威罗菲尼可治疗肺腺癌脑转移

威罗菲尼可治疗肺腺癌脑转移 目前的研究显示 1%-4% 的非小细胞肺癌 (NSCLC) BRAF 突变，这些具有 BRAF(V600E) 突变的病例中有 50% 为腺癌。目前未开展研究 BRAF 突变在 NSCLC 中的作用以及针对这种突变进行靶向治疗。最近美国 Sara D. Robinsona 报道了一例威罗菲尼治疗 BRAF-600E 突变的肺腺癌脑转移患者有效。 由于该患者肿瘤中存在 BRAF(V600) 突变，机体状态也不佳，作者对其使用威罗菲尼进行治疗，这是超出药品说明书治疗范围的，因为威罗菲尼作为 BRAF 的抑制剂目前仅批准在转移性黑色素瘤中使用。 所幸的是该患者疾病得以改善，说明威罗菲尼对 BRAF 突变 NSCLC 患者可能具有治疗作用。颅内疾病的改善说明威罗菲尼能透过血脑屏障，并且对该例肺癌脑转移患者具有治疗作用。 BRAF是 在 NSCLC 中新发现的一个启动子突变基因，它编码 MAPK 信号级联中 KRAS 下游的丝氨酸 / 苏氨酸激酶。BRAF 突变已被证实在黑色素瘤中起到了重要的作用，BRAF 突变最常在 600 位密码子的缬氨酸被谷氨酸所替换。最近发现肺腺癌患者中有 3%-4.9% 存在错义突变。 最开始的研究显示 50% 的 BRAF 突变是 V600E 替换，且发生在那些不吸烟的患者中。这种在后续的研究中未能重现，后续的研究显rAt present, we have formed a "three-three" Park. …… Industrial Park, according to ... ... The instructions of comrade, focus on development needs in the next decade, based on the original, and then extended the 6 square kilometers. Of the Park, to further improve the roads, power supply, communications, water supply and drainage and sewage pipe network and other infrastructure, to achieve full coverage of infrastructure and interconnection with the facilities and raise capacity. Each park to determine 1 leading industries, in particular stone Materials, cans, gloves, through guided, force and other measures to promote the "road company" Park, industrial agglomeration. Currently, to focus on building better ... ... Industrial Park, ... ... Wood Park as the starting area of the industrial park, planners need to take out plan, start construction as soon as possible, undertake in a timely manner ... ... Transfer of the wood industry. This opportunity slip by, so the timing must be tight. Second is to optimize government service. Low efficiency of government services, departments do not coordinate the views of businesses large, poor business environment, it is ... ... Short Board, decide to change. We will continue to deepen reform of the administrative examination and approval system, good digestion, implement the Government canceled, adjustment and devolution of administrative examination and approval matters, strengthen the existing supervision in matters of administrative power, has made it clear to cancel, are not allowed to keep or disguised approval. To do list list of administrative powers and responsibilities 示 BRAF 突变在那些既往吸烟的人群中出现的机率更高。 有研究显示883例 肿瘤中，36(4%)例具有 BRAF 突变 (V600E，18;非 V600E，18)。在这些 BRAF 突变的患者中 14 例被选为评估以铂类 方案 气瓶 现场处置方案 .pdf气瓶 现场处置方案 .doc见习基地管理方案.doc关于群访事件的化解方案建筑工地扬尘治理专项方案下载 为主的化疗的疗效。V600E 突变患者(n=7) 较非突变者具有较低的反应率和较短的 PFS(4.1VS8.9 月)。晚期 NSCLC 以铂类方案为基础的化疗者，平均 PFS 突变型较野生型患者更短(5.2vs6.7 月)，与先前的报道 BRAF-V600E 突变较 BRAF 野生型的预后要差。 因 此，二期临床试验的中期结果显示使用 BRAF 抑制剂达拉菲尼，用于治疗 BRAF V600E 突变的转移性 NSCLC 是合适的。达拉菲尼治疗的患者早期总体缓解率为 50%，中位无病进展存活期为 5.1 月;然而，患者合并脑转移未纳入。因此作者报道了超说明书使用另一 BRAF 抑制剂威罗菲尼用于治疗一例 BRAF V600E 突变的脑转移 NSCLC。 rAt present, we have formed a "three-three" Park. …… Industrial Park, according to ... ... The instructions of comrade, focus on development needs in the next decade, based on the original, and then extended the 6 square kilometers. Of the Park, to further improve the roads, power supply, communications, water supply and drainage and sewage pipe network and other infrastructure, to achieve full coverage of infrastructure and interconnection with the facilities and raise capacity. Each park to determine 1 leading industries, in particular stone Materials, cans, gloves, through guided, force and other measures to promote the "road company" Park, industrial