盘点:近期“黑色素瘤”相关研究汇总

2016-10-07 Mechront MedSci原创

黑色素瘤,又称恶性黑色素瘤,是来源于黑色素细胞的一类恶性肿瘤,常见于皮肤,亦见于黏膜、眼脉络膜等部位。黑色素瘤是皮肤肿瘤中恶性程度最高的瘤种,容易出现远处转移。早期诊断和治疗因而显得尤为重要。 【1】黑色素瘤劫持重要免疫信号途径对抗免疫治疗 研究者首先对16名接受ipilimumab治疗的黑色素瘤病人进行了全外显子测序数据分析。16名病人中只有4人应答ipilimumab治疗,另外

黑色素瘤,又称恶性黑色素瘤,是来源于黑色素细胞的一类恶性肿瘤,常见于皮肤,亦见于黏膜、眼脉络膜等部位。黑色素瘤是皮肤肿瘤中恶性程度最高的瘤种,容易出现远处转移。早期诊断和治疗因而显得尤为重要。

【1】黑色素瘤劫持重要免疫信号途径对抗免疫治疗

研究者首先对16名接受ipilimumab治疗的黑色素瘤病人进行了全外显子测序数据分析。16名病人中只有4人应答ipilimumab治疗,另外12人不应答。在不应答治疗者的肿瘤中共发现184个基因突变,其中142个为基因拷贝数变异,42个为单核苷酸变异,而在应答治疗者的肿瘤中只发现了4个基因突变。分析表明不应答治疗者在肿瘤的IFNγ信号途径上平均存在15.33个基因突变,基因拷贝数的变异最为显著。

12个不应答治疗者中有9人存在基因拷贝数的改变,其中一些基因的变异最为显著,包括IFNγ的两个受体IFNGR1和IFNGR2以及两个最重要的下游基因IRF-1和JAK2出现基因缺失。这条通路上两个已知的抑制因子SOCS1和PIAS4出现了基因扩增的情况。

对The Cancer Genome Atlas数据库中367名黑色素瘤病人的生存数据进行分析表明存在基因拷贝数变异的病人生存时间更短,相比于不存在突变的病人短了大约8个月。

研究人员在一个对IFNγ攻击比较敏感的黑色素瘤细胞系中敲除IFNGR1,结果发现肿瘤细胞在存在IFNγ的情况下也可以生长。他们又将相同的细胞系移植到小鼠体内,并用ipilimumab进行治疗,24只存在正常IFNγ受体的小鼠中只有4只发展为癌症,而移植了敲除IFNGR1的细胞系的25只小鼠中有12只发展为肿瘤。

所有未接受治疗的小鼠都死于肿瘤生长,80%接受了ipilimumab治疗并存在正常受体的小鼠存活下来,接受了治疗但受体表达被抑制的小鼠只有一半存活下来。

研究人员表示他们希望找到联合治疗策略克服IFNγ信号途径中一些关键的缺失,“我们希望能够刺激免疫系统产生其他细胞因子,治疗IFNγ信号途径发生损伤的肿瘤。”文章通讯作者Padmanee Sharma这样表示。(文章详见——Cell:黑色素瘤劫持重要免疫信号途径对抗免疫治疗

【2】治疗黑色素瘤脑转移,靶向治疗比传统化疗效果更好

研究人员对于接受免疫和定向放疗联合治疗的黑色素瘤脑转移病人能否得到比传统化疗更好的结果进行了研究。他们对96名黑色素瘤脑转移病人的临床数据进行了回顾性分析,这些病人都接受了立体定向放疗,并在3个月内接受了不同的靶向治疗(抗PD-1治疗,抗CTLA-4治疗,BRAF抑制剂加MEK抑制剂或单独使用BRAF抑制剂)或传统化疗。

研究人员发现靶向治疗能够更好地控制放疗区域之外脑部区域的肿瘤生长,治疗效果好于传统化疗。在所有得到分析的治疗组中,接受抗PD-1治疗或BRAF/MEK抑制剂治疗之后接受放射治疗的病人有更好的肿瘤控制情况。

