Pharmacotherapy of metastatic melanoma: Emerging trends and opportunities for a cure

Metastatic melanoma is one of the most deadly forms of cancer and is poorly responsive to standard chemotherapeutics, such as Dacarbazine and Paclitaxel. Recently, the advent of Vemurafenib and Ipilimumab has broadened the spectrum of therapeutic options for advanced melanoma patients but the occurrence of resistance and of high-grade toxicities call for better and more effective treatments. This review focuses on approved and experimental therapies for metastatic melanoma. The mechanism of action and the reported efficacy data for small molecule drugs and biologics are discussed, outlining directions for future pharmaceutical research in this field.     

转移性黑素瘤的治疗选择

黑素瘤的发病率不断增加,尽管该病早期发现可治愈,但晚期黑素瘤患者有全身器官的广泛的转移,且中位生存期<10个月。随着对黑素瘤细胞基因和恶性转化驱动因素的分子水平的研究,大量的治疗靶点研究和开发,新的治疗模式--免疫治疗已用于晚期黑素瘤的治疗。     

Malignant mucosal melanoma in the olfactory cleft of a 10-year-old child

Mucosal malignant melanoma is a rare but aggressive neoplasm with high rates of recurrence and death. It is known that two-thirds of mucosal melanoma cases arise in the nasal cavity and paranasal sinuses in adults. However, there have been few studies until now on children with mucosal malignant melanoma and the related treatment. We report on a 10-year-old girl with mucosal malignant melanoma presented as a nasal polyp, which was removed via endoscopic sinus surgery and adjuvant chemotherapy without recurrence.     

SM5-1: a new monoclonal antibody which is highly sensitive and specific for melanocytic lesions

Abstract Antibodies such as HMB-45 and anti-S100 protein have been widely used as markers of malignant melanoma despite evidence that HMB-45 has a sensitivity of only 67–93% and S100 is nonspecific for melanoma. Using a subtractive immunization protocol in a mouse model of human melanoma, we have generated several monoclonal antibodies with putative specificity for melanoma. After initial screenings, the antibody SM5-1 was chosen because of its intriguing reactivity with melanocytic tumors in both frozen and paraffin sections. The immunohistochemical staining of SM5-1 was studied in paraffin-embedded specimens of 401 melanomas (n = 401; 250 primary melanomas, 151 metastases), melanocytic nevi of the skin (n = 16), nonmelanocytic neoplasms (n = 84). The results were compared with HMB-45 and anti-S100 staining. All antibodies reacted with nevi and 97–99% with primary melanomas. Whereas both SM5-1 and anti-S100 stained 96% (146/151) of melanoma metastases, HMB-45 correctly identified only 83% (126/151). All HMB-45-negative metastases were positive for SM5-1. Whereas neither SM5-1 nor HMB-45 stained any of 84 specimens from 40 different nonmelanocytic neoplasms, anti-S100 was positive in 21/84 (25%). While the staining pattern of SM5-1 was mostly homogeneous, small tumor areas in some metastases remained unstained. Staining with SM5-1 was also observed in perivascular dendritic cells, in plasma cells, some myofibroblasts and the secretion of eccrine sweat glands. Nonactivated epidermal melanocytes, keratinocytes, endothelial cells, smooth muscle cells and peripheral nerves were all negative for SM5-1. These results suggest that SM5-1 is highly specific, as well as sensitive, for melanocytic lesions and is useful in the immunohistochemical evaluation of melanoma. Received: 16 June 2000 / Revised: 28 July 2000 / Accepted: 29 September 2000     

肢端恶性黑素瘤100例临床和病理分析

目的 探讨肢端恶性黑素瘤的临床、病理特点和外伤在发病中的意义以及现行分型方法的有效性。方法 选取最近诊断的具有完整临床、病理资料的100例肢端恶性黑素瘤，对其临床、病理数据进行统计分析。结果 原发于手28例，其中拇指甲下14例；足72例，足掌跖29例，足跟18例，拇趾甲下12例。31例原发部位有外伤史。40例肢端恶性黑素瘤难以用目前的分型方法分型，依据现行病理分型方法，肢端雀斑样痣性、结节性、浅表扩散性黑素瘤在肿瘤浸润深度、临床分期等方面差异无显著性。结论 足部是肢端恶性黑素瘤的好发部位，外伤是发病的重要诱因，现行分型方法的临床意义尚需进一步研究。     

