MAPK)和PI3K/AKT(AKT)两个信号传导通路。本文总结与黑素瘤发病机制最相关的信号传导通路及新的治疗策略。     

黑素瘤免疫检查点抑制剂治疗相关的生物标志物研究进展

近年来免疫检查点抑制剂在黑素瘤的治疗中取得了突破性的进展。但是只有一小部分患者对免疫治疗有持久反应, 且随着联合用药的出现, 免疫相关不良事件的风险和耐药性也在增加。本文对黑素瘤免疫检查点抑制剂疗效标志物的研究进展作一综述, 期望通过精准的预测标志物来筛选免疫治疗的获益人群, 指导个体化临床治疗, 降低耐药性及不良反应。     

免疫检查点抑制剂的皮肤并发症及治疗进展

免疫检查点抑制剂包括细胞毒性T淋巴细胞抗原4抑制剂,如易普利姆玛以及程序性死亡受体1/程序性死亡受体-配体1抑制剂nivolumab、派姆单抗和atezolizumab.随着免疫检查点抑制剂在肿瘤治疗领域应用的逐渐增加,免疫疗法相关不良反应已引起重视,其中最常见是皮肤并发症,主要包括以斑丘疹为代表的皮疹以及瘙痒症等疾病.临床上,对不同皮肤并发症早期诊断和制定正确的治疗方案十分重要,对常出现的以斑丘疹为代表的皮疹、瘙痒症等皮肤并发症应根据皮损的严重程度和临床分级进行监控和管理.     

Intralesional interleukin‐2: A novel option to maximize response to systemic immune checkpoint therapy in loco‐regional metastatic melanoma

The management of metastatic melanoma has been transformed by the development of immune checkpoint inhibitors. However, disease control in patients with extensive locoregional metastases remains a significant challenge. In this context, intralesional interleukin 2 (IL‐2) presents a useful therapeutic option to maximize intratumoural drug concentration and minimize systemic toxicity. The utility of combined intralesional IL‐2 and systemic immune checkpoint therapy, particularly in loco‐regional disease, is unknown. We report the clinical and cellular effects of combined anti‐programmed death‐1 blockade and intralesional IL‐2 therapy in two patients with loco‐regional metastatic melanoma. Combined intralesional and systemic therapy induced a lasting resolution of the injected skin tumors; maintained for up to 2 years. This impressive response was associated with increased PD‐L1 expression and CD8 T cell infiltration. To our knowledge, this is the first report that raises the possibility of a synergistic effect between intralesional IL‐2 and systemic checkpoint inhibition. The lasting remission of injected metastases may be in part due to an altered tumor microenvironment; characterized by increased PD‐L1 expression and increased CD8 T cell infiltration. If this interesting and novel preliminary observation is confirmed in larger studies, combined local and systemic immunotherapy could highlight a novel treatment strategy for extensive loco‐regional disease.     

Oral mucosal toxicities induced by immune checkpoint inhibitors: Clinical features and algorithm management

Immune checkpoint inhibitors (ICIs) have emerged as standard therapies for an increasing number of advanced cancers. Nonspecific immune activation may lead to immune-related adverse events among which dermatological reactions are one of the most prevalent (all-grade incidence ranging from 30 to 60%). Oral mucosal adverse reactions to ICIs are far less common than cutaneous adverse events. However, a spectrum of oral changes with characteristic features has recently emerged, including lichenoid reactions, sicca syndrome, and even autoimmune bullous disorders with oral involvement. Oral changes mainly occur during the first year of treatment, often concurrently with other dermatological changes, and may involve up to 10% of patients under ICI therapies. This article provides a systematic review of the oral changes reported with these therapies based on a rich iconography.     

Challenges in sarcoidosis and sarcoid‐like reactions associated to immune checkpoint inhibitors: A narrative review apropos of a case

Sarcoidosis and sarcoid‐like reactions (SLRs) may develop in association with various malignancies, as well as in association to certain oncologic drugs, including immune checkpoint inhibitors (ICIs). We aimed to perform a narrative review with regard to the development of ICIs‐associated sarcoidosis or SLRs, and to discuss the corresponding diagnostic and therapeutic challenges raised in this scenario. Apropos of a melanoma patient developing SLRs while treated with ipilimumab and nivolumab, we searched for clinically evident, ICIs‐associated sarcoidosis or SLRs in the English literature. We recorded the oncologic characteristics, including type of malignancy and type of ICI, the phenotypic characteristics of sarcoidosis/SLRs, as well as the impact on immunotherapy. Including our patient, we identified 80 ICIs‐associated sarcoidosis or SLRs cases. Both sexes were equally affected (40 F/40 M) and the most common malignancy was melanoma (65/80, 81.3%). Concerning the oncologic treatment, there was a predilection for pembrolizumab (23/80, 28.7%), followed by the ipilimumab/nivolumab combination (21/80, 26.3%), ipilimumab (18/80, 22.5%), nivolumab (16/80, 20.0%). Although in the majority of the cases (52/80, 65.0%) there was no need for systemic prednisolone for the management of sarcoidosis, a significant proportion of patients finally discontinued ICIs treatment (44/80, 55.0%). Phenotypically, sarcoidosis and SLRs highly imitate oncologic progression posing diagnostic difficulties. A therapeutic dilemma is also raised when there is a need for systemic prednisolone, since the latter may jeopardize the therapeutic efficacy of immunotherapy. Sarcoidosis and SLRs, though rare, can present in oncologic patients treated with ICIs. Clinicians should be aware of this possibility and the related diagnostic and therapeutic challenges they have to face in this scenario.     

Malignant melanoma treatment using brachytherapy: Two case reports and 15 case series

Malignant melanoma (MM) is usually resistant to radiotherapy. Brachytherapy may be an option in patients with bleeding or pain, and those in whom surgery is difficult. Brachytherapy has few side effects and can be used in combination with external beam radiotherapy or chemotherapy. We summarize the demographic and clinical characteristics of 15 patients who received brachytherapy for MM at our hospital and describe two of these representative cases. Patient 1 had an approximately 10-mm, dark-red nodule near the external urethral meatus. Excision was not performed to preserve urethral function. A gradual improvement was observed after 48 Gy of remote afterloading system (RALS) brachytherapy and nivolumab therapy. Patient 2 had a 38-mm, black tumor on the vagina. Post-resection, RALS brachytherapy was administered to treat the residual black macule and a lesion quickly disappeared. In all 15 cases, nine patients received radiotherapy for local control and six patients received palliative radiotherapy to reduce symptoms such as bleeding and pain. The irradiation site was the vagina in six patients, lymph node metastasis in five, head and neck in two, skin or subcutaneous metastases in two, and the anus in one. Treatment effect for local control and palliative care was 75% and 83% of patients, respectively. In particular, disappearance of the tumor or disappearance of symptoms was observed in half of the cases of brachytherapy to the vagina. On the other hand, brachytherapy was not very effective for lymph node metastases. Immediately after radiotherapy, eight (53%) patients experienced dermatitis or mucositis. Due to the histological and structural characteristics of mucosal melanoma of the luminal organs, brachytherapy may be an effective therapy. Hence, widespread use of brachytherapy with an appropriate irradiation technique aiming for local control and palliative care in case of unresectable MM should be considered.