相比于其他治疗组,立体放射治疗结合抗PD-1治疗或BRAF/MEK抑制剂治疗能够让病人的生存情况得到改善。41%接受抗PD-1治疗的病人以及39%接受BRAF/MEK抑制剂治疗的病人存活12个月,没有出现全身疾病进展,只有5%接受传统化疗的病人存活12个月没有出现全身疾病进展。与之类似,接受抗PD-1治疗、BRAF/MEK抑制剂治疗和传统化疗的病人其12个月的整体生存率为分别为48%,65%和10%。

这些结果表明对于黑色素瘤脑转移病人来说,抗PD-1治疗和BRAF/MEK抑制剂治疗结合立体定向放疗能够提供最佳的疾病控制方法。(文章详见——Ann Oncol :治疗黑色素瘤脑转移 靶向治疗比传统化疗效果更好

【3】春天出生的人,黑色素瘤风险更高?

研究纳入了2002年到2012年的28374例黑色素瘤患者,数据来自于巴伐利亚以人口为基础的癌症登记数据(CRB);将这个人群与巴伐利亚人口出生月份分布数据进行比较。采用负二项回归模型进行数据分析。

粗略分析显示,黑色素瘤患者中,3月份出生的人群尤其的多!调整性别和出生年份后,负二项回归模型分析显示,三月、四月和五月出生的人,与十二月出生的人相比较,黑色素瘤风险高出13–21%!不过,调整巴伐利亚人口出生月份分布后,这些联系显著下降,并且没有发现出生月份与黑色素瘤风险的联系。亚组分析也得到类型结果。

本项研究并没有得出与既往研究类似的结果,即是说,没有证据表明,不同出生季节会影响黑色素瘤风险。(文章详见——Int J Epidemiol:春天出生的人,黑色素瘤风险更高?

【4】2期试验支持nivolumab+ipilimumab作为晚期黑色素瘤一线治疗(CheckMate 069)

本研究纳入了2个国家(法国和美国)19个专科癌症中心的患者,所有患者均≥18岁、既往没有治疗、不可切除的III期或IV期黑色素瘤、东部肿瘤协作组性能状态0或1。患者按2:1随机分为静脉使用nivolumab 1 mg/kg+ipilimumab 3 mg/kg,或ipilimumab 3 mg/kg+安慰剂,每三周接受四个剂量;随后,nivolumab+ipilimumab组患者接受nivolumab 3 mg/kg,每两周一个剂量,直到疾病进展或不可接受的毒性反应;ipilimumab组患者则接受安慰剂,每两周一个剂量。主要终点在先前已有报告:BRAFV600野生型黑色素瘤患者达到客观缓解的比例。

2013年9月16日至2014年2月6日,筛选了179例患者,纳入了142例患者,nivolumab+ipilimumab组和ipilimumab组分别有95例和47例患者,此后因不接受研究药物,两组中均有1名患者不符合纳入标准。中位随访24.5个月(IQR 9·1–25·7),两组的2年总生存率分别为63·8% (95% CI 53·3–72·6)和53·6% (95% CI 38·1–66·8);两组中位总生存期均未达(HR 0·74, 95% CI 0·43–1·26; p=0·26);两组治疗相关3、4级不良事件分别有51/94(54%)例和9/46(20%)例;nivolumab+ipilimumab组最常见的治疗相关3、4级不良事件是结肠炎(12 [13%] )、丙氨酸转氨酶升高(10 [11%]),ipilimumab组最常见的治疗相关3、4级不良事件是腹泻(5[11%])、下垂体炎 (2 [4%])。nivolumab+ipilimumab组报告了34 (36%) 例治疗相关3、4级严重不良事件(结肠炎10[11%]、腹泻5[5%]),ipilimumab组报告了4(9%)例治疗相关3、4级严重不良事件(腹泻2[4%]、结肠炎1[2%]、下垂体炎1[2%])。本次更新数据研究期间,没有发现新类型治疗相关不良事件,也没有发现治疗相关死亡。

这项研究中的患者仍处于随访期间,不过现有的数据分析已经表明,nivolumab+ipilimumab联合治疗 vs ipilimumab单药治疗,可以改善晚期黑色素瘤患者的结局,支持其作为一线治疗。(文章详见——Lancet Oncol:2期试验支持nivolumab+ipilimumab作为晚期黑色素瘤一线治疗(CheckMate 069)

