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易瑞沙 耐药后的解决方案,请大家都来找出路

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发表于 2008-5-6 12:46:12 | 显示全部楼层 来自: 美国
In Reply<br/>Byoung Chul Cho, Joo Hang Kim<br/><br/>Yonsei Cancer Center and the Department of Internal Medicine, Yonsei University College of Medicine; and the Lung Cancer Clinic Severance Hospital, Yonsei University Medical Center, Seoul, Republic of Korea<br/><br/>We thank Dr Costa and his collaborators for their interest in our study. In their letter, they proposed a molecular explanation for response to erlotinib in non–small-cell lung cancer with acquired resistance to gefitinib. We do think that their work illustrated why patients in our phase II study and other anecdotal reports derived clinical benefit from erlotinib therapy after failure of gefitinib.<br/><br/>T790M gatekeeper mutations represent approximately 50% of tumors from patients who initially responded and then relapsed.1 In T790M mutation, the substituted methionine at position 790 makes sterical hindrance. Because of profound gatekeeper effect, T790M mutation can not be overcome by erlotinib. One of the patients in our phase II study revealed T790M mutation in addition to an exon 19 deletion mutation in tumor tissue that became resistant to gefitinib.2 This patient showed progressive disease on subsequent erlotinib therapy, further supporting this hypothesis. Therefore, strategy for overcoming resistance due to T790M mutation is irreversible inhibitors that covalently bind to epidermal growth factor receptor (EGFR).3<br/><br/>Certain second mutations, such as L747S or D761Y, confer much less resistance to gefitinib or erlotinib compared with T790M mutation. Based on crystal structure, D761Y mutation, which occurs in {alpha}-helix of EGFR, is not predicted to result in bulky steric clash as with T790M mutation.4 The importance of presence of T790M mutation as a negative predictor for salvage use of erlotinib after gefitinib therapy was also reported by Chang et al.5 They demonstrated a deletion mutation without T790M mutation in rebiopsied tumor sample from a patient who responded to erlotinib after gefitinib failure. Just as suggested by the authors, erlotinib might be able to overcome resistance due to these second mutations other than T790M mutation. It appears that precise position of mutation within the kinase domain of EGFR could be an important factor in determining which patients might respond to erlotinib. The tumor microenvironment and pharmacokinetics of the drug may influence the type of mutations.4,6<br/><br/>So, why does the tumor that becomes resistant to gefitinib respond to erlotinib? The molecular structure of gefitinib and erlotinib are similar, but not identical. Much lower IC50 value of erlotinib against wild-type EGFR compared with gefitinib might be translated into the higher antitumor effect.7 Furthermore, in case of second mutations with less sterical hindrance for drug binding, small change in molecular structure might allow erlotinib to be fit in the catalytic pocket of EGFR and thus to overcome resistance to gefitinib. Regarding the authors’ prediction that an increase in doses of gefitinib or switching to erlotinib would lead to clinical benefit, we prefer the switch to erlotinib rather than high-dose of gefitinib because of poor tolerability.