多靶点诱导治疗增殖性和膜性狼疮性肾炎前瞻对照性临床研究

目的:狼疮性肾炎(LN)尤其是重型LN的诱导疗效迄今仍不令人满意.我们的研究已表明,多靶点疗法[霉酚酸酯(MMF)+他克莫司(FK506)+激素]能够有效治疗Ⅴ+Ⅳ型LN.在此我们开展另一项研究,前瞻性比较多靶点疗法与传统环磷酰胺(CTX)疗法诱导治疗增殖性和膜性LN(包括Ⅲ、Ⅳ、Ⅴ、Ⅴ+Ⅲ和Ⅴ+Ⅳ型)的疗效差异. 方法:120例患者被随机分为多靶点治疗组和静脉环磷酰胺组(IVCY)组.诱导期初定6个月;若6个月内未达完全缓解,诱导期延长至9个月.两组患者均采用静脉甲基泼尼松龙冲击后口服泼尼松治疗.多靶点组诱导期采用FKS06、MMF及激素三联治疗,FK506起始剂量4 mg/d(体重<50 Kg,剂量为3 mg/d);MMF起始剂量1.0 g/d(体重<50 Kg,剂量为0.75 g/d).IVCY组采用静脉CTX冲击治疗,CTX首次剂量0.75 g/m2 BSA,此后根据情况调整在0.5～1.0 g/m2BSA,每月1次. 结果:多靶点治疗组6个月和9个月完全缓解率分别51.7%和63.3%,显著高于IVCY治疗组(26.7%,P<0.01;35.0%,P<0.01).多靶点治疗组Ⅲ、Ⅳ、Ⅴ、Ⅴ+Ⅲ和Ⅴ+Ⅳ型LN诱导9个月后完全缓解率分别为75.0%、60.0%、57.1%、66.7%和66.7%,而对照组完全缓解率分别为33.3%、51.9%、28.6%、20.0%和16.7%.多靶点治疗组主要不良反应包括高血压(10.0%)、胃肠道不适(10.0%)、上感(8.3%)、脱发(6.7%)和高血糖(5.0%).仅有1例患者出现一过性血肌酐增高,2例患者发生肺部感染. 结论:多靶点诱导治疗增殖性和膜性LN的疗效优于传统IVCY,且患者耐受性好.多靶点疗法为LN的诱导治疗提供了一种新理念.     

前瞻性比较普乐可复与环磷酰胺诱导治疗Ⅴ型伴Ⅳ型狼疮性肾炎的疗效

目的前瞻性比较普乐可复(FK506)与环磷酰胺(CTX)联合激素诱导治疗Ⅴ型合并Ⅳ型(Ⅴ+Ⅳ型)狼疮性肾炎LN)的临床疗效.方法经肾活检诊断为Ⅴ+Ⅳ型活动性、女性LN患者37例,平均年龄(30.0±9.8)岁,尿蛋白定量≥2.0 g/d,血清白蛋白＜3.0 g/dl,随机分为两组,分别给予口服FK506[FK506组,n=19,起始剂量0.1mg/(kg·d)]或CTX静脉冲击治疗(CTX组,n=18)(0.5～1.0g/m2 BSA,1/月×6月),同时口服泼尼松[起始剂量0.6 mg/(kg·d)],其中17例接受甲基泼尼松龙静脉冲击治疗.主要评价指标为治疗6个月完全缓解率(CR,定义为尿蛋白定量＜0.4 g/24h,尿红细胞正常范围,无管型尿及白细胞尿,血清白蛋白≥3.5 g/dl,SCr正常或上升不超过正常范围15%,无肾外狼疮活动),次要观察指标为治疗6个月部分缓解率(PR)和有效率(CR+PR).结果(1)临床疗效有31例患者完成6个月诱导期治疗,其中FK506组15例,CTX组16例;6例退出治疗,CTX组2例,FK506组4例.FK506组4例患者获得CR(26.7%),10例患者PR(66.7%),而CTX组仅1例CR(6.3%)、7例PR(43.8%).FK506组治疗有效率明显高于CTX组(93.3% vs 50%,P=0.015).两组患者治疗后SLE-DAI、血清白蛋白、补体较前有显著改善,但血尿及抗dsDNA抗体的阳性率无明显改变;FK506组平均尿蛋白较治疗前显著减少,而CTX组较治疗前无明显下降;(2)FK506剂量浓度与不良反应FK506诱导治疗剂量在0.086～0.091 mg/(kg·d),平均谷浓度水平为6.6～8.1 ng/ml.4例获得CR的患者FK506浓度在6.9～10.2 ng/ml,10例PR患者血药浓度平均为(8.1±3.3)ng/ml.在此剂量下治疗6个月,未见肾小管间质损害.FK506组不良反应的发生率(肝酶升高、上消化道不适、白细胞减少、感染、脱发、月经紊乱等)低于CTX组,尤其是月经紊乱的发生率显著低于CTX组(5.6% vs 38.9%,P=0.041);虽然血压升高、糖代谢异常等并发症高于CTX组,但两组间无统计学差异.结论FK506诱导治疗Ⅴ型合并Ⅳ型病变的LN疗效明显优于CTX治疗,不良反应小.     

