Recent advances in molecular targeted therapy for unresectable and metastatic BRAF-mutated melanoma.
- 作者列表："Kiniwa Y","Okuyama R
:The clinical outcome of BRAF-mutated advanced melanoma has been improved by both molecular targeted therapies and immune checkpoint inhibitors. Long-term follow-up data reveal durable clinical responses in patients receiving first-line combinations of BRAF inhibitors plus MEK inhibitors, particularly those showing a complete response. Clinical outcomes are also associated with the lactate dehydrogenase levels and the number of metastatic organs. Although brain metastasis is frequently difficult to control, systemic therapy is preferred in cases with small and asymptomatic brain metastases associated with progressive extra-cranial disease. Control of intra-cranial disease with BRAF inhibitors plus MEK inhibitors is comparable with that of immune checkpoint inhibitors, although immune checkpoint inhibitors are superior to targeted therapies with respect to survival. The BRAF inhibitors plus MEK inhibitors regimen is well-tolerated, and toxicities are usually manageable and reversible, but differ according to the specific regimen used. Guidelines in the United States, Europe, and Japan recommend targeted therapy for patients who need early tumor responses. A meta-analysis of retrospective data shows that the baseline lactate dehydrogenase level is significantly higher in patients treated with BRAF inhibitors plus MEK inhibitors than in those treated with immune checkpoint inhibitors, suggesting that clinicians tend to use BRAF inhibitors plus MEK inhibitors for more advanced disease. Since there is insufficient efficacy and safety data on the use of targeted therapies for acral and mucosal melanoma, a retrospective analysis may be useful. The combination of molecular targeted therapy plus immune checkpoint inhibitors is expected to elicit further improvement. The results of several trials using combination or sequential therapies will be available in the next few years.
: BRAF突变的晚期黑色素瘤的临床结果已经通过分子靶向治疗和免疫检查点抑制剂得到改善。长期随访数据揭示了接受BRAF抑制剂 + MEK抑制剂一线组合的患者的持久临床反应，特别是那些显示完全反应的患者。临床结果也与乳酸脱氢酶水平和转移器官的数量有关。尽管脑转移通常难以控制，但对于患有与进行性颅外疾病相关的小的和无症状的脑转移的病例，优选全身治疗。BRAF抑制剂加MEK抑制剂对颅内疾病的控制与免疫检查点抑制剂相当，尽管免疫检查点抑制剂在生存方面优于靶向治疗。BRAF抑制剂加MEK抑制剂方案耐受性良好，毒性通常是可控的和可逆的，但根据使用的具体方案而不同。美国、欧洲和日本的指南建议对需要早期肿瘤反应的患者进行靶向治疗。一项回顾性数据的荟萃分析显示，接受BRAF抑制剂联合MEK抑制剂治疗的患者的基线乳酸脱氢酶水平显著高于接受免疫检查点抑制剂治疗的患者，这表明临床医生倾向于使用BRAF抑制剂联合MEK抑制剂治疗更晚期的疾病.由于使用靶向治疗肢端和粘膜黑色素瘤的有效性和安全性数据不足，回顾性分析可能是有用的。分子靶向治疗加免疫检查点抑制剂的组合有望引起进一步的改善。使用联合或序贯疗法的几项试验的结果将在未来几年提供。
METHODS::The ATP binding-cassette superfamily corresponds the mostly transmembrane transporters family found in humans. These proteins actively transport endogenous and exogenous substrates through biological membranes in body tissues, so they have an important role in the regulation of many physiological functions necessary for human homeostasis, as well as in response regulation to several pharmacological substrates. The development of multidrug resistance has become one of the main troubles in conventional chemotherapy in different illnesses including cancer, being the increased efflux of antineoplastic drugs the main reason for this multidrug resistance, with a key role of the ABC superfamily. Likely, the interindividual variability in the pharmacological response among patients is well known, and may be due to intrinsically factors of the disease, genetic and environmental ones. Thus, the understanding of this variability, especially the genetic variability associated with the efficacy and toxicity of drugs, can provide a safer and more effective pharmacological treatment, so ABC genes are considered as important regulators due to their relationship with the reduction in pharmacological response. In this review, updated information about transporters belonging to this superfamily was collected, the possible role of these transporters in cancer, the role of genetic variability in their genes, as well as some therapeutic tools that have been tried to raise against main transporters associated with chemoresistance in cancer.
METHODS:BACKGROUND:Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). RESEARCH DESIGN AND METHODS:The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. RESULTS:A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × ε4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). CONCLUSIONS:Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.
METHODS::Since the discovery of dental pulp stem cells, a lot of teams have expressed an interest in dental pulp regeneration. Many approaches, experimental models and biological explorations have been developed, each including the use of stem cells and scaffolds with the final goal being clinical application in humans. In this review, the authors' objective was to compare the experimental models and strategies used for the development of biomaterials for tissue engineering of dental pulp with stem cells. Electronic queries were conducted on PubMed using the following terms: pulp regeneration, scaffold, stem cells, tissue engineering and biomaterial. The extracted data included the following information: the strategy envisaged, the type of stem cells, the experimental models, the exploration or analysis methods, the cytotoxicity or viability or proliferation cellular tests, the tests of scaffold antibacterial properties and take into account the vascularization of the regenerated dental pulp. From the 71 selected articles, 59% focused on the "cell-transplantation" strategy, 82% used in vitro experimentation, 58% in vivo animal models and only one described an in vivo in situ human clinical study. 87% used dental pulp stem cells. A majority of the studies reported histology (75%) and immunohistochemistry explorations (66%). 73% mentioned the use of cytotoxicity, proliferation or viability tests. 48% took vascularization into account but only 6% studied the antibacterial properties of the scaffolds. This article gives an overview of the methods used to regenerate dental pulp from stem cells and should help researchers create the best development strategies for research in this field.