维莫非尼治疗BRAF V600E突变晚期黑色素瘤达病理完全缓解1例报道

<正>皮肤黑色素瘤是一种侵袭性强、恶性程度高的皮肤恶性肿瘤,BRAF V600突变是其较为常见的驱动突变。随着精准医学的发展,以维莫非尼为首的靶向药物为BRAF V600突变的黑色素瘤患者带来了生存获益。现将一例BRAF V600E突变的晚期黑色素瘤患者经维莫非尼治疗后达病理完全缓解的治疗情况报告如下。     

可溶性PD-L1作为晚期肢端及黏膜黑色素瘤预后因素的研究

目的:可溶性PD-L1(sPD-L1)水平升高与肾细胞癌和多发性骨髓瘤预后相关.然而,sPD-L1在晚期黑色素瘤中的调节作用和功能尚不完全清楚.本研究旨在评估晚期肢端及黏膜黑色素瘤患者循环系统中sPD-L1浓度与预后的关系.方法:于2012年1月至2015年12月期间在北京大学肿瘤医院招募了未经治疗的晚期肢端及黏膜黑色...     

前哨淋巴结活检在中国皮肤和肢端恶性黑色素瘤患者诊治中的临床意义

背景与目的：恶性黑色素瘤近年来在中国发病率呈上升趋势。前哨淋巴结活检（sentinel lymph node biopsy,SLNB）在欧美是皮肤恶性黑色素瘤外科诊治规范的重要环节,但在中国却未广泛开展。中国黑色素瘤具有多肢端亚型、浸润深度厚、溃疡率高和预后差等特点。但中国黑色素瘤外科治疗后的预后仍未明确。该研究旨在分析中国黑色素瘤患者的临床数据,评价SLNB的可行性及其对预后的影响。方法：回顾性分析2009—2017年在复旦大学附属肿瘤医院治疗的无临床淋巴转移和远处转移征象的黑色素瘤患者。每例患者在接受原发病灶扩大切除的同时,进行相应区域淋巴结的SLNB。前哨淋巴结（sentinel lymph node,SLN）的定位通过美兰染色和同位素示踪完成。所有患者术后均进行随访。结果：本研究共纳入452例黑色素瘤患者。平均Breslow浸润深度为3.29 mm,66.4%为肢端病灶,溃疡率达59.7%。SLN阳性率为26.8%,假阴性率为4%,淋巴结总转移率为30.8%。本组患者5年总生存率（overall survival,OS）和无病生存率（disease-free survival,DFS）分别为66.6%和55.8%。SLN状态是显著影响患者预后的独立危险因素,而Breslow浸润深度是预测SLN转移状态的独立危险因素。结论：对于无临床大体转移的中国黑色素瘤患者,应常规开展SLNB。SLN状态是影响复发和总体生存的重要因素,SLNB能提高淋巴结微转移患者的生存,提供准确的临床分期。     

近5年单中心肢端型及皮肤型黑色素瘤外科治疗患者的预后因素分析

背景与目的：中国及亚洲部分国家和地区的恶性黑色素瘤（malignant melanoma,MM）患者的预后显著低于欧美人群,主要是因为肢端型黑色素瘤（acral melanoma,AM）无论是在生物学行为、临床特征、预后以及药物的疗效（主要是免疫治疗）上都差于皮肤型黑色素瘤（cutaneous melanoma,CM）。近5年在MM外科治疗和药物辅助治疗选择方面发生了一定的变化。本文回顾性分析近5年单中心经手术治疗的AM及CM患者的生存变化和相关的独立预后因素。方法：对2017—2021年在复旦大学肿瘤医院黑色素瘤诊治中心接受外科治疗的MM患者进行回顾性研究。通过病史回顾和随访收集患者完整的基本信息、原发灶特点、淋巴灶转移特征和生存状态,剔除黏膜型、原发不明、随访时间短于6个月的病例。通过生存分析和多因素分析,探讨患者生存的差异和相关预后因素。结果：本研究共入组585例黑色素瘤患者,其中AM 397例,CM 188例。中位年龄59（19~89）岁,女性占54%。AM和CM在性别、年龄、原发灶位置、基因突变分布和辅助治疗等方面存在差异,但在Breslow深度、溃疡、淋巴结转移等肿瘤负荷因素上差异无统计学意义。中位随访时间为24个月,中位无疾病生存期为36个月,1、2年无复发生存期（relapse-free survival,RFS）分别为75.6%和61.2%。但两亚型的预后差异无统计学意义。AM中RFS的独立风险因素包括：原发灶溃疡（HR=2.265,95% CI：1.257~4.080）,NRAS基因突变（HR=1.816,95% CI：1.211~2.725）,较晚的N分期（N₁、N₂、N₃相较N₀的HR分别为1.850、4.085、4.191）;保护因素为女性（HR=0.636,95% CI：0.433~0.933）和上肢原发灶（HR=0.259,95% CI：0.105~0.639）。CM中RFS的独立风险因素包括：原发灶溃疡（HR=4.073,95% CI：1.718~9.654）,较晚的N分期（其中N₃期的HR=5.482,95% CI：2.385~12.601）。结论：预后分析发现,原发灶的肿瘤负荷仍旧与CM和AM患者的预后密切相关,而NRAS基因的突变状态则提示AM预后更差。     