agglomeration. Currently, to focus on building better ... ... Industrial Park, ... ... Wood Park as the starting area of the industrial park, planners need to take out plan, start construction as soon as possible, undertake in a timely manner ... ... Transfer of the wood industry. This opportunity slip by, so the timing must be tight. Second is to optimize government service. Low efficiency of government services, departments do not coordinate the views of businesses large, poor business environment, it is ... ... Short Board, decide to change. We will continue to deepen reform of the administrative examination and approval system, good digestion, implement the Government canceled, adjustment and devolution of administrative examination and approval matters, strengthen the existing supervision in matters of administrative power, has made it clear to cancel, are not allowed to keep or disguised approval. To do list list of administrative powers and responsibilities 图 1:患者胸腹部 CT 图像。(A)治疗前的胸部 CT 图像。(B)威罗菲尼开始治疗四周后的 CT 图像。(C)威罗菲尼治疗 5 月后显示进展的胸部 CT 图像。(D)治疗前的腹部 CT 图像。网膜结节 (红色箭头)。(E) 治疗 4 周后腹部 CT 图像。 患者资料: 51岁 女性非吸烟患者，既往曾在 1999 年因乳腺局部进展的炎性浸润性导管癌。13 年后也就是 2013 年她因为气促和咳嗽而再次就诊于她的肿瘤科医生。乳腺癌为 ER/PR 阴性，HER2/neu 阳性，治疗手段包括术前化疗和右侧乳房切除后曲妥珠单抗和右侧胸壁和局部淋巴结照射。 rAt present, we have formed a "three-three" Park. …… Industrial Park, according to ... ... The instructions of comrade, focus on development needs in the next decade, based on the original, and then extended the 6 square kilometers. Of the Park, to further improve the roads, power supply, communications, water supply and drainage and sewage pipe network and other infrastructure, to achieve full coverage of infrastructure and interconnection with the facilities and raise capacity. Each park to determine 1 leading industries, in particular stone Materials, cans, gloves, through guided, force and other measures to promote the "road company" Park, industrial agglomeration. Currently, to focus on building better ... ... Industrial Park, ... ... Wood Park as the starting area of the industrial park, planners need to take out plan, start construction as soon as possible, undertake in a timely manner ... ... Transfer of the wood industry. This opportunity slip by, so the timing must be tight. Second is to optimize government service. Low efficiency of government services, departments do not coordinate the views of businesses large, poor business environment, it is ... ... Short Board, decide to change. We will continue to deepen reform of the administrative examination and approval system, good digestion, implement the Government canceled, adjustment and devolution of administrative examination and approval matters, strengthen the existing supervision in matters of administrative power, has made it clear to cancel, are not allowed to keep or disguised approval. To do list list of administrative powers and responsibilities 2013年 CT 扫描显示大量右侧胸腔积液和胸膜增厚考虑胸膜转移。左侧锁骨上窝，纵隔和腋窝淋巴结肿大。此外还有双侧肾上腺肿物，胰尾部肿物，心包积液和网膜结节 (图 1A 和 D)。胸膜腔穿刺和左侧锁骨上淋巴结活检证实为转移性腺癌。免疫组化(IHC) 提示为肺源性腺癌(TTF-1 阳性,HER2/neu 阴性)。她的原发性乳腺组织后来测定为 TTF-1 阴性。 患 者因为气促症状不断恶化和乏力而住院。尽管先前进行了胸膜腔穿刺术，患者还是因右侧大量胸腔积液和心包积液导致心包压塞。随后进行了心包开窗术和胸膜腔置 管术引流术，并进行了右上叶和胸膜活检。病理与锁骨上一致。诊断为转移性肺癌。全基因组测序显示其为 BRAF V600E 突变。 