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Is the neutrophil-to-lymphocyte ratio a useful prognostic indicator in melanoma patients? 中性粒细胞与淋巴细胞比值是黑色素瘤患者的有效预后指标吗?
IF 1 Q4 ONCOLOGY Pub Date : 2020-08-25 DOI: 10.2217/mmt-2020-0006
Joshua T Cohen, Thomas J Miner, Michael P Vezeridis

The neutrophil-to-lymphocyte ratio (NLR) is gaining traction as a biomarker with utility in a variety of malignancies including melanoma. Intact lymphocyte function is necessary for tumor surveillance and destruction, and neutrophils play a role in suppressing lymphocyte proliferation and in the induction of lymphocyte apoptosis. Early research in melanoma indicates that in high-risk localized melanoma, a high NLR is correlated with worse overall and disease-free survival. Similarly, in metastatic melanoma treated with both metastasectomy and immunotherapies, an elevated NLR is predictive of shortened overall survival and progression-free survival. Future studies incorporating NLR into more traditional melanoma prognostic markers while employing more granular outcomes, are needed to realize the full potential of NLR.

中性粒细胞与淋巴细胞比值(NLR)作为一种生物标志物,在包括黑色素瘤在内的多种恶性肿瘤中的应用正日益受到重视。完整的淋巴细胞功能是监控和摧毁肿瘤所必需的,而中性粒细胞在抑制淋巴细胞增殖和诱导淋巴细胞凋亡方面发挥作用。对黑色素瘤的早期研究表明,在高风险的局部黑色素瘤中,高 NLR 与较差的总生存期和无病生存期相关。同样,在接受转移灶切除术和免疫疗法的转移性黑色素瘤患者中,NLR升高预示着总生存期和无病生存期的缩短。未来的研究需要将 NLR 纳入更多传统的黑色素瘤预后指标,同时采用更精细的结果,以充分发挥 NLR 的潜力。
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引用次数: 0
Pandemic medicine: the management of advanced melanoma during COVID-19. 大流行医学:COVID-19期间晚期黑色素瘤的管理。
IF 3.6 Q1 Medicine Pub Date : 2020-07-31 DOI: 10.2217/mmt-2020-0012
James R Patrinely, Douglas B Johnson
Amid the COVID-19 pandemic cancer patients present a unique challenge, as they are often immunosuppressed or subject to treatment-related toxicities that may cause severe disease manifestations. The practical impact of the COVID-19 pandemic on the management of advanced melanoma warrants further consideration. Restrictions on the US healthcare system to mitigate COVID-19 transmission have significantly altered melanoma management practices from the initial diagnosis of primary cutaneous disease to systemic treatment for advanced and metastatic presentations. We herein report our experience and recommendations for this patient population, highlighting the importance patient-centered planning based on tumor characteristics, resource availability and the local state of COVID-19 control.
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引用次数: 7
Methylated circulating tumor DNA as a biomarker in cutaneous melanoma. 甲基化循环肿瘤DNA作为皮肤黑色素瘤的生物标志物。
IF 3.6 Q1 Medicine Pub Date : 2020-07-30 DOI: 10.2217/mmt-2020-0010
Russell J Diefenbach, Jenny H Lee, Helen Rizos
The detection and monitoring of circulating tumor DNA (ctDNA) in melanoma using mutation-detection techniques such as droplet digital PCR and targeted next-generation sequencing (NGS) panels has been well documented (reviewed in [1]). In melanoma, baseline ctDNA assessment predicts overall survival of stage III patients and longitudinal assessment predicts response and survival of stage IV patients treated with immune checkpoint inhibitors and targeted therapies [2–4]. ctDNA can also be used to monitor the appearance of treatment-resistant melanoma subclones [2], tumor heterogeneity [5], metabolic tumor burden [6] and differentiates true progression from pseudoprogression in melanoma patients treated with immunotherapy [7]. ctDNA can be detected in approximately 34% of stage III melanoma and 73% of stage IV melanoma [2,4]. Several customized melanoma-associated NGS mutation panels for ctDNA have been described [8,9], and these panels are designed to detect greater than 80% of melanomas with mutant allele frequency detection limits of only 0.1%. These sequencing panels have several limitations, however. They often yield lower coverage of guaninecytosine (GC)-rich DNA regions, and these regions can be extremely informative cancer markers. For instance, the TERT gene has a GC-rich promoter that is mutated in approximately 70% of melanomas [8]. The complete sequencing of large genes (such as the NF1 gene at >8 kb) is also difficult as the increased gene coverage comes at the expense of overall mutation detection sensitivity. Moreover, the significance of many, low-frequency mutations can be unclear and alterations in some genes, including the TP53 tumor suppressor gene, may not reflect tumor biology, but rather clonal hematopoiesis, a common age-associated phenomenon involving the expansion of nucleated blood cells with somatic mutations [10]. An alternative liquid biopsy approach for monitoring cancer, without prior knowledge of somatic mutation profiles, involves the detection of epigenetic DNA changes, such as methylation. Methylation of cytosine residues within CpG islands is important for the regulation of gene expression and is altered during the development and progression of many cancers, including melanoma. Importantly, aberrant methylation of CpG-rich gene promoters can be a very consistent feature of cancer [11] and thus, the analysis of methylated DNA in liquid biopsies is a rapidly emerging area of interest [12]. Patterns of DNA methylation can change during melanoma progression and the analysis of DNA methylation can provide valuable information related to the phenotypic behavior and stage of melanoma [13]. The analysis of ctDNA methylation is challenging due to the low amounts and highly fragmented nature of ctDNA. Typically, most methylation analysis workflows incorporate an initial bisulfite conversion step which preserves methylated cytosines prior to downstream sequencing. With limited amounts of ctDNA, it is imperative that the ef
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引用次数: 6
Melanoma in pregnancy: certainties unborn. 妊娠期黑色素瘤:不确定因素。
IF 3.6 Q1 Medicine Pub Date : 2020-07-30 DOI: 10.2217/mmt-2020-0007
Enrico Zelin, Claudio Conforti, Roberta Giuffrida, Teresa Deinlein, Nicola di Meo, Iris Zalaudek