激素联合赛可平和他克莫司治疗狼疮性肾炎的前瞻性临床研究

目的:前瞻性观察激素联合赛可平(MMF)和他克莫司(FK506)(多靶点组)诱导治疗狼疮性肾炎(LN)的疗效及安全性,并与激素联合环磷酰胺静脉冲击疗法(IV-CYC)进行比较。方法:79例经肾活检确诊的IV型、Ⅴ+Ⅳ型和Ⅴ+Ⅲ型LN患者随机分为多靶点组(n=45)和IV-CYC组(n=34)。两组患者均先使用甲泼尼龙静脉冲击治疗后口服泼尼松。多靶点组中MMF(杭州中美华东制药有限公司)治疗剂量1g/d,MMF血药浓度(MPA-AUC0～12h)目标值为20～30mg·h/L;FK506(杭州中美华东制药有限公司)剂量4mg/d,FK506谷浓度维持4～7ng/ml。IV-CYC组CYC剂量0.5～0.75g/m2BSA,每月1次。诱导治疗疗程6～9个月。疗效主要指标为完全缓解率(定义为尿蛋白<0.4g/24h,血清白蛋白≥35g/L,血清肌酐正常,无肾外活动),比较两组的临床疗效和不良反应。结果:多靶点组[女39例,男6例,平均年龄(25.1±9.3)岁]与IV-CYC组[女30例,男4例,平均年龄(30.4±8.9)岁]的基础临床指标和病理类型无统计学差异。诱导6月(53.3%vs29.4%P<0.05)和9月(62.2%vs42.6%,P<0.05)的完全缓解率多靶点组均显著高于IV-CYC组。多靶点组Ⅴ+Ⅳ型的完全缓解率显著高于IV-CYC组(50.0%vs16.7%,P<0.05),Ⅴ+Ⅲ型的完全缓解率也高于IV-CYC(54.5%vs22.2%,P>0.05)。IV型LN两组缓解率无差异。多靶点组总不良反应发生率低于IV-CYC(31.1%vs70.6%,P<0.01),其中多靶点组的主要不良反应为高血压(11.1%)和带状疱疹(6.7%),IV-CYC组的主要不良反应为胃肠道反应(23.5%)、白细胞减少(13.7%)和皮肤感染(8.8%)。两组分别有2例和1例并发肺部感染,无一例死亡。结论:激素联合赛可平和他克莫司组成的多靶点疗法治疗LN的疗效优于CYC静脉冲击疗法,尤其对Ⅴ+Ⅳ型疗效更为显著且不良反应发生率低。多靶点疗法的临床疗效和对远期预后的影响还需要多中心和长期随访的临床研究。     

