An evaluation of encorafenib for the treatment of melanoma.
- 作者列表："Carr MJ","Sun J","Eroglu Z","Zager JS
:Introduction: In the treatment of advanced BRAF-mutant melanoma, selective regulation of the MAPK pathway with BRAF and MEK inhibition has emerged as one of the mainstays of therapy.Areas covered: The authors present the current data on encorafenib as a compound, its pharmacokinetic and pharmacodynamics properties. This review includes current data on encorafenib therapy as a single agent as well as in combination with the MEK-inhibitor binimetinib and other systemic therapies.Expert opinion: BRAF inhibition with encorafenib exhibits substantial antitumor activity with less paradoxical MAPK pathway activation leading to treatment resistance. Combination therapy with MEK inhibitors improves response rate, progression-free survival, and overall survival in patients with BRAF-mutant metastatic melanoma compared to prior treatment regimens. Serious adverse events, including the development of cutaneous malignancies, are reported at lower rates with combination therapy, while less severe events such as pyrexia can be more common. Existing data is lacking for a recommendation of triplet therapy, although results from multiple ongoing trials are highly anticipated.
引言: 在晚期BRAF突变黑色素瘤的治疗中，通过BRAF和MEK抑制选择性调控MAPK通路已成为治疗的主要手段之一。涵盖的领域: 作者介绍了目前关于encorafenib作为化合物的数据，其药代动力学和药效学性质。本综述包括目前关于encorafenib作为单一药物治疗以及与MEK抑制剂binimetinib和其他全身治疗联合治疗的数据。专家意见: encorafenib抑制BRAF表现出实质性的抗肿瘤活性，不太矛盾的MAPK通路激活导致治疗抵抗。与之前的治疗方案相比，MEK抑制剂的联合治疗提高了BRAF突变转移性黑色素瘤患者的反应率、无进展生存期和总生存期。严重不良事件，包括皮肤恶性肿瘤的发展，联合治疗的发生率较低，而不太严重的事件如发热可能更常见。现有数据缺乏三联疗法的推荐，尽管多个正在进行的试验的结果备受期待。
METHODS::Blue rubber bleb naevus syndrome (BRBNS) is an extremely rare venous malformation that often manifests as multiple haemangioma-like lesions in the skin and gastrointestinal tract. The drug sirolimus plays a key role in the signalling pathway of angiogenesis and subsequent development of BRBNS and its use has been described in several case reports. We present a case series of four patients with BRBNS who exhibited good treatment response to sirolimus. All four patients were administered oral sirolimus at doses of 1.0-1.5 mg/m2 /day with a target drug level of 5-10 ng/mL and median treatment duration of 20 months. All patients had a reduction in the size of the lesions and a normalization of coagulopathy with tolerable drug adverse reactions at follow-up. Sirolimus may be effective and safe in paediatric patients with BRBNS. Further prospective studies are suggested to evaluate the long-term effectiveness of this drug.
METHODS:BACKGROUND:Human papillomavirus (HPV) infections are associated with common dermatologic and nondermatologic diseases. Although HPV vaccines are well established as preventive measures for genital warts and cervical neoplasia, their use as therapeutic agents deserves greater attention. OBJECTIVE:To evaluate the use of HPV vaccine(s) as a treatment modality for cutaneous and/or mucosal disease. METHODS:A primary literature search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted in January 2019 by using the PubMed and Cochrane databases. RESULTS:A total of 63 articles with 4439 patients were included. The majority of patients with cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas were successfully treated with HPV vaccination. Preliminary data on patients with pre-existing anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia is promising. LIMITATIONS:This review was limited by the lack of controls, patients' previous HPV vaccination status, and publication bias. CONCLUSION:The commercially available three-dose, quadrivalent HPV vaccine is a potential therapeutic option for the treatment of cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas. Noncommercially available HPV vaccines demonstrate therapeutic response for treating anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia. The vaccine's efficacy as an adjunct therapy for HPV-associated cutaneous and/or mucosal disease warrants further exploration.
METHODS::Our understanding of melanoma precursors and progression to melanoma has developed as a result of advances in the field of molecular diagnostics. We now better understand the potential for genetic heterogeneity within a single lesion. Combined tumors can pose a diagnostic challenge when deciding the line between benign and malignant, which in turn has direct implications for patient management. Primary cilia (PC) are ubiquitous sensory organelles that have essential functions in cellular proliferation, differentiation, and development. The ciliation index (percentage of ciliated melanocytes) has been shown to reliably differentiate melanoma, which fail to ciliate, from melanocytic nevi, which retain PC. We therefore analyzed the potential for using the ciliation index to differentiate benign and malignant components in combined melanocytic lesions. We collected patient samples (n = 10) of unequivocal combined lesions with both melanoma and associated nevus components. Melanocytes were highlighted with SOX10 and costained with gamma-Tubulin and acetylated alpha-Tubulin to highlight the basal body and cilium, respectively. The number of melanocytes retaining cilia under high-power microscopy was examined. The melanoma component had average of 4% ciliation (SD: 7%), whereas the associated nevus component was significantly higher with 59% ciliation (SD: 17%). These data show that PC may be a reliable means of distinguishing benign from malignant components within a single tumor. The ciliation index may be a helpful tool in distinguishing challenging cases of combined lesions of melanoma in situ with a dermal nevus component from invasive melanoma, thus promoting improved staging and clinical management.