BRAF V600E突变蛋白在皮肤黑素瘤中的表达

目的 探讨皮肤黑素瘤BRAF V600E突变蛋白表达情况,分析免疫组化法检测V600E突变的灵敏度和特异度。 方法 应用抗BRAF V600E单克隆抗体的免疫组化法检测103例皮肤黑素瘤、40例色素痣石蜡包埋组织切片中BRAF V600E突变蛋白表达水平。采用SPSS 17.0统计软件进行统计分析,率的比较采用χ2检验。 结果 BRAF V600E突变蛋白阳性表达率在皮肤黑素瘤中为20.4%（21/103）,色素痣中为5.0%（2/40）,两组差异有统计学意义（χ2 = 5.06,P < 0.05）。黑素瘤BRAF V600E突变蛋白的表达率在不同年龄组［＜ 60岁组表达率为29.8%（14/47）, ≥ 60岁组为12.5%（7/56）］、不同民族［维吾尔族组为30.2%（13/43）,汉族组为13.3%（8/60）］、不同发病部位［肢端为13.6%（6/42）、黏膜为11.8%（4/29）、非肢端为45.8%（11/32）］、不同Clark分级［Ⅰ ~ Ⅲ级组为8.6%（4/42）,Ⅳ ~ Ⅴ级组为12.4%（17/61）］组间表达差异均有统计学意义（P < 0.05）,而在不同性别、有无淋巴结转移组间表达差异均无统计学意义（P ＞ 0.05）。免疫组化检测恶性黑素瘤中BRAF V600E突变灵敏度为100%（15/15）,特异度为98.5%（65/66）。 结论 BRAF V600E突变蛋白在皮肤黑素瘤中高表达,在维吾尔族人群表达率高于汉族人群;免疫组化法检测BRAF V600E突变具有准确、快速等特点。     

肢端型黑素瘤NRAS基因突变检测及预后分析

目的 分析肢端黑素瘤临床及病理特点,检测肢端型黑素瘤NRAS基因突变情况,探讨NRAS基因突变与疾病预后的关系。方法 收集经病理确诊的55例肢端型黑素瘤患者的临床及病理资料,提取其石蜡包埋组织及15例色素痣石蜡包埋组织DNA,采用PCR及DNA直接测序法检测NRAS基因突变。采用Cox比例风险回归模型进行单因素和多因素分析。结果 55例肢端型黑素瘤患者中,6例（10.9%）发生NRAS突变,突变位于61密码子,以Q61R为主。NRAS基因1、2外显子及15例色素痣组织未见上述突变。6例NRAS突变患者中,4例发生淋巴结转移。多因素Cox回归模型分析中,临床分期晚（RR = 2.54,95% CI：1.062 ~ 6.066）、未手术切除（RR = 2.98,95% CI：1.316 ~ 3.525）、存在NRAS突变（RR = 2.73,95% CI：0.932 ~ 3.257）为预后不良的独立影响因素（均P < 0.05）。结论 肢端型黑素瘤患者NRAS突变可能与淋巴结转移相关,临床分期、治疗方法、NRAS突变与预后有关。NRAS突变可能为肢端型黑素瘤提供一个新的预后评估指标。     

新疆80例恶性黑素瘤BRAF基因突变分析

目的 探讨BRAF基因突变与恶性黑素瘤临床表现的关系。方法 PCR及DNA直接测序法对新疆80例恶性黑素瘤及30例正常皮肤石蜡包埋组织BRAF基因11、15外显子进行检测。结果 80例恶性黑素瘤19例发生BRAF基因突变,突变率为23.8%（19/80）;有17例突变发生于15外显子,突变率为89.5% （17/19）,其中V600E突变占BRAF基因15外显子突变的88.2% （15/17）;2例突变位于11外显子,突变率10.5%（2/19）;30例正常皮肤组织均未发现BRAF基因突变。患者平均发病年龄为57.5岁,年龄在60岁以下患者BRAF基因突变率显著高于60岁以上（χ2 = 6.613,P < 0.05）。黏膜、肢端、非肢端突变率分别为：18.2%（4/21）,14.7%（5/34）,41.7%（10/24）,差异具有统计学意义（χ2 = 6.167,P < 0.05）。BRAF基因突变与恶性黑素瘤患者性别、民族、有无淋巴结转移无明显相关性（P > 0.05）。结论 BRAF基因仍为新疆地区恶性黑素瘤热点突变基因,且以该基因15外显子V600E突变为主。BRAF基因突变与恶性黑素瘤患者发病年龄、发病部位密切相关,而与民族、性别、有无淋巴结转移无相关性。     