多靶点治疗Ⅳ+Ⅴ型狼疮性肾炎的长期随访

目的:既往研究证实多靶点疗法(MT)治疗Ⅳ+Ⅴ型狼疮性肾炎(LN)较传统静脉环磷酰胺冲击疗法(IVCY)能获得更高的诱导缓解率,本研究进一步探讨MT治疗Ⅳ+Ⅴ型LN的长期疗效和安全性。方法:将80例经肾活检证实的Ⅳ+Ⅴ型LN患者随机分为MT组(MT诱导缓解后MT维持,40例),和IVCY-硫唑嘌呤(AZA)组(IVCY诱导缓解后AZA维持,40例)。两组均同时予口服激素,总随访时间24月。主要疗效指标为完全缓解率,次要指标包括部分缓解、复发和不良反应发生率。结果:MT组和IVCY-AZA组分别有36例(90%)和24例(60%)获得诱导缓解(P0.01),MT组6月(45%vs12.5%,P0.01)和24月完全缓解率(80%vs47.5%,P0.01)显著高于IVCY-AZA组。MT组和IVCY-AZA组分别有36例、21例进入维持期观察,两组24月内肾脏复发率(8.3%vs4.8%,P0.05)及肾脏无复发生存率无明显差异。诱导期MT组和IVCY-AZA组感染发生率均为22.5%,IVCY-AZA组脱发、胃肠道症状发生率高于MT组(17.5%vs2.5%,22.5%vs5%,P0.05),新发高血压仅出现在MT组。维持期MT组和IVCY-AZA组分别有11.1%和28.6%患者出现白细胞减低(P0.05)。结论:采用多靶点疗法诱导,并维持治疗Ⅳ+Ⅴ型LN能获得较高缓解率、安全性好。     

吗替麦考酚酯诱导治疗弥漫增生性狼疮性肾炎的临床疗效

目的:比较吗替麦考酚酯(MMF)和间断静脉环磷酰胺(IV-CTX)诱导治疗伴新月体形成的弥漫增生性狼疮性肾炎(LN)的疗效。方法:80例经肾活检明确诊断的弥漫增生性LN(Ⅳ型LN)且伴新月体(≥15%)形成的患者,接受激素联合MMF诱导治疗(MMF组,n=39)或IV-CTX冲击治疗(IV-CTX组,n=41),回顾性分析两组诱导治疗6月的缓解率[总缓解率和完全缓解(CR)率]。结果:MMF组和IV-CTX组基线临床病理数据无显著差异,中位新月体比例分别为34.6%和31.0%(P=0.836)。MMF组6月总缓解率显著高于IV-CTX组(92.3%vs 73.1%,P=0.024),其中CR率亦高于IV-CTX组,但无统计学差异(48.7%vs 34.1%,P=0.186)。在新月体比例50%的LN(n=61)患者中,MMF组6月总缓解率(96.7%vs 74.2%,P=0.026)显著高于IV-CTX组,其中CR率高于IV-CTX组(46.7%vs 35.5%,P=0.375)。新月体比例≥50%LN患者(n=19)中MMF组6月总缓解率和CR率虽高于IV-CTX组,但无统计学差异。MMF组补体C3恢复正常比例显著高于IV-CTX组(64.1%vs 35.9%,P=0.013)。结论:MMF治疗伴新月体形成的Ⅳ型LN的诱导缓解率高于IV-CTX冲击治疗,但仍需前瞻性随机对照研究的证实。     