rAt present, we have formed a "three-three" Park. …… Industrial Park, according to ... ... The instructions of comrade, focus on development needs in the next decade, based on the original, and then extended the 6 square kilometers. Of the Park, to further improve the roads, power supply, communications, water supply and drainage and sewage pipe network and other infrastructure, to achieve full coverage of infrastructure and interconnection with the facilities and raise capacity. Each park to determine 1 leading industries, in particular stone Materials, cans, gloves, through guided, force and other measures to promote the "road company" Park, industrial agglomeration. Currently, to focus on building better ... ... Industrial Park, ... ... Wood Park as the starting area of the industrial park, planners need to take out plan, start construction as soon as possible, undertake in a timely manner ... ... Transfer of the wood industry. This opportunity slip by, so the timing must be tight. Second is to optimize government service. Low efficiency of government services, departments do not coordinate the views of businesses large, poor business environment, it is ... ... Short Board, decide to change. We will continue to deepen reform of the administrative examination and approval system, good digestion, implement the Government canceled, adjustment and devolution of administrative examination and approval matters, strengthen the existing supervision in matters of administrative power, has made it clear to cancel, are not allowed to keep or disguised approval. To do list list of administrative powers and responsibilities 图 2.(A) 头部 MRI 横截面显示右侧额部脑白质最大的转移病灶直径测量为 6mm(红色箭头)。(B)5 周后脑部 MRI 显示转移灶小于 2mm(红色箭头)。 头 部 MRI 显示幕前和幕下多发小转移灶以及出现的多发骨转移 (图 2A)。腹部和骨盆 CT 显示腹膜多处种植转移，卵巢肿块、腹水、L4 椎体压缩性骨折。考虑到患者的机体状况差以及已发现的驱动基因的突变，寻找替代治疗。最近的研究显示 BRAF 抑制剂在 BRAF 突变肺癌中的使用有效。 此外, 先前的研究显示 BRAF 抑制剂治疗 BRAFV600E 突变的进展性肺癌患者使有效。依据这些研究, 作者推荐患者使用 BRAF 抑制剂威罗菲尼 960mg 口服，一天两次。 一 月后患者症状得以改善，CT 显示右侧胸腔积液减少。此外，主动脉旁淋巴结 (4.6cm 减为 2.9cm)，气管前淋巴结以及腹部、骨盆和骨转移灶也 表 关于同志近三年现实表现材料材料类招标技术评分表图表与交易pdf视力表打印pdf用图表说话 pdf 现出了显著的反应 (图 1B 和 E)。复查头部 MRI 显示颅内转移灶在治疗 4 周后体积减小 (图 2B) 患者在接下来的一个月确实好转，尽管有 2 级皮肤斑丘疹和 1 级肝功能损害。2 个月后复查 CT 示治疗进一步改善了患者的胸膜实质结节，胸部转移灶和骨转移灶。复查头部 MRI 示疾病稳定 不幸的是，在治疗 4 周后，患者发生了呼吸功能障碍。肺部疾病恶化并新出现了肝脏转移 (图 1C)。由于患者病情恶化，未能复查头rAt present, we have formed a "three-three" Park. …… Industrial Park, according to ... ... The instructions of comrade, focus on development needs in the next decade, based on the original, and then extended the 6 square kilometers. Of the Park, to further improve the roads, power supply, communications, water supply and drainage and sewage pipe network and other infrastructure, to achieve full coverage of infrastructure and interconnection with the facilities and raise capacity. Each park to determine 1 leading industries, in particular stone Materials, cans, gloves, through guided, force and other measures to promote the "road company" Park, industrial agglomeration. Currently, to focus on building better ... ... Industrial Park, ... ... Wood Park as the starting area of the industrial park, planners need to take out plan, start construction as soon as possible, undertake in a timely manner ... ... Transfer of the wood industry. This opportunity slip by, so the timing must be tight. Second is to optimize government service. Low efficiency of government services, departments do not coordinate the views of businesses large, poor business environment, it is ... ... Short Board, decide to change. We will continue to deepen reform of the administrative examination and approval system, good digestion, implement the Government canceled, adjustment and devolution of administrative examination and approval matters, strengthen the existing supervision in matters of administrative power, has made it clear to cancel, are not allowed to keep or disguised approval. To do list list of administrative powers and responsibilities 部 MRI，也未再次肺活检。