Melanoma diagnosed during childbearing period or up to 1 year after delivery is defined as pregnancy-associated melanoma (PAM). There is some evidence that PAM has worse prognosis if compared with melanoma in nonpregnant women, although literature is still inconclusive. Many biological mechanisms could explain this behavior, such as hormonal and immune status, increased lymphangiogenesis but also delay in diagnostic and therapeutic management. If PAM is suspected, a prompt excisional biopsy under local anesthesia can be performed regardless of the gestational period. Conversely, additional staging procedures (such as sentinel lymph node biopsy or imaging) and systemic therapy are still debatable during pregnancy. A multidisciplinary tailored approach should be preferred, together with exhaustive counseling of the mother.

在育龄期或产后一年内确诊的黑色素瘤被定义为妊娠相关黑色素瘤(PAM)。有证据表明,与非妊娠期妇女的黑色素瘤相比,妊娠相关性黑色素瘤的预后较差,但目前尚无定论。许多生物学机制可以解释这种情况,如荷尔蒙和免疫状态、淋巴管生成增加以及诊断和治疗管理的延迟。如果怀疑是 PAM,无论妊娠期长短,都可以在局部麻醉下及时进行切除活检。相反,在妊娠期进行额外的分期手术(如前哨淋巴结活检或成像)和全身治疗仍有争议。应首选多学科的定制方法,并对母亲进行详尽的咨询。
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引用次数: 0
An update on GM-CSF and its potential role in melanoma management. GM-CSF及其在黑色素瘤治疗中的潜在作用的最新进展。
IF 3.6 Q1 Medicine Pub Date : 2020-07-29 DOI: 10.2217/mmt-2020-0011
Robert O Dillman

GM-CSF drives the differentiation of granulocytes and monocyte/macrophages from hematopoietic stem cell progenitors. It is required for differentiating monocytes into dendritic cells (DC). Although approved for recovery of granulocytes/monocytes in patients receiving chemotherapy, G-CSF is preferred. Enthusiasm for GM-CSF monotherapy as a melanoma treatment was dampened by two large randomized trials. Although GM-CSF has been injected into tumors for many years, the efficacy of this has not been tested. There is a strong rationale for GM-CSF as a vaccine adjuvant, but it appears of benefit only for strategies that directly involve DCs, such as intratumor talimogene laherparepvec and vaccines in which DCs are loaded with antigen ex vivo and injected admixed with GM-CSF.