活性诱导性胞嘧啶脱氨基酶表达与黑素瘤侵袭转移、预后的相关性分析

目的 探讨活性诱导性胞嘧啶脱氨基酶（AID）与黑素瘤侵袭转移、预后的关系和临床意义。方法 免疫组化SP法检测AID蛋白在80例黑素瘤、23例色素痣石蜡包埋组织切片中的表达,结合临床病理生物特性进行分析。 结果 黑素瘤AID蛋白的阳性表达率53.75%（43/80）,色素痣的表达率13.04%（3/23）,差异有统计学意义（P < 0.05）。AID蛋白的表达与黑素瘤淋巴结转移、Clark分级、浸润深度及预后密切相关（P < 0.05）,在年龄、性别、民族之间差异无统计学意义（均P ＞ 0.05）。19例发生BRAF突变黑素瘤组织中,AID蛋白17例阳性表达,其中15例BRAFV600E突变的黑素瘤AID蛋白均阳性表达。 结论 AID蛋白可能诱导了黑素瘤BRAF突变,并参与黑素瘤的侵袭、转移,与预后相关。     

环境微细颗粒物与过敏性皮肤病关系的Meta分析

目的：定量评估环境微细颗粒物PM10、PM2.5与过敏性皮肤病的关系。方法：检索国内外文献数据库，系统收集相关文献并提取效应量。使用 RevMan 5.3和Stata 14.2软件对文献进行Meta分析，根据异质性结果进行亚组分析和敏感性分析，并检验发表偏倚及校正合并效应量。结果：共纳入25篇文献；PM10、PM2.5每增高10 μg/m3，对过敏性皮肤病影响的合并效应量分别为1.0049（95% CI：1.0016~1.0081）与1.0066（95% CI：1.0033~1.0100）；亚组分析显示PM10和PM2.5对特应性皮炎影响的合并效应量分别为1.0108（95% CI：0.9999~1.0219）、1.0320（95% CI：1.0056~1.0590），对湿疹影响的合并效应量分别为1.0040（95% CI：1.0006~1.0075）、1.0066（95% CI：1.0029~1.0103）；PM2.5对荨麻疹影响的合并效应量为0.9994（95% CI：0.9852 ~1.0139）。结论：环境微细颗粒物与过敏性皮肤病发生相关，PM10和PM2.5浓度升高会增加特应性皮炎和湿疹的发生风险。     

5-羟甲基胞嘧啶表达与黑素瘤侵袭、转移、预后的相关性分析

目的 检测5-羟甲基胞嘧啶（5?hmc）在黑素瘤组织中的表达水平,分析5?hmc与黑素瘤侵袭、转移、预后的相关性。方法 采用免疫组化SP法检测5?hmc在67例黑素瘤、20例色素痣组织标本中的表达,采用Cox比例风险回归模型进行单因素和多因素回归分析5?hmc表达与黑素瘤患者预后的相关关系。结果 黑素瘤中5?hmc表达阳性率为40.30%（27/67）,色素痣为75%（15/20）,两组间差异有统计学意义（χ2 = 7.428,P = 0.006）。美国癌症联合会临床分期Ⅳ期黑素瘤中5?hmc表达水平明显低于Ⅱ、Ⅲ期黑素瘤（χ2 = 4.416,P = 0.036）,淋巴结转移患者5?hmc表达水平明显低于无淋巴结转移患者（χ2 = 5.902,P = 0.015）,且5?hmc表达水平随黑素瘤组织Clark分级升高而降低（χ2 = 4.828,P = 0.028）。5?hmc表达水平在不同年龄、性别、民族黑素瘤患者之间分布差异无统计学意义（P > 0.05）。Cox回归模型多因素分析显示,存在远处淋巴结转移（风险比：2.67,95% CI：1.22 ~ 5.84）、未手术切除（风险比：0.41,95% CI：0.18 ~ 0.95）、5?hmc低水平表达（风险比：3.54,95% CI：1.09 ~ 11.43）为预后不良的独立影响因素。结论 5?hmc可能参与黑素瘤侵袭转移,与黑素瘤预后相关。     