一月后患者死亡。距其诊断为转移性 NSCLC 时 5 月，家属拒绝尸检。 讨论: BRAF抑制剂威罗菲尼和达拉菲尼，在3期随机临床试验中，可以选择性作用于V600 BRAF突变的进展性黑色素瘤，已被FDA批准用于黑色素瘤。这类药物是否也对 BRAF V600E 突变的 NSCLC 也有用目前还在评估中。超过 80% 的黑色素瘤病例具有 V600E 氨基酸替换。而在 NSCLC 患者中，BRAF 阳性患者中仅有一半具有 V600E 突变。 目 前仅报道过 2 例 BRAF V600E 突变的进展型 NSCLC 患者服用威罗菲尼获益。一例报道患者在 3 周时显效, 但是死于充血性心衰，这与靶向治疗不相关。另一例报道显示，患者 2 线治疗使用威罗菲尼, 使用 PET-CT 随访 6 周，治疗完全有效，但是二者都没有脑转移。 目前没 有 BRAF 抑制剂治疗 NSCLC 脑转移有效的报道。作者报道了威罗菲尼治疗 BRAF V600E 突变的女性 NSCLC 患者 4 个月有效，患者具有多发转移灶包括头部。该例患者临床资料和活检被详细记录。患者为右侧 NSCLC, 继发于右侧乳房切除术后放疗，无其他危险因素，尽管这一 BRAF 突变 NSCLC 的自然病程属于早期, 既往报道显示该类型肺癌具有侵袭性强的生物学特点。 目 前无资料显示 BRAF 抑制剂对于 NSCLC 脑转移具有治疗作rAt present, we have formed a "three-three" Park. …… Industrial Park, according to ... ... The instructions of comrade, focus on development needs in the next decade, based on the original, and then extended the 6 square kilometers. Of the Park, to further improve the roads, power supply, communications, water supply and drainage and sewage pipe network and other infrastructure, to achieve full coverage of infrastructure and interconnection with the facilities and raise capacity. Each park to determine 1 leading industries, in particular stone Materials, cans, gloves, through guided, force and other measures to promote the "road company" Park, industrial agglomeration. Currently, to focus on building better ... ... Industrial Park, ... ... Wood Park as the starting area of the industrial park, planners need to take out plan, start construction as soon as possible, undertake in a timely manner ... ... Transfer of the wood industry. This opportunity slip by, so the timing must be tight. Second is to optimize government service. Low efficiency of government services, departments do not coordinate the views of businesses large, poor business environment, it is ... ... Short Board, decide to change. We will continue to deepen reform of the administrative examination and approval system, good digestion, implement the Government canceled, adjustment and devolution of administrative examination and approval matters, strengthen the existing supervision in matters of administrative power, has made it clear to cancel, are not allowed to keep or disguised approval. To do list list of administrative powers and responsibilities 用。初期的黑色素瘤临床研究常将具有脑转移的病例剔除出实验。理论上说血脑屏障限制 BRAF 抑制剂透过, 通过 P 糖蛋白和乳腺癌抑制蛋白导致主动流出。达拉菲尼表现出良好的脑屏障渗透, 但是也受完整的血脑屏障的限制。目前大多数资料显示 BRAF 抑制脑转移的作用来源于黑色素瘤的研究。 BRAF抑 制剂对转移性黑色素瘤脑转移的治疗作用已逐步清晰。2 期开放标签临床实验的结果显示达拉菲尼对 31-39% 的黑色素瘤患者的颅内病灶起作用。此外, 在单组 2 期研究中, 威罗菲尼治疗转移性黑色素瘤脑转移患者, 生存时间超过 6 个月，比预期的脑转移患者的自然病程 (要长小于 3 个月)。这些药物对 CNS 的作用的理论依据在于肿瘤活性破坏了血脑屏障。 这 是首次报道 BRAF V600E 突变 NSCLC 脑转移患者一线使用威罗菲尼治疗有效。这一病例支持了目前正在进行的研究 BRAF 抑制剂治疗 BRAF 突变 NSCLC 患者的作用，证实了威罗菲尼治疗有颅内转移灶的 BRAF 突变 NSCLC 患者有效。我们报道的这个病例是否因为炎症反应而破坏了血脑屏障还不得而知。BRAF 突变的 NSCLC 是一个侵袭性疾病。 需要进一步评价 BRAF 突变 NSCLC 的临床和分子特点, 以便更好的判断这类药物的治疗作用。最后, 和其他靶向治疗一样, 威罗菲尼是我们的一个选择, 其毒性小，尤其适合那些不能耐受化疗的患者。 