【5】治疗黑色素瘤的一线药物cobimetinib+vemurafenib


本研究将经病理证实为BRAFV600突变的IIIC、IV期黑色素瘤成年患者(年龄≥18年)被随机分配(1:1)到cobimetinib(28天为一个周期,前21天,60毫克每日一次;之后休息7天)或安慰剂治疗,均同时口服vemurafenib(960毫克每天两次)。

在2013年1月8日和2014年1月31日之间,符合条件的495例成人患者随机分配到cobimetinib+vemurafenib组(n = 247)或安慰剂+vemurafenib组(n = 248)。中位随访14.2个月(IQR 8.5–17.3),试验组和对照组的中位无进展生存期分别为12.3个月(95% CI 9.5–13.4)和7.2个月(5.6–7.5)(HR 0.58 [95% CI 0.46–0.72], p<0.0001)。对255 (52%)名死亡患者进行总生存期分析,试验组和对照组的总生存期分别为22.3个月(95% CI 20.3–?)和17.4个月(95% CI 15.0–19.8)(HR 0.70, 95% CI 0.55–0.90; p=0.005)。

安全性方面,vemurafenib和cobimetinib的耐受性好,安全可控,更长时间随访过程中没有发现新的安全隐患。试验组与对照组相比,发生频率较高的最常见的3-4级不良事件是γ-谷氨酰转移酶增加(36 [15%] vs 25 [10%])、血肌酸磷酸激酶升高(30 [12%] vs 1 [<1%])、丙氨酸转氨酶升高(28 [11%] vs 15 [6%])。试验组和对照组分别有92(37%)和69(28%)名患者出现不良事件。试验组最常见的严重不良事件为发热(6[2%])和脱水(5[2%])。总共有259名患者死亡,试验组和对照组死亡人数分别为117 (47%)和142 (58%)。大多数死因都是疾病进展,试验组和对照组人数分别为109/117(93%)和133/142(94%)。

结果表明,对于未经治疗的BRAFV600突变的晚期黑色素瘤患者,联合使用cobimetinib+vemurafenib,相比安慰剂+vemurafenib,能改善无进展生存期;支持cobimetinib+vemurafenib作为标准的一线治疗。(文章详见——Lancet Oncol:治疗黑色素瘤的一线药物cobimetinib+vemurafenib

【6】头颈部皮肤恶性黑色素瘤研究

大多数头颈部皮肤恶性黑色素瘤(CHNM)的研究表明,CHNM与其他部位黑色素瘤相比,生存更差,尤其是头皮或颈部的黑色素瘤。

研究纳入了2008-2012年在挪威诊断为皮肤黑色素瘤患者(n=8120)中的所有CHNM (n = 1074)患者。

与躯干和四肢皮肤黑色素瘤患者相比,CHNM患者更多见于男性,更有可能出现结节性和雀斑恶性皮肤黑色素瘤,并较高的T分期诊断风险更高(P ≤ .01)。后位CHNM与前位相比,有更高的T分期诊断,更可能诊断为溃疡和晚期阶段(P < .001)。多因素分析显示,T分期和临床分期是影响黑色素瘤特异性和整体死亡的唯一重要预后因素(P < .001)。

后位CHNM与前位相比,晚期CHNM风险更高;但多因素分析中,黑色素瘤部位与黑色素瘤特异性和整体死亡无关。(文章详见——J Am Acad Dermatol:头颈部皮肤恶性黑色素瘤研究

【7】安进溶瘤免疫疗法获英国NICE批准治疗晚期黑色素瘤

Imlygic(T-Vec)是一种溶瘤免疫疗法(oncolytic immunotherapy),这是一种基因工程化的病毒,能够表达GM-CFS。Imlygic直接注射入肿瘤组织,可在肿瘤细胞中大量复制直至细胞膜破裂或死亡(即细胞裂解),同时能够在肿瘤组织局部释放粒细胞-巨噬细胞集落刺激因子(GM-CSF),这是一种白细胞生长因子,能够激活系统性免疫反应。Imlygic通过2种重要且互补的方式发挥作用:引发肿瘤细胞溶解或死亡,使肿瘤释放出肿瘤特异性抗原,与GM-CSF共同激发一种全身性的抗肿瘤免疫反应。