头孢曲松治疗早期梅毒疗效的系统评价与Meta分析

【摘要】 目的 评价头孢曲松治疗早期梅毒的临床疗效。 方法 检索中英文文献数据库1985—2012年公开发表的有关头孢曲松治疗早期梅毒疗效研究的论著,使用Jadad评分对文献质量进行评价并纳入符合要求的文献,使用Stata 12.0软件进行Meta分析。 结果 共纳入符合条件的文献14篇,其中高质量文献5篇。以头孢曲松治疗有效率和青霉素治疗有效率的率比（RR值）为指标进行Meta分析。随访6个月、12个月、24个月时,两种药物的疗效差异无统计学意义。随访12个月时,头孢曲松组的有效率为92.3%（95% CI 88.5% ~ 96.1%）,青霉素组有效率为90.4%（95% CI 87.4% ~ 94.4%）。漏斗图结果近似对称,发表偏倚较小。 结论 头孢曲松可作为治疗早期梅毒的替代方案,疗效确切。有必要开展多中心大样本的随机对照试验以优化治疗剂量与确定疗程。     

31例维吾尔族黏膜黑素瘤临床与c-kit基因突变研究

目的 分析维吾尔族黏膜黑素瘤临床特点,检测c-kit基因突变,探讨与黏膜黑素瘤临床特征之间的关系。 方法 收集经病理确诊的31例维吾尔族黏膜黑素瘤患者的临床资料,采用PCR及DNA直接测序法进行c-kit基因突变检测。 结果 维吾尔族黏膜黑素瘤男女性别比为1 ∶ 1.2,平均年龄61.35岁。60 ~ 70岁为高发年龄段,51 ~ 59岁为次高发年龄段。头颈部为最常见的发病部位,其中以鼻腔黏膜居多;其次为泌尿生殖道和直肠黏膜。31例黏膜黑素瘤有4例发生c-kit基因突变（12.9%,4/31）,突变均位于11外显子,以L576P突变为主。4例突变中,3例发生于直肠黏膜,1例发生于尿道黏膜。直肠黏膜与其他黏膜部位c-kit基因突变率分别为3/7、4.17%（1/24）。发生淋巴结转移患者c-kit基因突变率高于无淋巴结转移者（P = 0.043）。c-kit基因突变与性别、年龄无相关性（P > 0.05）。 结论 维吾尔族黏膜黑素瘤好发于老年人,发病部位以头颈部黏膜为主。c-kit基因突变与黏膜黑素瘤发生部位、有无淋巴结转移密切相关。     

外伤相关黑素瘤87例临床病理特点与预后分析

【摘要】 目的 分析外伤相关黑素瘤的临床病理特点及其与患者预后间的关系。方法 回顾性分析2009—2020年第四军医大学西京皮肤医院87例外伤相关黑素瘤的临床病理特点,通过Mann-Whitney检验分析不同年龄、性别患者间肿瘤Breslow厚度的差异;通过Spearman秩相关分析外伤至发现皮疹的时间与Breslow厚度之间的相关性;采用Kaplan-Meier生存分析和Log-Rank检验法分析黑素瘤临床病理特点与患者预后间的关系;采用Cox回归模型分析影响外伤相关黑素瘤患者生存时间的危险因素。结果 87例外伤相关黑素瘤患者中,男47例（54.02%）、女40例（45.98%）,50例（57.47%）由锐伤引起,37例（42.53%）由钝伤引起。31例（35.63%）原发皮损位于手部,48例（55.17%）位于足部。> 55岁组患者原发肿瘤Breslow厚度显著高于 ≤ 55岁组（U = 623.500,P = 0.010）,而不同性别患者间差异无统计学意义（P = 0.138）。外伤至发现皮疹的时间与肿瘤Breslow厚度呈负相关（r = -0.203,P = 0.037）。患者年龄、肿瘤Breslow厚度、Ki67增殖指数和肿瘤遗传背景均显著影响外伤相关黑素瘤患者的生存时间（P < 0.05或 < 0.01）;性别、外伤类型、瘤团有无溃疡未明显影响患者的生存时间（均P > 0.05）。Cox回归模型分析显示,肿瘤Ki67增殖指数及Breslow厚度是影响外伤相关黑素瘤患者预后的独立危险因素［RR值（95% CI）分别为1.946（1.234,4.217）、1.839（1.014,3.332）,P值分别为0.039、0.045］。结论 外伤相关黑素瘤的Breslow厚度与患者年龄、外伤至发现皮疹的时间相关;年龄、肿瘤Breslow厚度、Ki67增殖指数和肿瘤遗传背景均影响黑素瘤患者的生存时间,且Ki67增殖指数和肿瘤Breslow厚度是影响预后的独立危险因素。     