肢端恶性黑色素瘤临床特征及预后因素分析

背景与目的：在中国，黑色素瘤常见于肢端，预后较差。该研究分析肢端黑色素瘤（acral melanoma，AM）的临床特征、治疗方法及疗效，探究不良预后的相关因素。方法：回顾性收集中南大学湘雅医学院附属肿瘤医院2010年1月—2017年12月收治的322例AM患者的临床资料，分析临床特征及预后影响因素。结果：AM多见于农民（66%）及工人（12%），70.5%的病灶位于足底；男女比例为1.3∶1.0，中位年龄58岁，在湖南省各地区分布无明显差异；局部物理刺激及炎症刺激与AM发生密切相关；Ⅱ~Ⅲ期患者接受规范外科手术治疗者预后明显优于未行手术治疗者；相比于腓肠神经营养血管皮瓣，足底内侧动脉皮瓣修复足底病灶术后皮瓣坏死感染率较低；术后接受全身辅助治疗的患者出现远处转移的时间较未行辅助治疗者延长；接受化疗的Ⅳ期患者远期生存率高于未行化疗者；Ⅳ期患者乳酸脱氢酶（lactic dehydrogenase，LDH）均值相比Ⅰ~Ⅲ期患者明显升高，且LDH≥281 U/L的患者生存率明显降低；AM患者5年生存率为66%，中位生存期为69.4个月。以性别、年龄、肿瘤部位、病程、卫星病灶、LDH值、红细胞沉降率（erythrocyte sedimentation rate，ESR）、Ki-67标记指数行多因素分析显示，肿瘤部位、病程、LDH、Ki-67标记指数为患者预后的独立危险因素。结论：AM多见于农民及工人，病变多位于足底。规范的外科手术和全身辅助治疗可显著改善患者预后。肿瘤部位、病程、LDH、Ki-67标记指数为影响患者预后的独立危险因素。     

替莫唑胺联合舒尼替尼治疗转移性黏膜黑色素瘤的疗效及安全性

目的:探索替莫唑胺(temozolomide,TMZ)联合舒尼替尼(sunitinib,SUN)在转移性黏膜黑色素瘤治疗中的应用价值.方法:回顾性纳入我中心2008年8月至2016年12月间接受TMZ联合SUN治疗的晚期黏膜黑色素瘤患者.患者均无BRAF/NRAS突变,服用TMZ (200 mg/m2,d 1～5)和SUN (37.5 mg,d 1～28)治疗,28 d为一个疗程,治疗直至病情进展或毒副反应无法耐受.主要观察客观有效率(ORR)、疾病无进展生存期(PFS)、总生存期(OS)和毒副反应发生率.结果:纳入的27例患者中,原发肠道4例、泌尿生殖道9例、鼻咽部5例、口腔7例、食管2例,有19例患者既往接受过抗肿瘤治疗,TMZ联合SUN治疗的中位治疗周期为3.0.治疗后ORR 19.2％,疾病控制率(DCR) 81.5％,中位PFS(3.0±0.7)个月,中位OS(7.1±0.9)个月.全组患者中有4例存在KIT突变,提示存在KIT突变/扩增的患者使用KIT抑制剂可能获益.联合治疗耐受性良好,仅2例患者因出现血小板抑制Ⅳ级,将SUN调整剂量为25 mg.Ⅲ～Ⅳ级副反应包括血小板下降(19.2％)、白细胞下降(19.2％)和肝功能损害(3.9％),未发生治疗相关性死亡事件.结论:TMZ联合SUN是治疗转移性黏膜黑色素瘤的有效方案,且安全性良好.     