吗替麦考酚酯治疗增殖性狼疮性肾炎的疗效和远期预后

目的:分析激素联合吗替麦考酚酯(MMF)治疗增殖性狼疮性肾炎(LN)的疗效及远期预后。方法:经肾活检病理诊断为Ⅲ型、Ⅳ型及Ⅲ/Ⅳ+Ⅴ型LN并接受激素和MMF诱导治疗≥3个月的235例患者纳入本研究。根据MMF维持治疗疗程不同分为MMF长期维持组(组Ⅰ)、MMF短期维持组(组Ⅱ)、非MMF维持组(组Ⅲ)。诱导治疗疗效分为完全缓解、部分缓解和未缓解。复合肾脏终点事件包括终末期肾病(ESRD)、肌酐倍增和估算的肾小球滤过率(e GFR)下降≥50%。结果:221例(94.0%)患者获得缓解,6个月和9个月的总缓解率分别为89.3%和90.2%,完全缓解分别为47.6%和53.1%,不同病理类型的缓解率无统计学差异(P0.05)。中位随访时间83个月。随访期间,共73例(33.0%)复发,组Ⅰ复发率(22.1%)显著低于组Ⅱ(45.5%,P0.05)和组Ⅲ(44.4%,P0.05)。多因素COX回归分析发现组Ⅱ(HR 2.29,95%CI 1.18~4.47,P=0.015)和组Ⅲ(HR 3.22,95%CI 1.85~5.61,P0.001)的复发风险显著高于组Ⅰ。10年复合肾脏终点事件发生率组Ⅰ(4.8%)低于组Ⅱ(10.6%)和组Ⅲ(13.9%),但无统计学差异(P0.05)。结论:MMF诱导缓解后长期MMF维持能获得较好的持续缓解率,长期MMF维持可降低复发率和终点事件发生率。     

普乐可复与环磷酰胺诱导治疗Ⅳ型狼疮性肾炎的疗效比较

目的:比较观察口服普乐可复(FK506)与环磷酰胺静脉冲击(IVC)联合激素诱导治疗Ⅳ型狼疮性肾炎(LN)的疗效及安全性,探讨FK506合适的治疗剂量与血药浓度范围。方法:经肾活检诊断为Ⅳ-G型(2003年ISN/RPS分类)活动性、女性LN患者34例,平均年龄(27·1±9·9)岁,尿蛋白定量≥2·0g/d,血清白蛋白<3·0g/dl,随机分为FK506组[n=17,起始剂量0·1mg/(k·/d)]和IVC组(n=17,0·5~1·0g/m2BSA,1/月×6月),同时口服泼尼松(0·6mg/kg·d),其中22例患者接受甲基泼尼松龙静脉冲击治疗。主要评价指标为治疗6个月完全缓解率(CR,定义为尿蛋白定量<0·4g/24h,尿红细胞正常范围,无管型尿及白细胞尿,血清白蛋白≥3·5g/dl,SCr正常或上升不超过正常范围15%,无肾外狼疮活动),次要观察指标为治疗6个月部分缓解(PR)率和有效率(CR+PR)。结果:(1)临床疗效:治疗6个月FK506组和IVC组的有效率分别为94·1%和82·4%,FK506组有11例患者获得CR(11/17,64·7%),高于IVC组(7/17,41·2%)(P=0·303);FK506组出现PR的时间明显短于IVC组[(1·9±1·2)月vs(3·2±1·8)月,P=0·034],而两组获得CR的时间分别为(4·0±1·3)月和(5·0±1·2)月;两组患者SLE-DAI、尿蛋白水平、血尿、血清白蛋白、补体C3、C4水平及A-dsDNA阳性率较治疗前均有显著改善;(2)FK506的剂量和浓度:FK506的剂量平均为0·08~0·09mg/(kg·d),血药浓度为5·7~7·1ng/ml;获得CR的患者血药浓度平均为(8·1±3·9)ng/ml,PR的患者为(5·2±2·7)ng/ml,其中3例血药浓度低于5ng/ml的患者亦获得CR;(3)不良反应:FK506组肝酶升高、感染等发生率低于IVC组,未见白细胞减少、月经紊乱,而短暂SCr升高、高血压、高血糖、脱发等并发症高于IVC组,但无统计学差异。结论:FK506是诱导治疗Ⅳ型LN的一种有效的免疫抑制剂,起效快,不良反应较小。     

