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The neurotoxic effects of immune checkpoint inhibitor therapy for melanoma. 免疫检查点抑制剂治疗黑色素瘤的神经毒性作用。
IF 3.6 Q1 Medicine Pub Date : 2019-05-31 DOI: 10.2217/mmt-2019-0001
Lavinia Spain, Rachel Wong
The advent of immune checkpoint inhibitors (ICIs), CTLA-4, PD-1 and PD-L1 inhibitors, have dramatically changed outcomes for patients with melanoma and other malignancies [1–3]. With this new class of antineoplastic agents comes a new range of adverse effects. These immune-related adverse events (irAEs) mediated by Tlymphocytes and other mechanisms including enhanced cytokine levels and antibodies [4] are often unpredictable, in contrast to adverse effects seen commonly with cytotoxic chemotherapy. Few of the initial Phase III trials evaluating the role of ICIs in the treatment of melanoma specifically reported immune-related neurotoxicity. When reported, the incidence of grade 3/4 neurotoxicity was low (<2%) [5]. Increasingly, immune-mediated neurological irAEs are being recognized and reported. Clinical presentation is varied and, while usually occurs early on in the course of therapy, in some cases neurological irAEs may occur many months after cessation of ICI therapy [6,7]. Importantly, the morbidity and mortality associated with this toxicity is relatively high. In a series of 613 fatal ICI-associated toxic events reported by Wang et al., 11% of these were attributed to neurological irAEs [8]. A review by Cuzzubbo et al. of neurological irAEs suggests that their incidence is higher with combination CTLA-4/PD-1 inhibition than for either class of agent when used as monotherapy. Interestingly, for monotherapy regimens, the reported rates of any grade neurotoxicity were higher for PD-1 inhibitors compared with CTLA4 inhibitors (anti-CTLA-4 3.8%, anti-PD-1 6.1%, combination therapy 13%). Severe (Grade 3 or 4) irAEs were infrequent, but more common with anti-CTLA-4 (0.7%) than anti-PD1 agents (0.4%). The majority of cases presented early with a median time to onset of 6 weeks [9]. These data are supported by other ‘real-world’ single-center retrospective series of patients treated with anti-CTLA-4 and/or anti-PD1 inhibitors [6] or anti-PD-1 inhibitors alone [10], reporting rates of neurological irAEs of 2.8 and 2.9%, respectively. In the former series, 14% of patients receiving combination therapy had neurological irAEs. In all three series, the clinical presentations were varied, highlighting the need for clinical vigilance when assessing patients for suspected irAEs.
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引用次数: 2
Patient-specific dendritic cell vaccines with autologous tumor antigens in 72 patients with metastatic melanoma 具有自体肿瘤抗原的患者特异性树突状细胞疫苗治疗72例转移性黑色素瘤
IF 3.6 Q1 Medicine Pub Date : 2019-05-31 DOI: 10.2217/mmt-2018-0010
R. Dillman, A. Cornforth, E. McClay, C. Depriest
Aim: Metastatic melanoma patients were treated with patient-specific vaccines consisting of autologous dendritic cells loaded with antigens from irradiated cells from short-term autologous tumor cell lines. Patients & methods: A total of 72 patients were enrolled in a single-arm Phase I/II (NCT00948480) trial or a randomized Phase II (NCT00436930). Results: Toxicity was minimal. Median overall survival (OS) was 49.4 months; 5-year OS 46%. A 5-year OS was 72% for 18 recurrent stage 3 without measurable disease when treated and 53% for 30 stage 4 without measurable disease when treated. A total of 24 patients with measurable stage 4 when treated (median of four prior therapies) had an 18.5 months median OS and 46% 2-year OS. Conclusion: This dendritic cell vaccine was associated with encouraging survival in all three clinical subsets. Clinicaltrial.gov NCT00436930 and NCT00948480.
目的:用患者特异性疫苗治疗转移性黑色素瘤患者,该疫苗由自体树突状细胞组成,该细胞负载来自短期自体肿瘤细胞系的辐照细胞的抗原。患者和方法:共有72名患者参加了一项单臂I/II期(NCT00948480)试验或一项随机II期试验(NCT00436930)。结果:毒性最小。中位总生存期(OS)为49.4个月;5年OS 46%。18例无可测量疾病的复发性3期患者在治疗时的5年OS为72%,30例无可测疾病的4期患者在处理时的5月OS为53%。共有24名可测量的4期患者在接受治疗时(之前四次治疗的中位数)有18.5个月的中位OS和46%的2年OS。结论:该树突状细胞疫苗可促进所有三个临床亚群的存活。Clinicaltrial.gov NCT00436930和NCT00948480。
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引用次数: 9
Re-biopsy of partially sampled thin melanoma impacts sentinel lymph node sampling as well as surgical margins. 部分取样薄黑色素瘤的重新活检影响前哨淋巴结取样和手术边缘。
IF 3.6 Q1 Medicine Pub Date : 2019-04-26 eCollection Date: 2019-06-01 DOI: 10.2217/mmt-2018-0011
Evan S Weitman, Matthew C Perez, Daniel Lee, Youngchul Kim, William Fulp, Vernon K Sondak, Amod A Sarnaik, Ricardo J Gonzalez, Carl W Cruse, Jane L Messina, Jonathan S Zager