肢端黑色素瘤前哨淋巴结活检临床结果分析

目的探讨肢端黑色素瘤前哨淋巴结活检的临床规律及临床意义。方法对2012年3月至2019年8月北京积水潭医院骨肿瘤科收治的肢端黑色素瘤患者中符合前哨淋巴结活检指征的110例行前哨淋巴结活检,前哨淋巴结活检结果阳性的患者再行淋巴结清扫术。术后常规行病理检查,统计非前哨淋巴结阳性结果。结果110例黑色素瘤患者中,发病于手部20例,其余90例发病于足部。所有病例均检出前哨淋巴结,检出率为100％。前哨淋巴结阳性24例,阳性率为22％。24例患者均行淋巴结清扫术,术后病理分析发现,非前哨淋巴结阳性患者9例,占38％。结论前哨淋巴结活检在肢端黑色素瘤的分期诊断、临床治疗中具有重要的临床意义。     

改良肢端恶性黑色素瘤前哨淋巴结活组织检查术应用可行性分析

目的:探讨改良肢端恶性黑色素瘤前哨淋巴结活组织检查（SLNB）应用的可行性。方法:回顾性分析2017年1月至2020年1月新疆医科大学附属肿瘤医院行手术治疗的60例肢端恶性黑色素瘤患者资料,根据前哨淋巴结（SLN）检测方法分为观察组（30例）及对照组（30例）。观察组使用超声造影联合亚甲蓝在腕关节或踝关节周围皮下注射法...     

丙泊酚麻醉在胃癌内镜黏膜下剥离术中的安全性和有效性研究

目的观察丙泊酚麻醉在胃癌患者内镜黏膜下剥离术中的安全性和有效性。方法选取胃癌患者共78例,依据麻醉方法不同随机分为对照组(39例)和观察组(39例);对照组采取维库溴铵和芬太尼进行麻醉;观察组在对照组基础上静脉持续泵入丙泊酚;两组均行内镜黏膜下剥离术(ESD)治疗。比较两组手术时间、住院时间以及术中出血量;记录两组1个月随访期间并发症;比较两组术后视觉模拟疼痛评分(VAS)和Ransay评分;检测两组血清高迁移率族蛋白B1(HMGB1)水平。结果对照组并发症发生率为17.95%,观察组并发症发生率为12.82%,比较差异无统计学意义(P>0.05);观察组患者在手术时间、住院时间以及术中出血量方面均明显优于对照组,比较差异有统计学意义(P<0.01);术后6 d,观察组VAS评分明显低于对照组,Ransay评分明显高于对照组(P<0.01);术后1 h和6 h,观察组血清HMGB1水平分别低于对照组,比较差异有统计学意义(P<0.01)。结论在胃癌患者内镜黏膜下剥离术中应用丙泊酚麻醉,具有较好的有效性和安全性,值得临床推广应用。     

Management of Acral and Mucosal Melanoma: Medical Oncology Perspective

Acral and mucosal melanomas (MM) are rare subtypes of melanoma that are biologically and clinically distinct from cutaneous melanoma. Despite the progress in the treatment of cutaneous melanomas with the development of targeted and immune therapies, the therapeutic options for these less common subtypes remain limited. Difficulties in early diagnosis, the aggressive nature of the disease, and the frequently occult sites of origin have also contributed to the poor prognosis associated with acral and MM, with substantially worse long-term prognosis. The rarity of these subtypes has posed significant barriers to better understanding their biological features and investigating novel therapies. Consequently, establishing standardized treatment guidelines has been a challenge. In this review, we provide a brief overview of the current knowledge regarding acral and MM, focusing on their epidemiology, genetic backgrounds, and unique clinical characteristics. Further discussion centers around the management of primary and advanced disease and the role of emerging targeted and immune therapies for these subtypes, specifically focusing on issues relevant to medical oncologists.     