<br/><br/>A similar example was described in chronic myeloid leukemia. Resistance frequently results from the emergence of point mutations within the kinase domain of the bcr/abl protein that reduce the binding affinity of imatinib.8 Interestingly, the degree of resistance ranges from a few fold for some of the mutation to complete resistance for the T315I mutation which is analogous to T790M in EGFR. Overcoming resistance to imatinib can be achieved through several approaches. These include escalating the dose of imatinib or using new inhibitors, such as nilotinib. Due to structural modifications, nilotinib is more potent in the killing of wild-type bcr/abl–expressing cells and also maintains activity against imatinib-resistant mutant, except T315I.9<br/><br/>In our article, we proposed prior response to gefitinib as a predictive marker for subsequent erlotinib therapy. However, based on the authors’ observation, molecular predictor can lead to better patient selection than clinical predictor. That is, although a tumor showed response to gefitinib and subsequently progressed, it may respond to erlotinib in the absence of T790M mutation. Therefore, it would be reasonable and probably important to perform rebiopsy of tumor tissue on acquisition of resistance in order to optimize and individualize subsequent targeted therapy. As a practical point, acquiring adequate tissue for EGFR mutation analysis, however, is often not feasible, particularly in heavily pretreated patients. We sincerely expect a highly sensitive and noninvasive method for the detection of EGFR mutation in serum DNA to become available as soon as possible.10<br/><br/>The authors’ observation did not address why erlotinib produced a response in our patient with wt EGFR who had stable disease (SD) on gefitinib. This important conclusion in our study may imply that these tumors have resistant mechanisms that could be overcome by erlotinib. In the BR.21 study, a significant prolongation of survival was achieved despite response rate of less than 10%, perhaps because of high proportion of the patients had durable SD while receiving treatment.11 Until today, however, little has been studied about the resistant mechanisms in this large group of patients. Further understanding of mechanism of resistance will facilitate more effective ways to overcome the acquired resistance.<br/><br/>Several published data are now available regarding the clinical activity of erlotinib after the failure of gefitinib. We summarized 16 patients who achieved clinical benefit to erlotinib in Table 1.2,5,12-18 Consistent with our previous assertion, nine among 16 patients showed SD on gefitinib. Seven patients showed partial response (PR) on erlotinib, with time-to-progression of over 90 days in all patients. Most of patients contain wild-type EGFR. Brain lesions showed PR in patients 7 and 8. In patient 11, rebiopsy after progression on gefitinib showed only exon 19 deletion without T790M mutation. Among 17 patients who did not achieve clinical benefit, almost all had PR or progressive disease on gefitinib (Table 2).2,5,12-18 Rebiopsy in patient 5 after progression on gefitinib showed T790M mutation, together with exon 19 deletion.<br/><br/>Table 1. Summary of Patients Who Derived Benefit From Erlotinib After Failure of Gefitinib<br/><br/>Case &#160;&#160; &#160;Histology &#160;&#160; &#160;Sex &#160;&#160; &#160;Smoking &#160;&#160; &#160;No. of Prior Chemotherapy &#160;&#160; &#160;Response to Gefitinib &#160;&#160; &#160;TTP to Gefitinib (days) &#160;&#160; &#160;Response to Erlotinib &#160;&#160; &#160;TTP to Erlotinib (days) &#160;&#160; &#160;EGFR Mutation<br/>1 &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;3 &#160;&#160; &#160;SD &#160;&#160; &#160;181 &#160;&#160; &#160R &#160;&#160; &#160;180 &#160;&#160; &#160;No<br/>2 &#160;&#160; &#160;Ad &#160;&#160; &#160;M &#160;&#160; &#160;Never &#160;&#160; &#160;3 &#160;&#160; &#160;SD &#160;&#160; &#160;204 &#160;&#160; &#160R &#160;&#160; &#160;140 &#160;&#160; &#160;No<br/>3 &#160;&#160; &#160;BAC &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;3 &#160;&#160; &#160;SD &#160;&#160; &#160;549 &#160;&#160; &#160;SD &#160;&#160; &#160;150+ &#160;&#160; &#160;No<br/>4 &#160;&#160; &#160;BAC &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;NR &#160;&#160; &#160;SD &#160;&#160; &#160;681 &#160;&#160; &#160;SD &#160;&#160; &#160;192 &#160;&#160; &#160;No<br/>5 &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;NR &#160;&#160; &#160;SD &#160;&#160; &#160;117 &#160;&#160; &#160R &#160;&#160; &#160;99 &#160;&#160; &#160;No<br/>6 &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;0 &#160;&#160; &#160;SD &#160;&#160; &#160;540 &#160;&#160; &#160R &#160;&#160; &#160;390+ &#160;&#160; &#160;N/A<br/>7* &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;2 &#160;&#160; &#160;SD &#160;&#160; &#160;360 &#160;&#160; &#160;SD &#160;&#160; &#160;390+ &#160;&#160; &#160;N/A<br/>8* &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;2 &#160;&#160; &#160;SD &#160;&#160; &#160;720 &#160;&#160; &#160;SD &#160;&#160; &#160;210+ &#160;&#160; &#160;N/A<br/>9 &#160;&#160; &#160;Ad &#160;&#160; &#160;M &#160;&#160; &#160;Former &#160;&#160; &#160;2 &#160;&#160; &#160;SD &#160;&#160; &#160;120 &#160;&#160; &#160;SD &#160;&#160; &#160;90 &#160;&#160; &#160;No<br/>10 &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;0 &#160;&#160; &#160R &#160;&#160; &#160;420 &#160;&#160; &#160R &#160;&#160; &#160;360+ &#160;&#160; &#160;N/A<br/>11{dagger} &#160;&#160; &#160;Ad &#160;&#160; &#160;M &#160;&#160; &#160;Former &#160;&#160; &#160;1 &#160;&#160; &#160R &#160;&#160; &#160;270 &#160;&#160; &#160R &#160;&#160; &#160;540 &#160;&#160; &#160;Yes<br/>12 &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;3 &#160;&#160; &#160R &#160;&#160; &#160;496 &#160;&#160; &#160;SD &#160;&#160; &#160;111 &#160;&#160; &#160;Yes<br/>13 &#160;&#160; &#160;SCC &#160;&#160; &#160;M &#160;&#160; &#160;Current &#160;&#160; &#160;3 &#160;&#160; &#160R &#160;&#160; &#160;180 &#160;&#160; &#160;SD &#160;&#160; &#160;101 &#160;&#160; &#160;N/A<br/>14 &#160;&#160; &#160;Ad &#160;&#160; &#160;M &#160;&#160; &#160;Current &#160;&#160; &#160;2 &#160;&#160; &#160;PD &#160;&#160; &#160;63 &#160;&#160; &#160;SD &#160;&#160; &#160;104 &#160;&#160; &#160;No<br/>15 &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;NR &#160;&#160; &#160;PD &#160;&#160; &#160;81 &#160;&#160; &#160;SD &#160;&#160; &#160;96 &#160;&#160; &#160;No<br/>16 &#160;&#160; &#160;Ad &#160;&#160; &#160;M &#160;&#160; &#160;Former &#160;&#160; &#160;2 &#160;&#160; &#160;PD &#160;&#160; &#160;60 &#160;&#160; &#160;PR &#160;&#160; &#160;210+ &#160;&#160; &#160;N/A<br/><br/>Abbreviation: EGFR, epidermal growth factor receptor; M, male; F, female; NR, not reported; N/A, not available; Ad, adenocarcinoma; BAC, bronchioloalveolar carcinoma; SCC, squamous-cell carcinoma; TTP, time to progression; PR, partial response; SD, stable disease; PD, progressive disease.<br/><br/>* Brain lesions showed PR.<br/><br/>{dagger} Rebiopsy after progression on gefitinib showed only exon 19 deletion without T790 M mutation.<br/><br/>Table 2. Summary of Patients Who Did Not Derive Benefit From Erlotinib After Failure of Gefitinib<br/><br/>Case &#160;&#160; &#160;Histology &#160;&#160; &#160;Sex &#160;&#160; &#160;Smoking &#160;&#160; &#160;No. of Prior Chemotherapy &#160;&#160; &#160;Response to Gefitinib &#160;&#160; &#160;TTP to Gefitinib (days) &#160;&#160; &#160;EGFR Mutation<br/>1 &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Ever &#160;&#160; &#160;2 &#160;&#160; &#160;PR &#160;&#160; &#160;540 &#160;&#160; &#160;N/A<br/>2 &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;1 &#160;&#160; &#160;PR &#160;&#160; &#160;1,200 &#160;&#160; &#160;N/A<br/>3 &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Ever &#160;&#160; &#160;3 &#160;&#160; &#160;PR &#160;&#160; &#160;660 &#160;&#160; &#160;N/A<br/>4 &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;0 &#160;&#160; &#160;PR &#160;&#160; &#160;300 &#160;&#160; &#160;N/A<br/>5* &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;3 &#160;&#160; &#160;PR &#160;&#160; &#160;365 &#160;&#160; &#160;Yes<br/>6 &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;2 &#160;&#160; &#160;PR &#160;&#160; &#160;120 &#160;&#160; &#160;Yes<br/>7 &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;2 &#160;&#160; &#160;PR &#160;&#160; &#160;344 &#160;&#160; &#160;N/A<br/>8 &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Current &#160;&#160; &#160;2 &#160;&#160; &#160;PR &#160;&#160; &#160;145 &#160;&#160; &#160;N/A<br/>9 &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;2 &#160;&#160; &#160;PR &#160;&#160; &#160;80 &#160;&#160; &#160;Yes<br/>10 &#160;&#160; &#160;SCC &#160;&#160; &#160;M &#160;&#160; &#160;Current &#160;&#160; &#160;0 &#160;&#160; &#160;PD &#160;&#160; &#160;14 &#160;&#160; &#160;N/A<br/>11 &#160;&#160; &#160;Ad &#160;&#160; &#160;M &#160;&#160; &#160;Never &#160;&#160; &#160;2 &#160;&#160; &#160;PD &#160;&#160; &#160;30 &#160;&#160; &#160;N/A<br/>12 &#160;&#160; &#160;MEC &#160;&#160; &#160;M &#160;&#160; &#160;Current &#160;&#160; &#160;2 &#160;&#160; &#160;PD &#160;&#160; &#160;63 &#160;&#160; &#160;Yes<br/>13 &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;2 &#160;&#160; &#160;PD &#160;&#160; &#160;60 &#160;&#160; &#160;No<br/>14 &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;2 &#160;&#160; &#160;PD &#160;&#160; &#160;60 &#160;&#160; &#160;No<br/>15 &#160;&#160; &#160;Ad &#160;&#160; &#160;M &#160;&#160; &#160;Current &#160;&#160; &#160;2 &#160;&#160; &#160;PD &#160;&#160; &#160;60 &#160;&#160; &#160;Yes<br/>16 &#160;&#160; &#160;Ad &#160;&#160; &#160;M &#160;&#160; &#160;Former &#160;&#160; &#160;2 &#160;&#160; &#160;PD &#160;&#160; &#160;60 &#160;&#160; &#160;No<br/>17 &#160;&#160; &#160;Ad &#160;&#160; &#160;M &#160;&#160; &#160;Current &#160;&#160; &#160;2 &#160;&#160; &#160;PD &#160;&#160; &#160;60 &#160;&#160; &#160;No<br/>18 &#160;&#160; &#160;SCC &#160;&#160; &#160;M &#160;&#160; &#160;Former &#160;&#160; &#160;2 &#160;&#160; &#160;PD &#160;&#160; &#160;60 &#160;&#160; &#160;No<br/>19 &#160;&#160; &#160;SCC &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;2 &#160;&#160; &#160;PD &#160;&#160; &#160;60 &#160;&#160; &#160;No<br/>20 &#160;&#160; &#160;Ad &#160;&#160; &#160;M &#160;&#160; &#160;Current &#160;&#160; &#160;2 &#160;&#160; &#160;PD &#160;&#160; &#160;80 &#160;&#160; &#160;No<br/>21 &#160;&#160; &#160;Ad &#160;&#160; &#160;M &#160;&#160; &#160;Former &#160;&#160; &#160;2 &#160;&#160; &#160;PD &#160;&#160; &#160;60 &#160;&#160; &#160;No<br/>22 &#160;&#160; &#160;Ad &#160;&#160; &#160;F &#160;&#160; &#160;Never &#160;&#160; &#160;2 &#160;&#160; &#160;SD &#160;&#160; &#160;122 &#160;&#160; &#160;N/A<br/><br/>Abbreviation: EGFR, epidermal growth factor receptor; NR, not reported; N/A, not available; Ad, adenocarcinoma; BAC, bronchioloalveolar carcinoma; SCC, squamous-cell carcinoma; MEC, mucoepidermoid carcinoma; TTP, time to progression; PR, partial response; SD, stable disease; PD, progressive disease.<br/><br/>* Rebiopsy after progression on gefitinib showed T790 M mutation, together with exon 19 deletion.
有爱,就有奇迹!
发表于 2008-5-6 23:36:13 | 显示全部楼层 来自: 中国江苏苏州
我母亲是服用两年英版易后,产生耐药现象的,今天主任医生跟我们商量说下一次做CT检查,如果不好的话,建议我母亲服用易二代.希望大家能帮我,因为我对易二代不了解,有哪位有见过易耐药后,二代能继续有效的控制病情的吗?
有爱,就有奇迹!
发表于 2008-5-8 00:24:42 | 显示全部楼层 来自: 中国山西太原
<p>max你是哪里的阿?易瑞沙二代已经正式上市了么?</p>
有爱,就有奇迹!
发表于 2008-5-10 23:05:18 | 显示全部楼层 来自: 中国江苏苏州
<p>我是苏州的,是主任医生推荐的,他说是免费服用,具体没有讲.他等下次报告出来后,再做决定.</p>
有爱,就有奇迹!
发表于 2008-5-13 00:21:09 | 显示全部楼层 来自: 中国上海
<div class="msgheader">QUOTE:</div><div class="msgborder"><b>以下是引用<i>max</i>在2008-5-10 23:05:18的发言:</b><br/><p>我是苏州的,是主任医生推荐的,他说是免费服用,具体没有讲.他等下次报告出来后,再做决定.</p></div><p>应该是入组试验的吧</p><p></p><p>上海怎么好像没有呢</p>
有爱,就有奇迹!