普乐可复诱导治疗弥漫增生性狼疮性肾炎疗效的影响因素分析

目的:前瞻性观察普乐可复(FK506)联合激素诱导治疗弥漫增生性狼疮性肾炎(DPLN)的疗效,分析影响FK506疗效的因素。方法:20例尿蛋白>1.5g/24h,肾功能正常的活动性DPLN患者,均给予FK506联合激素治疗,FK506起始剂量0.1mg/(kg·d),调整剂量维持血药浓度5～15ng/ml。按是否行甲基强的松龙(MP)冲击、初治/复治及治疗前狼疮疾病活动指数(SLEDAI)各分为两个亚组进行分析。疗效分为完全缓解(CR)、部分缓解(PR)及无效。结果:经过6个月治疗,20例患者中10例(50%)CR,9例(45%)PR,SLEDAI由13.8±3.29下降至3.68±3.28(P<0.01),达到CR的时间为1～10(4.50±2.84)个月。MP冲击治疗组、初治组及治疗前SLEDAI≥18组治疗6个月时CR率高于未行MP冲击治疗组(57.1%vs46.2%)、复治组(83.3%vs57.1%)及治疗前SLEDAI≤12组(60.0%vs36.4%),达到CR的时间分别短于未行MP冲击治疗组(3.50±1.21vs6.00±2.81)、复治组(2.00±1.64vs6.00±2.59)及治疗前SLEDAI≤12组(3.00±1.00vs6.17±3.00)。CR组6个月内平均FK506浓度略高于PR组(7.13±3.16vs5.40±2.90)。16例(7例CR,9例PR)治疗6个月时重复肾活检,结果示肾小球细胞性新月体、内皮下及系膜区免疫复合物明显减少或消失,袢坏死/核碎裂、微血栓消失,肾组织AI由10.6±4.10降至4.50±2.99(P<0.01)。5例(25%)患者治疗早期出现一过性血肌酐升高,其中多数FK506浓度偏高,肝脏细胞色素P4503A5基因型为3/3型。其余副作用包括轻度肝酶升高(25%)、感染(25%)及糖代谢异常(15%),无一例退出治疗。结论:FK506联合激素能有效、迅速诱导DPLN缓解。激素用量、初治/复治、疾病活动程度及FK506血药浓度影响FK506疗效。     

狼疮性肾炎患者并发感染的临床分析

目的:分析狼疮性肾炎(LN)治疗过程中感染的临床特点和流行病学特征. 方法:回顾性分析699例Ⅱ、Ⅲ、Ⅳ、Ⅴ、Ⅳ+Ⅴ及Ⅴ+Ⅲ型LN患者在治疗过程中感染的发生率、发生时期、部位及病原体种类特点.结果:(1)699例LN患者,其中男92例,女607例,平均年龄28.4±11.1岁,平均随访46月.191例(27.3％)患者共发生225例次感染,其中30例2次感染,2例3次感染.(2)225例次感染中,124例次(55.1％)发生在诱导期,发生时间2.6±1.6月;101例次(44.9％)发生在维持期,发生时间24.3±16.6月.(3)感染部位以皮肤软组织、肺、泌尿系统为主(89.3％);感染病原体以细菌最常见(54.2％),其次为病毒(39.6％)和深部真菌(4％)感染.(4)诱导期感染部位主要为皮肤软组织(50.8％)、肺(32.3％)和泌尿系统(11.3％);维持期感染部位主要为泌尿系统(35.6％)、皮肤软组织(30.7％)和肺(16.8％).(5)诱导期病毒(50.8％ vs 25.7％,P＜0.01)和真菌(6.5％vs 1％,P＜0.01)感染比例高于维持期,而细菌感染比例低于维持期(42.7％ vs 68.3％,P ＜0.01). 结论:LN并发感染的总体发生率为27.3％,感染最常发生于诱导治疗3月内,诱导期与维持期感染部位及病原体种类均存在差异.     