Efficacy and safety of ipilimumab 3 mg/kg in patients with pretreated,metastatic, mucosal melanoma

BackgroundMucosal melanoma is an extremely rare and aggressive malignancy that often remains undetected until it reaches an advanced stage, when effective treatment options are limited. The activity and safety of ipilimumab were assessed in an Expanded Access Programme (EAP) that included patients with metastatic, mucosal melanoma.MethodsIpilimumab was available upon physician request for patients aged ⩾16 years with stage III (unresectable) or IV skin, ocular or mucosal melanoma, who had failed or did not tolerate previous treatments and had no other therapeutic option available. Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. Patients with stable disease or an objective response to ipilimumab were eligible for retreatment upon disease progression. Tumour assessments were conducted at baseline and week 12 using immune-related response criteria. Patients were monitored for adverse events (AEs), including immune-related AEs, within 3 to 4 days of each scheduled visit.ResultsOf 855 patients participating in the EAP in Italy, 71 (8%) had metastatic, mucosal melanoma. With a median follow-up of 21.8 months, the response rate was 12% and the immune-related disease control rate was 36%. Median progression-free survival and overall survival were 4.3 and 6.4 months, respectively. In total, 34% of patients reported treatment-related AEs of any grade, which were grade 3 or 4 in 9% of patients. AEs were generally manageable as per protocol-specific guidelines.Conclusion/interpretationIpilimumab may be a feasible treatment option in pretreated patients with metastatic mucosal melanoma, and warrants further investigation in prospective clinical trials.     

Efficacy and Safety of Apatinib in Patients with Recurrent or Refractory Melanoma

BackgroundThe prognosis of patients with metastatic malignant melanoma is very poor and partly due to resistance to conventional chemotherapies. The study’s objectives were to assess the activity and tolerability of apatinib, an oral small molecule anti-angiogenesis inhibitor, in patients with recurrent advanced melanoma.MethodsThis was a single-arm, single-center phase II trial. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Eligible patients had received at least one first-line therapy for advanced melanoma and experienced recurrence. Apatinib (500 mg) was orally administered daily.ResultsFifteen patients (V660E BRAF status: 2 mutation, 2 unknown, 11 wild type) were included in the analysis. The median PFS was 4.0 months. There were two major objective responses, for a 13.3% response rate. Eleven patients had stable disease, with a DCR of 86.7%. The median OS was 12.0 months. The most common treatment-related adverse events of any grade were hypertension (80.0%), mucositis oral (33.3%), hand-foot skin reaction (26.7%), and liver function abnormalities, hemorrhage, diarrhea (each 20%). The only grade ≥3 treatment-related adverse effects that occurred in 2 patients was hypertension (6.7%) and mucositis (6.7%). No treatment-related deaths occurred.ConclusionApatinib showed antitumor activity as a second- or above-line therapy in patients with malignant melanoma. The toxicity was manageable.ClinicalTrials.gov Identifier{"type":"clinical-trial","attrs":{"text":"NCT03383237","term_id":"NCT03383237"}}NCT03383237     

Vemurafenib in patients with BRAFV600 mutation-positive melanoma with symptomatic brain metastases: Final results of an open-label pilot study