Aim: To assess the impact of re-biopsy on partially sampled melanoma in situ (MIS), atypical melanocytic proliferation (AMP) and thin invasive melanoma.

Materials & methods: We retrospectively identified cases of re-biopsied partially sampled neoplasms initially diagnosed as melanoma in situ, AMP or thin melanoma (Breslow depth ≤0.75 mm).

Results & conclusion: Re-biopsy led to sentinel lymph node biopsy (SLNB) in 18.3% of cases. No patients upstaged from AMP or MIS had a positive SLNB. One out of nine (11.1%) initially diagnosed as a thin melanoma ≤0.75 mm, upstaged with a re-biopsy, had a positive SLNB. After re-biopsy 8.5% underwent an increased surgical margin. Selective re-biopsy of partially sampled melanoma with gross residual disease can increase the accuracy of microstaging and optimize treatment regarding surgical margins and SLNB.

目的:评估重新活检对部分取样原位黑色素瘤(MIS)、非典型黑色素细胞增殖(AMP)和薄侵袭性黑色素瘤的影响。材料与方法:我们回顾性地确定了一些重新活检的部分取样肿瘤,最初诊断为原位黑色素瘤、AMP或薄黑色素瘤(Breslow深度≤0.75 mm)。结果与结论:18.3%的病例重新活检导致前哨淋巴结活组织检查(SLNB)。从AMP或MIS中抢出来的患者没有SLNB阳性。九分之一(11.1%)最初诊断为≤0.75 mm的薄黑色素瘤,经重新活检后,SLNB呈阳性。再次活检后,8.5%的患者手术切缘增加。对部分采样的伴有严重残留疾病的黑色素瘤进行选择性重新活检可以提高显微分期的准确性,并优化手术边缘和SLNB的治疗。
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引用次数: 1
Application of CO2 laser evaporation in locally advanced melanoma. CO2激光蒸发在局部晚期黑色素瘤中的应用。
IF 3.6 Q1 Medicine Pub Date : 2019-04-18 eCollection Date: 2019-03-01 DOI: 10.2217/mmt-2018-0008
Otis M Vrielink, Schelto Kruijff, Barbara L van Leeuwen, Jan Ln Roodenburg

Aim: This study aims to investigate the role of CO2 laser evaporation in the treatment of melanoma patients with satellite or in-transit metastases.

Materials & methods: Patients who underwent CO2 laser evaporation were retrospectively included between November 2002 and August 2018. The Sharplan 40C CO2 laser was used with a high pulse wave mode. Data concerning patient and tumor characteristics, CO2 laser evaporation and subsequent therapies were collected.

Results: A total of 26 patients were included. Median duration of local control was 5.5 months. The median number of lesions evaporated per treatment was three (1-16); patients received a median of three (1-19) treatments.

Conclusion: In a selected group of melanoma patients with satellite or in-transit metastases, CO2 laser evaporation should be considered as treatment for local control.

目的:本研究旨在探讨CO2激光蒸发在黑色素瘤伴卫星或中转转移患者治疗中的作用。材料与方法:回顾性纳入2002年11月至2018年8月期间接受CO2激光蒸发治疗的患者。Sharplan 40C CO2激光器采用高脉冲波模式。收集患者及肿瘤特征、CO2激光蒸发及后续治疗等资料。结果:共纳入26例患者。局部控制的中位持续时间为5.5个月。每次治疗中消失的病灶数为3 (1-16);患者平均接受3次(1-19次)治疗。结论:在一组有卫星或传输转移的黑色素瘤患者中,CO2激光蒸发治疗可作为局部控制的治疗方法。
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引用次数: 1
Surveillance imaging for metastasis in high-risk melanoma: importance in individualized patient care and survivorship. 高危黑色素瘤转移监测成像:对个体化患者护理和生存的重要性。
IF 1 Q4 ONCOLOGY Pub Date : 2019-04-18 eCollection Date: 2019-03-01 DOI: 10.2217/mmt-2019-0003
Morganna Freeman, Shachar Laks