Imlygic是全球获批上市的首个溶瘤免疫疗法。在美国,FDA于2015年10月批准Imlygic用于首次手术后病情复发的不可切除性黑色素瘤患者,用于皮肤性、皮下及结节病变的局部治疗。需要指出的是,Imlygic并不能改善总生存期,也不能改善发生内脏转移的黑色素瘤病情。在欧洲,Imlygic于2015年12月获欧盟委员会批准,用于无骨骼、大脑、肺部或其他内脏转移的局部或远端转移(IIIB、IIIC、IVM1a期)不可切除性黑色素瘤成人患者的治疗。

根据NICE,与其他免疫疗法相比,Imlygic治疗黑色素瘤的副作用更少,这是由于Imlygic是直接被注射入肿瘤组织内部,而其他免疫疗法则是系统性(全身性)治疗。来自黑色素瘤临床试验的数据显示,Imlygic注射瘤内治疗使64%的肿瘤体积缩小50%或以上。

在NHS中,Imlygic 1ml小瓶装的价格是1670英镑。临床专家预计,Imlygic适用于大约10-15%的不可手术切除性转移性晚期黑色素瘤患者。(文章详见——喜讯!安进溶瘤免疫疗法获英国NICE批准治疗晚期黑色素瘤

【8】日本Oncolys BioPharma 将在美国开展黑色素瘤溶瘤疗法OBP-301临床试验


Oncolys BioPharma是一家位于日本东京的生物技术公司,即将在晚期的、不可切除性的黑色素瘤患者中展开Telomelysin (OBP-301)的II期临床试验。

该溶瘤疗法是一种病毒疗法,将经过基因工程改造的病毒直接注射到肿瘤部位,病毒就可以感染肿瘤细胞并将其杀灭,与此同时,这一过程还会释放抗原,引起肿瘤相关的免疫应答。这种经过基因工程改造的病毒只会在肿瘤细胞中复制,而正常的细胞不会受到影响。

Telomelysin是基因工程改造后的腺病毒,目前已经在16个患有不同实体瘤的患者中进行I期安全性试验,相关试验数据发表在顶级期刊Nature上。临床试验发现,注射完一次的患者出现肿瘤体积的缩小,并且产生了针对肿瘤细胞的免疫应答。(文章详见——挑战安进!日本Oncolys BioPharma 将在美国开展黑色素瘤溶瘤疗法OBP-301临床试验