性传播疾病门诊就诊者1 475例尿液和尿道/宫颈拭子沙眼衣原体DNA检测结果分析

【摘要】 目的 比较尿液法与尿道/宫颈拭子法检测生殖道沙眼衣原体（CT）DNA阳性率的差异。方法 2018年12月至2019年12月,广州市皮肤病防治所性病科等7个医疗单位共收集性传播疾病门诊初诊者1 475例,男1 118例、女357例。依次采集每例患者尿道/宫颈拭子、尿液标本各1份,采用实时荧光PCR法检测尿液和拭子标本中CT-DNA,配对χ2检验比较2种标本CT-DNA阳性率。采用随机或固定效应Meta分析对7个医疗单位的尿液、拭子标本CT-DNA阳性率进行异质性检验及合并。结果 4个医疗单位尿液标本CT-DNA阳性率均高于拭子标本（均P < 0.05）,而3个医疗单位2种标本CT-DNA阳性率差异无统计学意义（均P > 0.05）。不同医疗单位间尿液和拭子标本CT-DNA阳性检出率异质性I 2分别为78.6%（95% CI：55.9% ~ 89.6%）、73.7%（95% CI：43.7% ~ 87.7%）;经Meta合并,尿液标本CT-DNA总阳性率为10.8%（95% CI：7.2% ~ 15.9%）,显著高于拭子标本（7.8%,95% CI：4.9% ~ 12.1%;χ2 = 39.2,P < 0.05）。以拭子标本CT-DNA检测法为对照,尿液标本CT-DNA检测法的敏感性为97.0%（128/132）,特异性为96.3%（1 293/1 343）,阳性预测值为71.9%（128/178）,阴性预测值为99.7%（1 293/1 297）,符合率为96.3%（1 421/1 475）。1 118例男性尿液CT-DNA阳性率为11.0%（95% CI：7.2% ~ 16.5%）,显著高于拭子CT-DNA阳性率（7.6%,95% CI：4.9% ~ 11.8%;χ2 = 34.3,P < 0.05）。357例女性尿液CT-DNA阳性率（11.9%,95% CI：7.7% ~ 17.9%）与拭子CT-DNA阳性率（10.4%,95% CI：7.6% ~ 14.0%）差异无统计学意义（χ2 = 3.2,P > 0.05）。结论 尿液CT-DNA阳性率高于或持平于拭子CT-DNA阳性率,采用尿液标本检测CT-DNA具有取材方便、无创、无痛苦、成本低等特点,值得临床推广。     

Adjuvant therapy for cutaneous melanoma: a systematic review and network meta-analysis of new therapies