Most patients newly diagnosed with melanoma have early-stage disease considered of good prognosis. However, with a risk of recurrence, appropriate follow-up may include surveillance imaging for early relapse detection. Previously, surveillance imaging to detect recurrences was considered unjustified, given the lack of effective treatments. Now, systemic therapies have improved, and patients with low tumor burden may derive benefit from surveillance imaging. Despite this, controversy exists regarding the role of surveillance imaging in early-stage melanoma survivorship, in part reflected by the lack of consensus on specific imaging protocols and broad guidelines. This review discusses published evidence on surveillance imaging to detect metastasis in high-risk melanoma, the need for early recurrence detection and implications for value-based clinical decision-making, survivorship care and multidisciplinary patient management.

大多数新确诊的黑色素瘤患者属于早期疾病,预后良好。然而,由于存在复发风险,适当的随访可能包括监测成像以早期发现复发。以前,由于缺乏有效的治疗方法,人们认为监测成像以检测复发是不合理的。现在,系统性疗法有所改善,肿瘤负担较轻的患者可能会从监测成像中获益。尽管如此,关于监测成像在早期黑色素瘤存活率中的作用仍存在争议,部分原因是对具体的成像方案和广泛的指南缺乏共识。本综述将讨论已发表的有关监测成像检测高危黑色素瘤转移的证据、早期复发检测的必要性以及对基于价值的临床决策、生存期护理和多学科患者管理的影响。
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引用次数: 0
Hypophysitis induced by immune checkpoint inhibitors in a Scottish melanoma population. 苏格兰黑色素瘤人群中免疫检查点抑制剂诱导的垂体炎。
IF 3.6 Q1 Medicine Pub Date : 2019-04-15 eCollection Date: 2019-03-01 DOI: 10.2217/mmt-2018-0009
Khor Zhong Wei, Mark Baxter, Richard Casasola

Aim: This study aims to determine the incidence of all immune-mediated adverse events (IMAEs) with a focus on hypophysitis in patients with metastatic melanoma receiving immune checkpoint inhibitors (ICI).

Methods: 51 patients with metastatic melanoma who received immune checkpoint inhibitors (ipilimumab, pembrolizumab and nivolumab) in Ninewells Hospital, Dundee between 2014 and 2018 were identified. Patient demographic data and outcomes were recorded retrospectively.

Results: A total of 6 patients (11.7%) developed hypophysitis, while 15 patients (29.4%) developed IMAEs. A significant improvement in overall survival (p = 0.03) and progression-free survival (p = 0.041) was seen in patients who developed IMAEs compared with those who did not.

Conclusion: This study demonstrates a high rate of hypophysitis in melanoma patients receiving ipilimumab. Careful monitoring of symptoms is crucial to detect and appropriately manage IMAEs.

目的:本研究旨在确定所有免疫介导的不良事件(imae)的发生率,重点关注接受免疫检查点抑制剂(ICI)治疗的转移性黑色素瘤患者的垂体炎。方法:选取2014年至2018年在邓迪Ninewells医院接受免疫检查点抑制剂(ipilimumab、pembrolizumab和nivolumab)治疗的51例转移性黑色素瘤患者。回顾性记录患者人口统计资料和结果。结果:6例(11.7%)发生垂体炎,15例(29.4%)发生imae。与未发生imae的患者相比,发生imae的患者的总生存期(p = 0.03)和无进展生存期(p = 0.041)有显著改善。结论:本研究表明,接受伊匹单抗治疗的黑色素瘤患者发生垂体炎的几率很高。仔细监测症状对于发现和适当管理imae至关重要。
{"title":"Hypophysitis induced by immune checkpoint inhibitors in a Scottish melanoma population.","authors":"Khor Zhong Wei,&nbsp;Mark Baxter,&nbsp;Richard Casasola","doi":"10.2217/mmt-2018-0009","DOIUrl":"https://doi.org/10.2217/mmt-2018-0009","url":null,"abstract":"<p><strong>Aim: </strong>This study aims to determine the incidence of all immune-mediated adverse events (IMAEs) with a focus on hypophysitis in patients with metastatic melanoma receiving immune checkpoint inhibitors (ICI).</p><p><strong>Methods: </strong>51 patients with metastatic melanoma who received immune checkpoint inhibitors (ipilimumab, pembrolizumab and nivolumab) in Ninewells Hospital, Dundee between 2014 and 2018 were identified. Patient demographic data and outcomes were recorded retrospectively.</p><p><strong>Results: </strong>A total of 6 patients (11.7%) developed hypophysitis, while 15 patients (29.4%) developed IMAEs. A significant improvement in overall survival (p = 0.03) and progression-free survival (p = 0.041) was seen in patients who developed IMAEs compared with those who did not.</p><p><strong>Conclusion: </strong>This study demonstrates a high rate of hypophysitis in melanoma patients receiving ipilimumab. Careful monitoring of symptoms is crucial to detect and appropriately manage IMAEs.</p>","PeriodicalId":44562,"journal":{"name":"Melanoma Management","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2019-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2217/mmt-2018-0009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37358790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 14
Checkpoint inhibitor use in two heart transplant patients with metastatic melanoma and review of high-risk populations. 检查点抑制剂在两例转移性黑色素瘤心脏移植患者中的应用及高危人群的回顾
IF 3.6 Q1 Medicine Pub Date : 2018-10-26 eCollection Date: 2018-12-01 DOI: 10.2217/mmt-2018-0004
Michael J Grant, Nicholas DeVito, April K S Salama