GM-CSF驱动粒细胞和单核/巨噬细胞从造血干细胞祖细胞分化。它是单核细胞向树突状细胞(DC)分化所必需的。虽然已批准用于化疗患者的粒细胞/单核细胞恢复,但G-CSF是首选。两项大型随机试验抑制了对GM-CSF单一疗法作为黑色素瘤治疗的热情。虽然GM-CSF已被注射到肿瘤中多年,但其疗效尚未得到检验。GM-CSF作为疫苗佐剂有很强的理论依据,但它似乎只对直接涉及dc的策略有好处,例如肿瘤内的talimogene laherparepvec和将dc体外装载抗原并与GM-CSF混合注射的疫苗。
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引用次数: 11
Laparoscopically assisted ilio-inguinal lymph node dissection versus inguinal lymph node dissection in melanoma. 腹腔镜辅助髂-腹股沟淋巴结清扫与黑色素瘤腹股沟淋巴结清扫。
IF 3.6 Q1 Medicine Pub Date : 2020-07-21 DOI: 10.2217/mmt-2019-0023
Enrique Boldo, Araceli Mayol, Rafael Lozoya, Alba Coret, Diana Escribano, Carlos Fortea, Andres Muñoz, Juan Carlos Pastor, Guillermo Perez De Lucia

Aim: Morbidity of open inguinal lymphadenectomy (OIL) is high. We use laparoscopy for pelvic time, preservation of the greater saphenous vein and transverse inguinal incisions (laparoscopically assisted ilio-inguinal lymphadenectomy, LIIL) to improve postoperative outcomes.

Patients & methods: Retrospective comparison of 14 patients who underwent LIIL and seven patients who underwent OIL.

Results: Fourteen LIIL compared with seven OIL showed a statistically significant reduction in morbidity (15.3 vs 75%) and hospital stay (7 vs 15.7 days). Pelvic lymph node involvement (27%) was not detected preoperatively. With a mean follow-up of 36.2 (range: 3-137) months, local recurrence rate was 58.3% in LIIL and 40% in OIL. Overall survival was significantly higher in OIL than in LIIL.

Conclusion: Compared with OIL, LIIL reduced postoperative complications and hospital stay.