New drugs have been recently approved as adjuvant therapies for melanoma. In this Bayesian network meta-analysis, we aimed to assess the best therapeutic option in terms of recurrence-free survival (RFS), overall survival (OS) and adverse events (AEs). PubMed, Embase, Cochrane library and the American Society of Clinical Oncology databases were searched from inception until 20 August 2018. We estimated adjusted hazard ratios (HRs) for RFS and OS and relative odds ratios (ORs) for AEs and surface under the cumulative ranking (SUCRA) probabilities were calculated. A number of 872 records were identified, and six were finally included in the meta-analysis. A total of 4244 patients in six studies were randomized. The following therapies were considered in the selected studies: combined dabrafenib and trametinib, vemurafenib, nivolumab, ipilimumab and pembrolizumab. Nivolumab demonstrated the highest probability (75.1%) of being the best in term of RFS, followed by dabrafenib+trametinib, pembrolizumab, ipilimumab and vemurafenib; however, OS was not estimable. Concerning AEs, pembrolizumab and nivolumab showed the highest probability to be less associated with any and 3–4 grade AEs (83.1% and 64.4%, respectively). In conclusion, all new drugs are highly effective in adjuvant setting, and the best choice is dependent of patient's context.     

Two cases of BRAF-mutated,bulbar conjunctival melanoma,and review of the published literature

We describe two patients with BRAF-mutated melanoma of the epithelioid cell type arising from primary acquired melanosis with severe atypia of the right bulbar conjunctiva. Patient 1 was a 71-year-old Japanese man. After adjuvant cryotherapy and enucleation of the right eyeball, therapy with vemurafenib was administered for a distant metastasis to a lumbar vertebra, accompanied by erythema multiforme and two keratinous tumours. The patient died due to metastases to the liver and multiple vertebrae, despite therapy with nivolumab and combination therapy with dabrafenib plus trametinib. Patient 2 was a 72-year-old Japanese man. After adjuvant cryotherapy, periodic mitomycin C eye drops, and excision of the superficial portion of the right parotid gland and the dissection of cervical lymph nodes, he was treated with adjuvant combination therapy with dabrafenib plus trametinib. Dermatologists should be familiar with BRAF-mutated conjunctival melanoma, which is usually located on the bulbar conjunctiva and associated with more frequent distant metastasis.     

Treatment of High Risk Resected Melanoma in Australia: Current Landscape and Practises

Stage III melanoma involves regional lymph nodes and/or in-transit or satellite disease, without spread to distant metastatic sites. Stage IIIA melanoma includes a T1a-T2a primary lesion with N1a or N2a nodal involvement, whilst stage IIID melanoma includes a T4b primary lesion with N3a-N3c nodal involvement. With surgery alone, patients with stage IIIA melanoma have 10-year survival rates of ~88%; however, patients with stage IIID melanoma have 10-year survival rates of only ~24%. Targeted therapy and immunotherapy are being explored in stage III disease as adjuvant therapy after surgical resection, to eliminate micro-metastatic disease and thereby prevent relapse of melanoma and increase patient survival. A number of pivotal trials published in the last two years have shown improved relapse-free survival (RFS) and overall survival in patients with stage III melanoma treated with adjuvant therapy. COMBI-AD showed adjuvant dabrafenib and trametinib improving RFS compared with placebo (HR 0.49; 95% CI 0.40–0.59). Checkmate-238 demonstrated an improvement in RFS of adjuvant nivolumab over ipilimumab (HR 0.68, P < 0.001) whilst Keynote-054 demonstrated an improvement in RFS with adjuvant pembrolizumab over placebo (HR 0.57, P < 0.001). Many nuances need to be considered when interpreting this data, including implications of an updated staging system, which patients are suitable for adjuvant therapy and the choice between adjuvant targeted therapy and immunotherapy in BRAF mutant patients. This review article summaries the currently available literature on adjuvant targeted therapy and provides a guide on applying this data in everyday practise.     

Efficacy and safety of dabrafenib–trametinib in the treatment of unresectable advanced/metastatic melanoma with BRAF‐V600 mutation: A systematic review and network meta‐analysis