Background & AimBrain metastases are frequent in patients with metastatic melanoma, indicating poor prognosis. We investigated the BRAF kinase inhibitor vemurafenib in patients with advanced melanoma with symptomatic brain metastases.MethodsThis open-label trial assessed vemurafenib (960 mg twice a day) in patients with BRAF^V600 mutation-positive metastatic melanoma with non-resectable, previously treated brain metastases. The primary end-point was safety. Secondary end-points included best overall response rate, and progression-free and overall survival.ResultsTwenty-four patients received vemurafenib for a median treatment duration of 3.8 (0.1–11.3) months. The majority of discontinuations were due to disease progression (n = 22). Twenty-three of 24 patients reported at least one adverse event (AE). Grade 3 AEs were reported in four (17%; 95% confidence interval [CI], 4.7–37.4%) patients and included cutaneous squamous cell carcinoma in four patients. Median progression-free survival was 3.9 (95% CI, 3.0–5.5) months, and median survival was 5.3 (95% CI, 3.9–6.6) months. An overall partial response (PR) at both intracranial and extracranial sites was achieved in 10 of 24 (42%; 95% CI, 22.1–63.4) evaluable patients, with stable disease in nine (38%; 95% CI, 18.8–59.4) patients. Of 19 patients with measurable intracranial disease, seven (37%) achieved >30% intracranial tumour regression, and three (16%; 95% CI, 3.4–39.6%) achieved a confirmed PR. Other signs of improvement included reduced need for corticosteroids and enhanced performance status.ConclusionsVemurafenib can be safely used in patients with advanced symptomatic melanoma that has metastasised to the brain and can result in meaningful tumour regression.     

Safety,Efficacy, and Pharmacokinetics of Rezivertinib (BPI-7711) in Patients With Advanced NSCLC With EGFR T790M Mutation: A Phase 1 Dose-Escalation and Dose-Expansion Study

IntroductionRezivertinib (BPI-7711) is a novel third-generation EGFR tyrosine kinase inhibitor selective for EGFR-sensitizing and T790M mutations. This study was designed to evaluate the safety, efficacy, and pharmacokinetics of rezivertinib for patients having advanced NSCLC with EGFR T790M mutation.MethodsThis phase 1 study (NCT03386955) was conducted across 20 sites in the People's Republic of China. Patients received rezivertinib at six oral dose levels (30 mg, 60 mg, 120 mg, 180 mg, 240 mg, 300 mg) once daily until disease progression, unacceptable toxicity, or patient withdrawal. The primary end points were safety for the dose-escalation phase and objective response rate by the blinded independent central review for the total study population.ResultsA total of 19 patients in dose-escalation phase using the standard 3 + 3 design principle and 153 patients in dose-expansion phase were enrolled from September 11, 2017, to August 23, 2019. The data cutoff date was on June 15, 2020. No dose-limiting toxicity occurred in the dose-escalation phase. The treatment-related adverse events were observed in 82.0% (141 of 172) of patients, and 17.4% (30 of 172) had grade greater than or equal to 3, among which decreased neutrophil count (2.9%), leukopenia (2.9%), and pneumonia (2.9%) were the most common. The overall blinded independent central review–evaluated objective response rate was 59.3% (102 of 172, 95% confidence interval: 51.6–66.7), and the median progression-free survival was 9.7 (95% confidence interval: 8.3–11.1) months.ConclusionsRezivertinib was found to have promising efficacy with a manageable safety profile in patients with EGFR T790M-mutated advanced NSCLC. Further study is warranted.     

颌面部血管瘤患者瘤腔内注射平阳霉素联合介入栓塞治疗的有效性及安全性研究

目的 探讨颌面部血管瘤患者瘤腔内注射平阳霉素联合介入栓塞治疗的有效性及安全性.方法 选取诊治的颌面部血管瘤患者100例,随机分为对照组与观察组,每组50例,对照组采取瘤腔内注射平阳霉素治疗,观察组采取瘤腔内注射平阳霉素联合介入栓塞治疗,观察两组治疗前、治疗后1个月、3个月、6个月时的血管瘤面积变化,术中及术后并发症发生...     

恩度微量泵入与腹腔注射联合表阿霉素治疗小鼠乳腺癌的疗效对比观察

目的 比较恩度微量泵入或腹腔注射联合表阿霉素对小鼠乳腺癌的疗效。方法 建立乳腺癌4T1细胞的BALB/c小鼠移植瘤模型,随机分为空白对照组（0.9%NaCl, ip）、标准对照组（EPI, ip）及4个实验组：（1）rhES（ip）+EPI（ip）;（2）rhES（pump）+EPI（ip）;（3）rhES（ip）;（4）rhES（pump）。监测肿瘤大小和小鼠体重,治疗第10天行小动物活体成像,治疗结束后采用免疫组织化学法测定瘤内血小板-内皮细胞黏附分子（CD31）的表达。结果 恩度单药持续微量泵入（7 mg/（kg.d））疗效显著优于腹腔注射（P=0.01）;恩度持续微量泵入联合表阿霉素与双药联合腹腔注射疗效相当（P>0.05）,但前者不良反应略低。结论 恩度微量泵入联合表阿霉素治疗小鼠乳腺癌疗效与传统静脉滴注相当,为开展乳腺癌患者携泵回家治疗的可能性提供了实验依据,但还需要进一步的临床试验加以证实。     