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createdName=shenxlcyp, createdTime=Fri Aug 18 00:47:00 CST 2017, time=2017-08-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=154725, encodeId=7a6a154e2597, content=在次学习,同样受益!, beContent=null, objectType=article, channel=null, level=null, likeNumber=59, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/ajNVdqHZLLC1BMzZWdMSPQWuib6BtQGicK8ygGBM6YakpfkRc67soFSuKbZr86enL1KggQZEZbgWSeicJibafmYfQ3AibicIHMwwicmDShfRFvvI38/0, createdBy=272a110164, createdName=laoli, createdTime=Thu Nov 10 07:56:54 CST 2016, time=2016-11-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=151675, encodeId=69b71516e5e3, content=特别好,收获很大, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTJHmctib8wsjB1Y0etxU20nsCbR8rZ2fpibp2STmwH2YzicIsTe9oHRGB6XIMeBqNdIvxODicmzfeQibIw/132, createdBy=82211964557, createdName=清幽蓝燕yan, createdTime=Fri Oct 28 10:29:56 CST 2016, time=2016-10-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=151195, encodeId=33451511956e, content=认真看了,特别好,还会再搜索相关英文再看看, beContent=null, objectType=article, channel=null, level=null, likeNumber=57, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTJHmctib8wsjB1Y0etxU20nsCbR8rZ2fpibp2STmwH2YzicIsTe9oHRGB6XIMeBqNdIvxODicmzfeQibIw/132, createdBy=82211964557, createdName=清幽蓝燕yan, createdTime=Tue Oct 25 22:13:57 CST 2016, time=2016-10-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=149546, encodeId=54f614954691, content=赞一个!好文章拜读了,如果避免黑色素瘤,岂不是更好啊?认真学习了。有待探究!, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7s7ZCKOmmbBTD6nE7gcd5OZpvyGEzkxBP3S275k5ZJVrsPkotZhBglRHM9rKvcj1OgkssqhcnoPw8zIaMZTF8c/0, createdBy=4c441942088, createdName=ylzr123, createdTime=Tue Oct 18 19:55:36 CST 2016, time=2016-10-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=145310, encodeId=c93614531082, content=好文章,受益, beContent=null, objectType=article, channel=null, level=null, likeNumber=48, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzdAIB7UwTkHt6fQkBP8ictliaXtc5gCUmYdAW1sAETC2nhO3q6YjRHkUibyOCtP8ibmXNObTyd63A076/0, createdBy=d4111948983, createdName=1e10c84am36(暂无匿称), createdTime=Tue Oct 11 20:13:57 CST 2016, time=2016-10-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=143065, encodeId=ac06143065bc, content=文章很好,继续关注, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzdAIB7UwTkHt6fQkBP8ictliaXtc5gCUmYdAW1sAETC2nhO3q6YjRHkUibyOCtP8ibmXNObTyd63A076/0, createdBy=d4111948983, createdName=1e10c84am36(暂无匿称), createdTime=Mon Oct 10 10:53:28 CST 2016, time=2016-10-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1558765, encodeId=2caf1558e65f0, content=<a href='/topic/show?id=e27610332666' target=_blank style='color:#2F92EE;'>#黑色素#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=103326, encryptionId=e27610332666, topicName=黑色素)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=778d36, createdName=柳叶一刀, createdTime=Sun Oct 09 07:47:00 CST 2016, time=2016-10-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1564774, encodeId=e70d1564e74c6, content=<a href='/topic/show?id=e27610332666' target=_blank style='color:#2F92EE;'>#黑色素#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=103326, encryptionId=e27610332666, topicName=黑色素)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=150614999302, createdName=cqlidoudou, createdTime=Sun Oct 09 07:47:00 CST 2016, time=2016-10-09, status=1, ipAttribution=)]
    2017-04-14 sunylz
  2. 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  3. 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createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTJHmctib8wsjB1Y0etxU20nsCbR8rZ2fpibp2STmwH2YzicIsTe9oHRGB6XIMeBqNdIvxODicmzfeQibIw/132, createdBy=82211964557, createdName=清幽蓝燕yan, createdTime=Fri Oct 28 10:29:56 CST 2016, time=2016-10-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=151195, encodeId=33451511956e, content=认真看了,特别好,还会再搜索相关英文再看看, beContent=null, objectType=article, channel=null, level=null, likeNumber=57, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTJHmctib8wsjB1Y0etxU20nsCbR8rZ2fpibp2STmwH2YzicIsTe9oHRGB6XIMeBqNdIvxODicmzfeQibIw/132, createdBy=82211964557, createdName=清幽蓝燕yan, createdTime=Tue Oct 25 22:13:57 CST 2016, time=2016-10-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=149546, encodeId=54f614954691, content=赞一个!好文章拜读了,如果避免黑色素瘤,岂不是更好啊?认真学习了。有待探究!, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7s7ZCKOmmbBTD6nE7gcd5OZpvyGEzkxBP3S275k5ZJVrsPkotZhBglRHM9rKvcj1OgkssqhcnoPw8zIaMZTF8c/0, createdBy=4c441942088, createdName=ylzr123, createdTime=Tue Oct 18 19:55:36 CST 2016, time=2016-10-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=145310, encodeId=c93614531082, content=好文章,受益, beContent=null, objectType=article, channel=null, level=null, likeNumber=48, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzdAIB7UwTkHt6fQkBP8ictliaXtc5gCUmYdAW1sAETC2nhO3q6YjRHkUibyOCtP8ibmXNObTyd63A076/0, createdBy=d4111948983, createdName=1e10c84am36(暂无匿称), createdTime=Tue Oct 11 20:13:57 CST 2016, time=2016-10-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=143065, encodeId=ac06143065bc, content=文章很好,继续关注, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzdAIB7UwTkHt6fQkBP8ictliaXtc5gCUmYdAW1sAETC2nhO3q6YjRHkUibyOCtP8ibmXNObTyd63A076/0, createdBy=d4111948983, createdName=1e10c84am36(暂无匿称), createdTime=Mon Oct 10 10:53:28 CST 2016, time=2016-10-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1558765, encodeId=2caf1558e65f0, content=<a href='/topic/show?id=e27610332666' target=_blank style='color:#2F92EE;'>#黑色素#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=103326, encryptionId=e27610332666, topicName=黑色素)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=778d36, createdName=柳叶一刀, createdTime=Sun Oct 09 07:47:00 CST 2016, time=2016-10-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1564774, encodeId=e70d1564e74c6, content=<a href='/topic/show?id=e27610332666' target=_blank style='color:#2F92EE;'>#黑色素#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=103326, encryptionId=e27610332666, topicName=黑色素)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=150614999302, createdName=cqlidoudou, createdTime=Sun Oct 09 07:47:00 CST 2016, time=2016-10-09, status=1, ipAttribution=)]
    2016-11-10 laoli