The current systematic review aimed to evaluate and compare the efficacy and safety of dabrafenib – trametinib with those of other therapeutic alternatives in the treatment of patients with unresectable advanced/metastatic melanoma with BRAF‐V600 mutation. The search was carried out on four databases up to July 2018. Two separate network meta‐analyses (NMA) were performed using the frequentist method (random effects): one with an exclusive population with BRAF‐V600 mutation (NMA‐pBRAFV600) and another with mixed population (with or without the mutation: NMA‐pMixed). An evidence profile was included using the GRADE method for NMA. The validity of the final estimator in the NMA‐pMixed was assessed via a sensitivity analysis. Nine clinical trials were included in the NMA‐pBRAFV600. Dabrafenib–trametinib was found to have a favorable effect on overall survival (OS) and progression‐free survival (PFS) compared with dabrafenib, vemurafenib, and dacarbazine and on partial response rate (PRR) and overall response rate compared with dacarbazine and vemurafenib. In the NMA‐pMixed, dabrafenib–trametinib was found to have a positive effect on OS versus ipilimumab 3 mg/kg and on PFS and PRR versus ipilimumab, nivolumab, and pembrolizumab. However, dabrafenib–trametinib and vemurafenib–cobimetinib significantly differed in terms of efficacy. In addition, dabrafenib–trametinib has a favorable effect on Grades 3 and 4 adverse events.     

Neoadjuvant immunotherapy with combined ipilimumab and nivolumab in patients with melanoma with primary or in transit disease

The introduction of new therapeutic agents has revolutionized the treatment of metastatic melanoma. The approval of adjuvant anti-programmed death-1 monotherapy with nivolumab or pembrolizumab, and dabrafenib plus trametinib has recently set a new landmark in the treatment of stage III melanoma. Now, clinical trials have shown that immune checkpoint blockade can be performed in a neoadjuvant setting, an approach established as a standard therapeutic approach for other tumour entities such as breast cancer. Recent studies suggest that a pathological response achieved by neoadjuvant immunotherapy is associated with long-term tumour control and that short neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy. Most recently, neoadjuvant ipilimumab plus nivolumab in stage III melanoma was reported. With two courses of dose-optimized ipilimumab (1 mg kg⁻¹) combined with nivolumab (3 mg kg⁻¹), pathological responses were observed in 77% of patients, while only 20% of patients experienced grade 3 or 4 adverse events. However, the neoadjuvant trials employing combined immune checkpoint blockade conducted so far have excluded patients with in transit metastases, a common finding in stage III melanoma. Here we report four patients with in transit metastases or an advanced primary tumour who have been treated with neoadjuvant ipilimumab plus nivolumab according to the OpACIN-neo trial scheme (arm B). All patients achieved radiological disease control and a pathological response. None of the patients has relapsed so far. Linked Comment:   Blankenstein and van Akkooi. Br J Dermatol 2020; 183 :421–422 .     

Systemic therapy of metastatic melanoma

For patients with metastatic melanoma, there are currently several effective therapeutic options. The BRAF inhibitors vemurafenib and dabrafenib are characterized by rapid tumor control and high response rates. In combination with one of the two MEK inhibitors trametinib and cobimetinib, they achieve response rates (CR + PR, complete plus partial remissions) of 70 %, while delaying the development of treatment resistance, as well as a median overall survival of > 2 years with tolerable side effects. Showing long‐term survival rates of approximately 20 %, the anti‐CTLA‐4 antibody ipilimumab is the first substance that has led to a significant prolongation of overall survival in patients with metastatic melanoma. However, delayed treatment response and severe immune‐mediated side effects may pose limitations to its therapeutic benefit. Usually well tolerated, anti‐PD‐1 antibody monotherapy using nivolumab and pembrolizumab has yielded response rates (CR + PR) of up to 45 % and one‐year survival rates of > 70 %. The combination of ipilimumab and nivolumab has shown response rates of up to 58 % and a median progression‐free survival of > 11 months. While this combination is expected to result in a rapid and long‐lasting response, this potential benefit comes at the expense of a high level of toxicity. Strategies for treatment sequencing and treatment combinations are currently being investigated in clinical studies. Overall, the prognosis for patients with metastatic melanoma has significantly improved. With long‐term survival a possibility, not only acute but also long‐term therapeutic side effects must be taken into account.     

Which adjuvant treatment for patients with BRAFV600-mutant cutaneous melanoma?