老年进展期NSCLC培美曲塞/卡铂方案化疗中培美曲塞持续一线巩固的疗效及安全性

目的 探讨老年进展期NSCLC培美曲塞/卡铂方案化疗中培美曲塞持续一线巩固的疗效及安全性.方法 选取经影像学或病理组织学确诊的ⅢB期或Ⅳ期非小细胞肺癌(NSCLC)患者76例,均为接受4个周期培美曲塞/卡铂方案诱导化疗治疗后疾病得到控制者,以1:1随机分为巩固组和对照组.对照组治疗不变,巩固组采用培美曲赛单药治疗,以21 d为1个周期.4个周期后比较2组的临床疗效、无疾病进展生存期(PFS)、总生存期(OS)及不良反应.结果 巩固组的有效率(42.11％)及疾病控制率(68.42％)和对照组(36.84％和65.79％)比较,差异无统计学意义(P＞0.05).巩固组的PFS(4.4个月)显著高于对照组(3.2个月),差异有统计学意义(P＜0.05).巩固组的平均OS(15.1个月)显著高于对照组(13.2个月),差异有统计学意义(P＜0.05).巩固组的粒细胞减少(34.21％)、血小板减少(13.16％)和贫血(44.73％)发生率明显低于对照组(分别为47.37％,23.68％,55.26％),差异有统计学意义(P＜0.05).结论 培美曲塞持续一线巩固治疗老年进展期非小细胞肺癌与培美曲塞联合卡铂方案化疗的临床疗效相当,但使用培美曲塞单药进行巩固化疗药物毒性更低,是一种安全有效的治疗措施.     

Safety,Clinical Activity,and Pharmacokinetics of Alflutinib (AST2818) in Patients With Advanced NSCLC With EGFR T790M Mutation

IntroductionAlflutinib (AST2818) is a newly developed third-generation EGFR tyrosine kinase inhibitor selective for EGFR-sensitizing and T790M-resistant mutations. We assessed the safety, efficacy, and pharmacokinetics of alflutinib in patients with advanced NSCLC with confirmed EGFR T790M mutation, whose status progressed after the first- or second-generation EGFR tyrosine kinase inhibitor therapy.MethodsIn the dose-escalation (NCT02973763) and dose-expansion (NCT03127449) studies, patients received alflutinib orally until disease progression, unacceptable toxicity, or subject withdrawal. The primary end points were safety, tolerability, and pharmacokinetics for the dose-escalation study and the objective response rate (assessed by an independent radiological review committee) for the dose-expansion study.ResultsBetween November 30, 2016, and July 24, 2018, a total of 130 patients (14 in dose escalation, 116 in dose expansion) received alflutinib treatment (20 mg, 40 mg, 80 mg, 160 mg, or 240 mg once daily). On October 30, 2018, 79 patients (61%) remained on the treatment. No dose-limiting toxicities were observed in the dose-escalation study. In the dose-expansion study (40–240 mg), the overall objective response rate was 76.7% (89 of 116), and it was 70.6% in patients with central nervous system metastases (12 of 17). A total of 79% of all patients had possibly treatment-related adverse events (AEs) (103 of 130); 8% had treatment-related grade 3 or higher AEs (11 of 130). Serious AEs were reported in 15% of patients (20 of 130), and two serious AEs were related to treatment. No clear dose-response (antitumor activity and AEs) relationships were observed. Exposures to alflutinib and its active metabolite (AST5902) were comparable at steady state.ConclusionsAlflutinib was clinically effective with an acceptable toxicity profile in patients with advanced NSCLC (including those with central nervous system metastases) with EGFR T790M mutation. Further investigation is ongoing.