    在次学习,同样受益!

    0

  4. 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createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTJHmctib8wsjB1Y0etxU20nsCbR8rZ2fpibp2STmwH2YzicIsTe9oHRGB6XIMeBqNdIvxODicmzfeQibIw/132, createdBy=82211964557, createdName=清幽蓝燕yan, createdTime=Fri Oct 28 10:29:56 CST 2016, time=2016-10-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=151195, encodeId=33451511956e, content=认真看了,特别好,还会再搜索相关英文再看看, beContent=null, objectType=article, channel=null, level=null, likeNumber=57, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTJHmctib8wsjB1Y0etxU20nsCbR8rZ2fpibp2STmwH2YzicIsTe9oHRGB6XIMeBqNdIvxODicmzfeQibIw/132, createdBy=82211964557, createdName=清幽蓝燕yan, createdTime=Tue Oct 25 22:13:57 CST 2016, time=2016-10-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=149546, encodeId=54f614954691, content=赞一个!好文章拜读了,如果避免黑色素瘤,岂不是更好啊?认真学习了。有待探究!, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7s7ZCKOmmbBTD6nE7gcd5OZpvyGEzkxBP3S275k5ZJVrsPkotZhBglRHM9rKvcj1OgkssqhcnoPw8zIaMZTF8c/0, createdBy=4c441942088, createdName=ylzr123, createdTime=Tue Oct 18 19:55:36 CST 2016, time=2016-10-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=145310, encodeId=c93614531082, content=好文章,受益, beContent=null, objectType=article, channel=null, level=null, likeNumber=48, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzdAIB7UwTkHt6fQkBP8ictliaXtc5gCUmYdAW1sAETC2nhO3q6YjRHkUibyOCtP8ibmXNObTyd63A076/0, createdBy=d4111948983, createdName=1e10c84am36(暂无匿称), createdTime=Tue Oct 11 20:13:57 CST 2016, time=2016-10-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=143065, encodeId=ac06143065bc, content=文章很好,继续关注, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzdAIB7UwTkHt6fQkBP8ictliaXtc5gCUmYdAW1sAETC2nhO3q6YjRHkUibyOCtP8ibmXNObTyd63A076/0, createdBy=d4111948983, createdName=1e10c84am36(暂无匿称), createdTime=Mon Oct 10 10:53:28 CST 2016, time=2016-10-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1558765, encodeId=2caf1558e65f0, content=<a href='/topic/show?id=e27610332666' target=_blank style='color:#2F92EE;'>#黑色素#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=103326, encryptionId=e27610332666, topicName=黑色素)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=778d36, createdName=柳叶一刀, createdTime=Sun Oct 09 07:47:00 CST 2016, time=2016-10-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1564774, encodeId=e70d1564e74c6, content=<a href='/topic/show?id=e27610332666' target=_blank style='color:#2F92EE;'>#黑色素#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=103326, encryptionId=e27610332666, topicName=黑色素)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=150614999302, createdName=cqlidoudou, createdTime=Sun Oct 09 07:47:00 CST 2016, time=2016-10-09, status=1, ipAttribution=)]
    2016-10-28 清幽蓝燕yan