Treatment of patients with melanoma has considerably improved over the past decade and more recently with adjuvant therapies for patients with American Joint Committee on Cancer (AJCC) stage III (loco-regional metastases) or IV (distant metastases) totally resected melanoma, in order to prevent recurrence. In the adjuvant setting, two options are available to patients with BRAF^V600-mutant AJCC stage III totally resected melanoma: anti-PD-1 blockers (nivolumab or pembrolizumab) or BRAF plus MEK inhibitors (dabrafenib plus trametinib). In the absence of comparative studies, it is difficult to determine which of these options is best. Our aim was to review published studies focusing on the management of patients with BRAF^V600-mutant melanoma in the adjuvant setting. We also reviewed the main clinical trials of BRAF plus MEK inhibitors and immunotherapy in advanced (i.e. unresectable metastatic) BRAF-mutant melanoma in an attempt to identify results potentially affecting the management of patients on adjuvants. More adverse events are observed with targeted therapy, but all resolve rapidly upon drug discontinuation, whereas with immune checkpoint blockers some adverse events may persist. New therapeutic strategies are emerging, notably neoadjuvant therapies for stage III patients and adjuvant therapies for stage II patients; the place of the adjuvant strategy amidst all these options will soon be re-evaluated. The choice of adjuvant treatment could influence the choice of subsequent treatments in neo-adjuvant or metastatic settings. This review will lead clinicians to a better understanding of the different adjuvant treatments available for patients with totally resected AJCC stage III and IV BRAF^V600-mutant melanoma before considering subsequent treatment strategies.     

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

The combination of dabrafenib and trametinib demonstrated encouraging antitumor activity and tolerability, at initial analysis, in Japanese patients with BRAF V600 mutant advanced melanoma warranting further investigation. This study evaluated the safety and tolerability, pharmacokinetics (PK) and preliminary efficacy of dabrafenib 150 mg b.i.d. plus trametinib 2 mg q.d. in Japanese patients with BRAF V600E/K mutant solid tumors (phase 1) and melanoma (phase 2). Phase 1 was primarily intended to assess safety and tolerability as assessed by adverse events (AE), and the primary end‐point in phase 2 was to assess confirmed overall response rate (ORR). The secondary end‐points in phase 1 included PK, confirmed/unconfirmed ORR and duration of response (DOR). The secondary end‐points in phase 2 were PK, unconfirmed ORR, DOR, safety and tolerability. A total of 12 cutaneous melanoma patients were enrolled in the study (six in phase 1 and six in phase 2) and received the combination therapy of dabrafenib and trametinib. Common AE (≥50.0%) included pyrexia (75%), increased aspartate aminotransferase (67%), peripheral edema (50%) and nasopharyngitis (50%). The investigator‐assessed ORR was reported in five patients (83%) in phase 1 and was also reported in five patients (83%; 95% confidence interval, 35.9–99.6; P < 0.0001) in phase 2. Plasma concentrations of both dabrafenib and trametinib seemed to a reach steady state by week 3. Overall, efficacy and PK properties for the dabrafenib plus trametinib combination in Japanese patients were comparable with those seen in global studies.     

Serum soluble CD163 and proinflammatory chemokines may be biomarkers of the onset of adverse events in dabrafenib plus trametinib combination therapy for advanced melanoma

Various adverse events (AEs) have been reported to occur at a high rate in patients treated with dabrafenib plus trametinib (D + T) combination therapy. Among such AEs, the incidence of pyrexia was highest among the series of AEs in patients treated with D + T combination therapy. Although little is known about the mechanisms of pyrexia caused by D + T combination therapy, a recent report suggested that sCD163, as well as interferon‐inducible chemokines (CXCL9, CXCL10, CXCL11), might correlate with pyrexia caused by encorafenib plus binimetinib combination therapy. In addition to these soluble factors, CXCL5 is a biomarker for predicting immune‐related AEs in melanoma patients treated with nivolumab. From the above findings, we hypothesized that these soluble factors might also correlate with the onset of AEs in D + T combination therapy. The serum levels of sCD163 were increased in patients with pyrexia in parallel with their severity, whereas the serum levels of CXCL5 were increased in patients without pyrexia. Moreover, increased levels of CXCL9, CXCL10, and CXCL11 were prominent in patients with AEs over G2 levels. As these chemokines recruit Th1, Th17, and activated CD8+ T cells, increased serum levels of these chemokines might correlate with the positive feedback of inflammatory reactions related to AEs.