目的:开放式腹股沟淋巴结切除术(OIL)的发病率高。我们使用腹腔镜检查盆腔时间,保留大隐静脉和腹股沟横切口(腹腔镜辅助髂-腹股沟淋巴结切除术,LIIL)来改善术后预后。患者与方法:回顾性比较14例LIIL患者和7例OIL患者。结果:14例LIIL与7例OIL相比,发病率(15.3 vs 75%)和住院时间(7 vs 15.7天)有统计学意义。术前未发现盆腔淋巴结受累(27%)。平均随访36.2个月(范围:3-137个月),LIIL和OIL的局部复发率分别为58.3%和40%。OIL患者的总生存率明显高于LIIL患者。结论:与OIL相比,LIIL减少了术后并发症和住院时间。
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引用次数: 2
Primary cilia: putting a sensor on the underlying melanocytic tumor cell state. 初级纤毛:对潜在的黑色素细胞肿瘤细胞状态进行传感器。
IF 3.6 Q1 Medicine Pub Date : 2020-07-17 DOI: 10.2217/mmt-2020-0008
Ursula E Lang
Melanocytic neoplasms constitute some of the most challenging histopathologic entities in pathology and trigger high levels of diagnostic uncertainty among general practice pathologists and even among expert dermatopathologists [1,2]. When histopathologic findings are ambiguous or indeterminate, one turns to immunohistochemical and/or genetic analyses, given sufficient tissue and resources [3]. These additional tests can provide valuable information about the underlying genetic drivers, level of genomic instability and relative levels of key transcripts, which are then integrated with histopathology and clinical information [4]. When fortunate enough to obtain the genetic data, the hope is for a compelling basis to definitively classify the tumor. Analysis may be less than straightforward, as mutations or chromosomal changes of unknown significance may be uncovered. Additional impediments to diagnosis include poor quality DNA, low purity of tumor cells and a chromosomal copy-number neutral melanoma. For these reasons, the gold standard remains histopathologic review by an experienced dermatopathologist. Often the true malignant potential remains a mystery, and management is aimed at balancing caution with morbidity. In such instances, one can wonder if microRNA (miRNA), transcriptomic or DNA methylation data would shed more light onto the underlying biologic potential [5–7]. In the case of miRNAs, which are stable in formalin-fixed paraffin-embedded (FFPE) tissue, several studies have shown the potential for use as diagnostic biomarkers [6,8]. Although mRNA is less stable than miRNAs in FFPE, commercially available kits leverage a limited panel of gene transcripts that can predict risk of recurrence, metastasis and assist in diagnosis [9]. DNA methylation shares the advantage of stability similar to miRNAs, and appears to correlate with poor prognosis in advanced melanoma [5]. The epigenetic information gained from methylation analysis remains unknown in histopathologically indeterminate lesions. Challenges in using these tests include the lack of high-quality evidence guiding best practice use [10]. As any cell biologist will attest, it is the proteome and interactome of cells that ultimately results in behavior. While the complexity can be overwhelming, it remains a fascination and continues to propel the field of melanoma biology. It is in this vein that the assessment of primary cilia has emerged as a window into melanoma cell biology. The primary cilium is ubiquitous cell surface organelle that acts as cellular antenna, sensing the extracellular environment and transmitting downstream signals [11]. Many important signaling pathways have been linked to the primary cilium in a cell-context-dependent manner and implicated in cancer pathogenesis [12]. With respect to melanocytes and melanoma progression, there are limited but intriguing data to support the WNT/β-catenin pathway being repressed by an intact primary cilium [13]. Additionally, the
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引用次数: 0
Disparity in outcomes of melanoma adjuvant immunotherapy by demographic profile. 黑色素瘤辅助免疫治疗结果的人口统计学差异。
IF 3.6 Q1 Medicine Pub Date : 2020-07-16 DOI: 10.2217/mmt-2020-0002
Alexandra Ikeguchi, Michael Machiorlatti, Sara K Vesely

Background: Randomized comparisons have demonstrated survival benefit of adjuvant immunotherapy in node-positive melanoma patients but have limited power to determine if this benefit persists across various demographic factors.

Materials & methods: We assessed the impact of demographic factors on the survival benefit of adjuvant immunotherapy in a database of 38,189 node-positive melanoma patients using the Kaplan-Meier method and Cox proportional hazards models.

Results: All assessed demographic factors other than race significantly impacted survival of node-positive melanoma patients in univariate analysis. In multivariable analysis, only the age group interacted with immunotherapy.

Conclusion: Analysis of this large database of unselected node-positive melanoma patients demonstrated a positive survival benefit of immunotherapy across all demographic factors assessed and the impact was greater for patients 65 years of age and older.