发表于 2008-5-13 11:34:38 | 显示全部楼层 来自: 美国
<span style="font-family: pmingliu;">对非小细胞肺癌患者IRESSA</span><span>耐药后</span><span style="font-family: pmingliu;">TARCEVA</span><span></span><span style="font-family: pmingliu;"></span><span>仍可有效讨论的回复<br/><br/></span>金炳哲町,金周杭<br/>&#160;<br/>延世大学癌症中心和新闻部内部医药,延世大学医学院的;和肺癌的临床Severance医院,延世大学医学中心,汉城,大 韩民国<br/>&#160;<br/>我们感谢医生科斯塔和他的合作者对我们的研究感兴趣。在信中,他&#160;&#160; 们对IRESSA耐药后TARCEVA可有效,提出了一个分子解释。我 们认为他们的工作说明了为什么病人在我们的第II期研究和其他传闻的报告得出的IRESSA耐药后TARCEVA的临床受益。 <br/><br/>&#160;<br/>T790M守门基因的突变,代表大 约50%的IRESSA耐药的肿瘤病人。在&#160; T790m突变时,取代蛋氨酸在 790的位置,造成了空间结构(sterical)障碍。因为具有深刻的把关作用, T790m突变不能被TARCEVA克服。在我们第二阶段的研究中,一个病例 结果显示,在肿瘤组织中 T790M突变,再加上外 显子19缺失突变,造成了IRESSA耐药。这名病人出现了病情进展,而其后TARCEVA治疗,进一步支持这一假说。因此,克服&#160; 由于T790m突变产生的耐药 战略,是不可逆 转的抑制剂即共价结合的表皮生长因子受体( EGFR )&#160;&#160;<br/><br/>&#160;<br/>某些第二次突变,如&#160; L747S或D761Y ,相比 T790M突变,这些突变赋予IRESSA或TARVREVA少得多的阻力。基于D761Y突变的晶体结构,其中 发生在阿尔法-螺旋表皮生长因子受体,是不会导致T790M突变那样大量的立体的冲突的 。根据 Dr 陈等人的研究,T790m突变的存在,是IRESSA耐药后,预测 TARCEVA结果时的重大不利因素。他 们展示了一例IRESSA耐药后TARCEVA有效病人的肿瘤样本,其表现出没有t790m突变的<br/>缺失突变。正如作者所指出的, TARCEVA也许能够克服这些除了T790m突变以外的第二种突变造成的耐药。看来,突&#160; 变和激酶域的表皮生长因子受体的精确位置,可能在确定哪些病人&#160; IRESSA耐药后,TARCEVA可能有效,是一个重要因素。肿瘤微环境和药物的药动学可能影响变异类的型。 <br/><br/><div id="result_box" dir="ltr">所以,为什么IRESSA耐药后TARCEVA会有效?IRESSA分子结构和TARCEVA(埃罗替尼)相似,但并不完全相同。&#160;&#160;&#160; IRESSA中抵抗广义表皮生长因子受体的IC50值 比TARCEVA 低得多,正是这种IC50可能会转化为较高的抗肿瘤效果(见文献7),此外,在第二次突&#160; 变中,较少空间结构(sterical)障碍对药物有约束力的。分子结构微小的变化,可能会允许TARCEVA插进适合表皮生长因子受体起作用的小块区域,从而克服IRESSA耐药。关于作者预测,增加IRESSA剂量或切换到TARCEVA将导致临床受益,我们宁愿切换到TARCEVA,而非高 剂量的IRESSA,这是因为对副作用的耐受性。</div><br/><br/>&#160;<br/>待续<br/>

[此贴子已经被作者于2008-5-20 12:35:15编辑过]
有爱,就有奇迹!
发表于 2008-5-13 15:27:02 | 显示全部楼层 来自: 中国广东广州
<p>我父亲08年4月查出左下肺鳞癌T4N2期(CTCT诊断:左侧舌叶见一大小约67*55mm分叶状软组织肿块,密度较均匀,纵隔内主动脉弓旁见一21mm大小肿大淋巴结,首先考虑左侧舌叶肺癌并纵隔淋巴结转),医生建议是化疗加中药治疗,但父亲坚绝不化疗,后来医生说如果不愿意化疗的话可以服用靶向药物加中药。医生推荐的药是特罗凯,现在正在考虑是否服用该药。我几个疑问:</p><p>1、我父亲现在都已经是晚期了,但身体状况很好,没有明显的消瘦,跟平时一样的,除了有点咳嗽,他现在服用该药会不会反而不好,现在用这药是不是早了点。</p><p>2、是服用易瑞沙好还是特罗凯好呢?</p>
有爱,就有奇迹!
发表于 2008-5-13 20:40:20 | 显示全部楼层 来自: 中国上海
<div class="msgheader">QUOTE:</div><div class="msgborder"><b>以下是引用<i>莉莉周13</i>在2008-5-13 0:21:09的发言:</b><br/><p>应该是入组试验的吧</p><p></p><p>上海怎么好像没有呢</p></div><p>如果参加实验组的话,前提是不是必须是服用的英国的易瑞沙呢?</p>
有爱,就有奇迹!
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