Due to the unique side-effect profile of immune checkpoint inhibitors (ICIs), groups of patients deemed to be at high risk of complications were excluded from trials that proved the efficacy and safety of these agents in patients with various malignancies. Among these excluded patients were those with prior solid organ transplantation, chronic viral infections and pre-existing autoimmune diseases including paraneoplastic syndromes. We present follow-up on a patient from a previously published case report with an orthotopic heart transplantation who was treated with both cytotoxic T-lymphocyte antigen 4 and PD-1 inhibition safely, without organ rejection. Additionally, we describe the case of a patient with a cardiac allograft who also did not experience organ rejection after treatment with pembrolizumab. Through smaller trials, retrospective analyses, case series and individual case reports, we are accumulating initial data on how these agents are tolerated by the aforementioned groups. Our survey of the literature has found more evidence of organ transplant rejection in patients treated with PD-1 inhibitors than those treated with inhibitors of cytotoxic T-lymphocyte antigen 4. Patients with chronic viral infections, especially hepatitis C, seem to have little to no risk of treatment-related increase in serum RNA levels. The literature contains few documented cases of devastating exacerbations of pre-existing autoimmune disease during treatment with ICIs, and flares seem to be easily controlled by immunosuppression in the vast majority of cases. Last, several cases allude to a promising role for disease-specific antibodies and other serum biomarkers in identifying patients at high risk of developing certain immune-related adverse events, detecting subclinical immune-related adverse event onset, and monitoring treatment response to immunosuppressive therapy in patients treated with ICIs. Though these excluded populations have not been well studied in randomized placebo-controlled trials, we may be able to learn and derive hypotheses from the existing observational data in the literature.

由于免疫检查点抑制剂(ICIs)独特的副作用,被认为有高风险并发症的患者组被排除在证明这些药物在各种恶性肿瘤患者中的有效性和安全性的试验之外。在这些被排除的患者中,有既往实体器官移植、慢性病毒感染和既往自身免疫性疾病(包括副肿瘤综合征)的患者。我们对一名接受原位心脏移植的患者进行了随访,该患者接受了细胞毒性t淋巴细胞抗原4和PD-1抑制剂的安全治疗,无器官排斥反应。此外,我们描述了一例心脏同种异体移植患者,在接受派姆单抗治疗后也没有出现器官排斥反应。通过小型试验、回顾性分析、病例系列和个案报告,我们正在积累有关上述人群如何耐受这些药物的初步数据。我们的文献调查发现,与细胞毒性t淋巴细胞抗原抑制剂相比,使用PD-1抑制剂治疗的患者出现器官移植排斥反应的证据更多。慢性病毒感染患者,尤其是丙型肝炎患者,似乎几乎没有与治疗相关的血清RNA水平升高的风险。文献中很少有证据表明,在使用ICIs治疗期间,已有的自身免疫性疾病的破坏性恶化,并且在绝大多数情况下,耀斑似乎很容易通过免疫抑制来控制。最后,一些病例暗示疾病特异性抗体和其他血清生物标志物在识别发生某些免疫相关不良事件的高风险患者,检测亚临床免疫相关不良事件的发生,以及监测接受免疫抑制剂治疗的患者对免疫抑制治疗的治疗反应方面具有很好的作用。虽然这些被排除在外的人群还没有在随机安慰剂对照试验中得到很好的研究,但我们可能能够从文献中现有的观察数据中学习和得出假设。
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引用次数: 20
Combatting mucosal melanoma: recent advances and future perspectives. 抗击粘膜黑色素瘤:最新进展与未来展望。
IF 3.6 Q1 Medicine Pub Date : 2018-10-08 eCollection Date: 2018-09-01 DOI: 10.2217/mmt-2018-0003
Helen Tyrrell, Miranda Payne