rAt present, we have formed a "three-three" Park. …… Industrial Park, according to ... ... The instructions of comrade, focus on development needs in the next decade, based on the original, and then extended the 6 square kilometers. Of the Park, to further improve the roads, power supply, communications, water supply and drainage and sewage pipe network and other infrastructure, to achieve full coverage of infrastructure and interconnection with the facilities and raise capacity. Each park to determine 1 leading industries, in particular stone Materials, cans, gloves, through guided, force and other measures to promote the "road company" Park, industrial agglomeration. Currently, to focus on building better ... ... Industrial Park, ... ... Wood Park as the starting area of the industrial park, planners need to take out plan, start construction as soon as possible, undertake in a timely manner ... ... Transfer of the wood industry. This opportunity slip by, so the timing must be tight. Second is to optimize government service. Low efficiency of government services, departments do not coordinate the views of businesses large, poor business environment, it is ... ... Short Board, decide to change. We will continue to deepen reform of the administrative examination and approval system, good digestion, implement the Government canceled, adjustment and devolution of administrative examination and approval matters, strengthen the existing supervision in matters of administrative power, has made it clear to cancel, are not allowed to keep or disguised approval. To do list list of administrative powers and responsibilities 考 虑到威罗菲尼治疗 NSCLC 相对短期的治疗作用，弄清楚其耐药的机制显得非常重要。多种机制可能参与了 BRAF 抑制剂的耐药，这已在转移性黑色素瘤中报道了。这些机制包括:MAPK 信号通路上调 (RAS 突变，剪接变体，BRAF 过度表达)，PTEN 缺失。 目 前,BRAF 靶向治疗结合 MEK 抑制剂已在有 BRAF V600E 突变的色素瘤患者中使用, 显著改善 PFS。研究人员推测在 NSCLC 中也存在相似的耐药机制。特别是,RAS 的活性增加可能与先前进行 BRAF 抑制剂治疗患者的获得性耐药有关。这些突变在转移性 NSCLC 患者中具有复合靶向治疗。 现在, 临床试验正在进行寻找联合选择性的 BRAF 激酶抑制剂达拉菲尼和 MAPK 激酶抑制剂曲美替尼治疗具有 BRAF V600E 突变转移性 NSCLC(四期)。 rAt present, we have formed a "three-three" Park. …… Industrial Park, according to ... ... The instructions of comrade, focus on development needs in the next decade, based on the original, and then extended the 6 square kilometers. Of the Park, to further improve the roads, power supply, communications, water supply and drainage and sewage pipe network and other infrastructure, to achieve full coverage of infrastructure and interconnection with the facilities and raise capacity. Each park to determine 1 leading industries, in particular stone Materials, cans, gloves, through guided, force and other measures to promote the "road company" Park, industrial agglomeration. Currently, to focus on building better ... ... Industrial Park, ... ... Wood Park as the starting area of the industrial park, planners need to take out plan, start construction as soon as possible, undertake in a timely manner ... ... Transfer of the wood industry. This opportunity slip by, so the timing must be tight. Second is to optimize government service. Low efficiency of government services, departments do not coordinate the views of businesses large, poor business environment, it is ... ... Short Board, decide to change. We will continue to deepen reform of the administrative examination and approval system, good digestion, implement the Government canceled, adjustment and devolution of administrative examination and approval matters, strengthen the existing supervision in matters of administrative power, has made it clear to cancel, are not allowed to keep or disguised approval. To do list list of administrative powers and responsibilities