    特别好,收获很大

    0

  5. 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createdName=柳叶一刀, createdTime=Sun Oct 09 07:47:00 CST 2016, time=2016-10-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1564774, encodeId=e70d1564e74c6, content=<a href='/topic/show?id=e27610332666' target=_blank style='color:#2F92EE;'>#黑色素#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=103326, encryptionId=e27610332666, topicName=黑色素)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=150614999302, createdName=cqlidoudou, createdTime=Sun Oct 09 07:47:00 CST 2016, time=2016-10-09, status=1, ipAttribution=)]
    2016-10-25 清幽蓝燕yan

    认真看了,特别好,还会再搜索相关英文再看看

    0

  6. 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createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTJHmctib8wsjB1Y0etxU20nsCbR8rZ2fpibp2STmwH2YzicIsTe9oHRGB6XIMeBqNdIvxODicmzfeQibIw/132, createdBy=82211964557, createdName=清幽蓝燕yan, createdTime=Fri Oct 28 10:29:56 CST 2016, time=2016-10-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=151195, encodeId=33451511956e, content=认真看了,特别好,还会再搜索相关英文再看看, beContent=null, objectType=article, channel=null, level=null, likeNumber=57, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTJHmctib8wsjB1Y0etxU20nsCbR8rZ2fpibp2STmwH2YzicIsTe9oHRGB6XIMeBqNdIvxODicmzfeQibIw/132, createdBy=82211964557, createdName=清幽蓝燕yan, createdTime=Tue Oct 25 22:13:57 CST 2016, time=2016-10-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=149546, encodeId=54f614954691, content=赞一个!好文章拜读了,如果避免黑色素瘤,岂不是更好啊?认真学习了。有待探究!, beContent=null, objectType=article, 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createdName=柳叶一刀, createdTime=Sun Oct 09 07:47:00 CST 2016, time=2016-10-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1564774, encodeId=e70d1564e74c6, content=<a href='/topic/show?id=e27610332666' target=_blank style='color:#2F92EE;'>#黑色素#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=103326, encryptionId=e27610332666, topicName=黑色素)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=150614999302, createdName=cqlidoudou, createdTime=Sun Oct 09 07:47:00 CST 2016, time=2016-10-09, status=1, ipAttribution=)]
    2016-10-18 ylzr123

    赞一个!好文章拜读了,如果避免黑色素瘤,岂不是更好啊?认真学习了。有待探究!

    0

  7. 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GetPortalCommentsPageByObjectIdResponse(id=143065, encodeId=ac06143065bc, content=文章很好,继续关注, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzdAIB7UwTkHt6fQkBP8ictliaXtc5gCUmYdAW1sAETC2nhO3q6YjRHkUibyOCtP8ibmXNObTyd63A076/0, createdBy=d4111948983, createdName=1e10c84am36(暂无匿称), createdTime=Mon Oct 10 10:53:28 CST 2016, time=2016-10-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1558765, encodeId=2caf1558e65f0, content=<a href='/topic/show?id=e27610332666' target=_blank style='color:#2F92EE;'>#黑色素#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=103326, encryptionId=e27610332666, topicName=黑色素)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=778d36, createdName=柳叶一刀, createdTime=Sun Oct 09 07:47:00 CST 2016, time=2016-10-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1564774, encodeId=e70d1564e74c6, content=<a href='/topic/show?id=e27610332666' target=_blank style='color:#2F92EE;'>#黑色素#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=103326, encryptionId=e27610332666, topicName=黑色素)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=150614999302, createdName=cqlidoudou, createdTime=Sun Oct 09 07:47:00 CST 2016, time=2016-10-09, status=1, ipAttribution=)]
    2016-10-11 1e10c84am36(暂无匿称)

    好文章,受益

    0

  8. 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createdName=柳叶一刀, createdTime=Sun Oct 09 07:47:00 CST 2016, time=2016-10-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1564774, encodeId=e70d1564e74c6, content=<a href='/topic/show?id=e27610332666' target=_blank style='color:#2F92EE;'>#黑色素#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=103326, encryptionId=e27610332666, topicName=黑色素)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=150614999302, createdName=cqlidoudou, createdTime=Sun Oct 09 07:47:00 CST 2016, time=2016-10-09, status=1, ipAttribution=)]
    2016-10-10 1e10c84am36(暂无匿称)

    文章很好,继续关注

    0

  9. 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