Mucosal melanomas are a rare subtype of melanoma and are associated with a particularly poor prognosis. Due to the rarity of the diagnosis, and the pace with which the management of cutaneous melanoma has evolved over recent years, there is little good evidence to guide management and evidence-based clinical guidelines are still in development in the UK. In this review we provide an overview of the management of mucosal melanoma, highlighting the critical differences between cutaneous and mucosal melanomas, before examining recent advances in the systemic treatment of this disease and likely future directions.

粘膜黑色素瘤是黑色素瘤的一种罕见亚型,预后特别差。由于这一诊断的罕见性,以及近年来皮肤黑色素瘤治疗方法的发展速度,目前几乎没有可靠的证据来指导治疗,英国的循证临床指南仍在制定中。在这篇综述中,我们将概述粘膜黑色素瘤的治疗方法,强调皮肤黑色素瘤和粘膜黑色素瘤之间的重要区别,然后再探讨这种疾病的系统治疗方面的最新进展以及未来可能的发展方向。
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引用次数: 0
Next-generation melanoma prevention efforts for overlooked populations and populations with health disparities: a South African perspective. 针对被忽视人群和健康差异人群的下一代黑色素瘤预防工作:南非视角。
IF 3.6 Q1 Medicine Pub Date : 2018-07-10 eCollection Date: 2018-09-01 DOI: 10.2217/mmt-2018-0006
Caradee Y Wright
This commentary was developed from a plenary presentation given at the 4th International UV and Skin Cancer Prevention conference held at Ryerson University in Toronto, Ontario, Canada from the 1–4 May 2018.
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引用次数: 0
Melanoma & nuclear medicine: new insights & advances. 黑色素瘤与核医学:新的见解和进展。
IF 3.6 Q1 Medicine Pub Date : 2018-06-28 DOI: 10.2217/mmt-2017-0022
Andrés Perissinotti, Daphne Dd Rietbergen, Sergi Vidal-Sicart, Ana A Riera, Renato A Valdés Olmos

The contribution of nuclear medicine to management of melanoma patients is increasing. In intermediate-thickness N0 melanomas, lymphoscintigraphy provides a roadmap for sentinel node biopsy. With the introduction of single-photon emission computed tomography images with integrated computed tomography (SPECT/CT), 3D anatomic environments for accurate surgical planning are now possible. Sentinel node identification in intricate anatomical areas (pelvic cavity, head/neck) has been improved using hybrid radioactive/fluorescent tracers, preoperative lymphoscintigraphy and SPECT/CT together with modern intraoperative portable imaging technologies for surgical navigation (free-hand SPECT, portable gamma cameras). Furthermore, PET/CT today provides 3D roadmaps to resect 18F-fluorodeoxyglucose-avid melanoma lesions. Simultaneously, in advanced-stage melanoma and recurrences, 18F-fluorodeoxyglucose-PET/CT is useful in clinical staging and treatment decision as well as in the evaluation of therapy response. In this article, we review new insights and recent nuclear medicine advances in the management of melanoma patients.

核医学对黑色素瘤患者管理的贡献正在增加。在中厚N0黑色素瘤中,淋巴闪烁扫描为前哨淋巴结活检提供了路线图。随着单光子发射计算机断层扫描图像与集成计算机断层扫描(SPECT/CT)的引入,用于精确手术计划的3D解剖环境现在成为可能。使用混合放射性/荧光示踪剂、术前淋巴闪烁扫描和SPECT/CT以及用于手术导航的现代术中便携式成像技术(徒手SPECT、便携式伽马相机),已经改进了复杂解剖区域(盆腔、头部/颈部)的前哨结识别。此外,PET/CT今天提供了切除18F-氟脱氧葡萄糖狂热的黑色素瘤病变的3D路线图。同时,在晚期黑色素瘤和复发中,18F-氟脱氧葡萄糖PET/CT可用于临床分期和治疗决策以及评估治疗反应。在这篇文章中,我们回顾了在黑色素瘤患者管理方面的新见解和最新的核医学进展。
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引用次数: 23
期刊
Melanoma Management
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