背景:随机比较已经证明了辅助免疫治疗对淋巴结阳性黑色素瘤患者的生存益处,但确定这种益处是否在各种人口因素中持续存在的能力有限。材料与方法:我们使用Kaplan-Meier法和Cox比例风险模型评估了人口统计学因素对38189例淋巴结阳性黑色素瘤患者辅助免疫治疗生存获益的影响。结果:在单变量分析中,除种族外,所有评估的人口统计学因素显著影响淋巴结阳性黑色素瘤患者的生存。在多变量分析中,只有年龄组与免疫治疗相互作用。结论:对未选择淋巴结阳性黑色素瘤患者的大型数据库的分析表明,免疫治疗在所有评估的人口统计学因素中都有积极的生存益处,对65岁及以上患者的影响更大。
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引用次数: 7
Observational study of talimogene laherparepvec use in the anti-PD-1 era for melanoma in the US (COSMUS-2). 美国黑色素瘤抗 PD-1 时代使用 talimogene laherparepvec 的观察性研究(COSMUS-2)。
IF 3.6 Q1 Medicine Pub Date : 2020-06-15 DOI: 10.2217/mmt-2020-0005
James Sun, Brian R Gastman, Lucy McCahon, Elizabeth I Buchbinder, Igor Puzanov, Michele Nanni, James M Lewis, Richard D Carvajal, Shahnaz Singh-Kandah, Anupam M Desai, Leon Raskin, Carrie M Nielson, Rubina Ismail, Jonathan S Zager

Aim: Talimogene laherparepvec (T-VEC) is an intralesional therapy for unresectable, metastatic melanoma. T-VEC real-world use in the context of anti-PD1-based therapy requires further characterization.

Materials & methods: A retrospective review of T-VEC use from 1 January 2017 and 31 March 2018 for melanoma patients was conducted at seven US institutions.

Results: Among 83 patients, three categories of T-VEC and anti-PD-1 therapy were identified: T-VEC used without anti-PD-1 (n = 29, 35%), T-VEC after anti-PD-1-based therapy (n = 22, 27%) and concurrent T-VEC and anti-PD-1-based therapy (n = 32, 39%). 25% of patients discontinued T-VEC therapy due to no remaining injectable lesions, 37% discontinued T-VEC due to progressive disease. Discontinuation of T-VEC did not differ by anti-PD-1-based therapy use or timing.

Conclusion: In real-world settings, T-VEC may be used concurrently with or after anti-PD-1-based therapy.

目的:Talimogene laherparepvec(T-VEC)是一种治疗无法切除的转移性黑色素瘤的瘤内疗法。T-VEC在抗PD1疗法中的实际使用情况需要进一步确定:美国七家机构对2017年1月1日至2018年3月31日期间黑色素瘤患者使用T-VEC的情况进行了回顾性审查:在83名患者中,确定了三类T-VEC和抗PD-1疗法:T-VEC在不使用抗PD-1的情况下使用(n = 29,35%),T-VEC在使用抗PD-1疗法后使用(n = 22,27%),T-VEC和抗PD-1疗法同时使用(n = 32,39%)。25%的患者因无剩余可注射病灶而停止T-VEC治疗,37%的患者因疾病进展而停止T-VEC治疗。T-VEC的停用与抗PD-1疗法的使用或时间没有差异:结论:在现实世界中,T-VEC可与抗PD-1疗法同时使用或在其后使用。
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引用次数: 0
Melanoma brain metastases: review of histopathological features and immune-molecular aspects. 黑色素瘤脑转移:组织病理学特征和免疫分子方面的回顾。
IF 3.6 Q1 Medicine Pub Date : 2020-06-08 DOI: 10.2217/mmt-2019-0021
Lorenzo Salvati, Mario Mandalà, Daniela Massi

Patients with melanoma brain metastases (MBM) have a dismal prognosis, but the unprecedented advances in systemic therapy alone or in combination with local therapy have now extended the 1-year overall survival rate from 20-25% to nearing 80-85%, mainly in asymptomatic patients. The histopathological and molecular characterization of MBM and the understanding of the microenvironment are critical to more effectively manage patients with advanced melanoma and to design biologically driven clinical trials. This review aims to give an overview of the main histopathological features and the immune-molecular aspects of MBM.

黑色素瘤脑转移(MBM)患者预后不佳,但单用全身治疗或联合局部治疗的前所未有的进步,现在将1年总生存率从20-25%延长到接近80-85%,主要用于无症状患者。MBM的组织病理学和分子特征以及对微环境的理解对于更有效地管理晚期黑色素瘤患者和设计生物学驱动的临床试验至关重要。本文综述了MBM的主要组织病理学特征和免疫分子方面。
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引用次数: 6
期刊
Melanoma Management
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