BAG-1蛋白在皮肤恶性黑素瘤皮损中的表达及其与P53、Bcl-2的关系

目的 探讨皮肤恶性黑素瘤组织及黑素瘤细胞株中BAG-1蛋白、P53、Bcl-2的表达及意义。方法 免疫组化法检测32例皮肤恶性黑素瘤、20例色素痣皮损石蜡包埋标本中BAG-1蛋白、P53和Bcl-2的表达情况，并结合患者临床资料进行分析；免疫细胞化学法检测BAG-1蛋白在黑素瘤细胞株M14和B16F10细胞的表达情况。结果 BAG-1蛋白在32例皮肤恶性黑素瘤组织中25例阳性，阳性表达率为78%；色素痣组20例中阳性3例，阳性表达率为15%，两组比较，差异有统计学意义（P < 0.001）。BAG-1蛋白在皮肤恶性黑素瘤组织中的表达与Clark分级呈正相关（r = 0.47，P < 0.05），与P53、Bcl-2表达无显著相关性（r 值分别为0.05和0.11，P > 0.05）。BAG-1蛋白在黑素瘤细胞株M14、B16F10细胞均呈阳性表达。结论 BAG-1蛋白在皮肤恶性黑素瘤组织中的表达显著升高，并与肿瘤的Clark分级呈正相关。     

白癜风患者血清抗黑素细胞抗体与恶性黑素瘤的相关性研究

目的分析白癜风患者血清抗黑素细胞抗体与恶性黑素瘤的相关性。方法利用活黑素细胞ELISA法筛选白癜风患者血清;制备黑素瘤细胞的全息膜蛋白,通过双向电泳技术分离其蛋白;转膜后分别用白癜风患者抗黑素细胞抗体阳性血清和正常血清作为一抗行W estern B lotting检测。结果获得抗黑素细胞抗体的阳性血清;优化膜蛋白提纯的条件,获得了黑素瘤细胞全息膜蛋白分辨率高、重复性好的双向电泳图;利用W estern B lotting方法比较正常人血清和患者血清与黑素瘤细胞膜蛋白的免疫印迹点,发现1个阳性差异蛋白点,表观分子量为70-75KD,表观等电点约为6.5。结论证明了在黑素瘤细胞表面存在与白癜风患者血清抗黑素细胞抗体结合的膜抗原。     

载脂蛋白D在皮肤恶性黑素瘤中的水平检测及临床意义

目的　检测皮肤恶性黑色素瘤(CMM)中载脂蛋白D(apoD)的水平并研究其临床意义。方法　用免疫组化SP法检测65例原发性CMM和20例黑色素细胞痣中apoD的水平。结果　CMM中apoD阳性25例(38. 46% ),所有黑色素细胞痣均阴性。apoD的阳性与患者的年龄、性别及肿瘤发生的部位无明显关系, 而与CMM的组织病理分型和Clark分级有关(P<0. 05)。apoD阳性患者,术后3年生存率显著低于阴性患者(P<0. 05)。结论　apoD参与了CMM的发生发展过程,可能是CMM预后不良的一个新的预测指标。     

Let-7b对人黑色素瘤细胞增殖及有氧糖酵解的影响

目的研究let-7b对人黑色素瘤细胞增殖及有氧糖酵解的影响。方法将人工合成的microRNA单核苷酸let-7bmimics及inhibitor通过脂质体转染人黑色素瘤细胞株A375,上调或抑制let-7b在细胞内的表达水平,不同时相点检测细胞葡萄糖消耗和乳酸产量,MTT法检测细胞增殖。运用单因素方差分析探讨let-7b表达水平与黑色素瘤细胞有氧糖酵解及增殖的关系。结果let-7bmimics组24、48h时相点检测MTr吸光度值分别为0．396±0．030、0．525±0．037,低于其他组（P〈0．05）,提示高表达let-7b抑制细胞增殖;各组黑色素瘤细胞24、48h葡萄糖消耗及乳酸产量差异无统计学意义（P〉0．05）,乳酸产量与葡萄糖消耗比值各组间差异无统计学意义（P〉0．05）,其中空白组在24h和48h内葡萄糖转化为乳酸效率约为57％和43％。结论黑色素瘤A375细胞具有显著的有氧糖酵解表型,过表达let-7b可抑制人恶性黑色素瘤细胞A375增殖,但对于细胞的有氧糖酵解效率,尚未发现let-7b对其有显著影响。