霉酚酸酯治疗35例Ⅳ型狼疮性肾炎的长期随访

目的回顾性总结霉酚酸酯(MMF)治疗Ⅳ型狼疮性肾炎(LN)的临床疗效,探讨MMF的剂量,了解复发情况.方法35例活动性LN患者(其中10例为初治,25例已经使用大剂量激素或联合间断环磷酰胺静脉冲击疗法),采用MMF联合激素治疗6个月以上.所有患者治疗前尿蛋白＞2.0g/24h,有明显血尿或管型尿,肾活检显示活动性Ⅳ型LN.MMF起始剂量1.0～1.5g/d,初治患者同时给予足量激素诱导治疗,对已经使用大剂量激素者继续口服中、小剂量强的松.疗效标准分为缓解、部分缓解及无效.在患者病情明显好转后MMF逐步减至0.5～0.75g/d维持.结果①MMF治疗时间6～36个月(平均12.7±6.8月).在治疗期间共有27例(占77.1%)获得缓解(尿蛋白＜1.0g/d,无活动性尿沉渣、肾功能稳定、血清A-dsDNA阴性,无肾外活动),6例获部分缓解,2例无效.获得缓解的时间为3～15个月(平均6.5±4.7月).随着MMF治疗时间延长,缓解率逐步增高MMF治疗3、6、12、24个月的缓解率分别为25.7%、60%、72.7%及83.3%.18例患者减量或停药前行重复肾活检,肾组织活动性指数显著下降.②30例患者在治疗3～6个月,临床获得缓解或部分缓解后开始减量.在MMF维持治疗3～9个月间12.5%患者复发,7例患者停用MMF3～9个月后3例复发.③治疗过程中各有2例患者并发肺炎及疱疹病毒感染,未见肝功能异常及白细胞减少.结论MMF1.0～1.5g/d剂量联合激素治疗能有效控制狼疮性肾炎活动,诱导治疗时间应6个月以上.在获得缓解或部分缓解后MMF可逐步减量,但维持剂量不宜太小.停止MMF治疗后复发率高,因此必须有替代药物治疗以降低MMF停药后的高复发率.     

Quadruple,sequential, and concomitant first-line therapies for H. pylori eradication: a prospective,randomized study

BackgroundCurrent Italian guidelines recommend 10-day bismuth-based or bismuth-free (sequential and concomitant) regimens for first-line H. pylori eradication. However, comparison among these regimens is lacking in our country.AimTo perform a ‘head-to-head’ comparison among these three therapies as first-line treatment for H. pylori eradication in clinical practice.MethodsThis was a prospective, open-label randomized study enrolling consecutive patients diagnosed with H. pylori infection never previously treated. Patients were randomized to receive one of the following 10-day therapies: (a) Bismuth-based therapy: esomeprazole 20 mg b.i.d and Pylera 3 tablets q.i.d; (b) Concomitant therapy: esomeprazole 20 mg plus amoxicyllin 1,000 mg, clarithromycin 500 mg and tinidazole 500 mg (all b.i.d.), and (c) Sequential therapy: esomeprazole 20 mg plus amoxicyllin 1,000 mg for 5 days followed by esomeprazole 20 mg plus clarithromycin 500 mg and tinidazole 500 mg for 5 days (all b.i.d). H. pylori eradication was assessed by using UBT 4-6 weeks after the end of therapy.ResultsOverall, 187 patients were enrolled. The eradication rates achieved with Pylera, concomitant and sequential were 85.2%, 95.2%, and 93.6%, respectively, at intention to treat, and 94.5%, 96.7%, and 95.1% at per protocol analyses, without a statistically significant difference. The incidence of severe side-effects was higher with the bismuth-based therapy than with the two bismuth-free regimens (9.8% vs 1.6%; p = 0.046).ConclusionsBismuth-based and bismuth-free therapies are equally effective for first-line H. pylori eradication. However, bismuth therapy was more frequently interrupted for side-effects than bismuth-free therapies.     

Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer

Oncogenic mutations in the BRAF kinase occur in 6–8% of nonsmall cell lung cancers (NSCLCs), accounting for more than 90,000 deaths annually worldwide. The biological and clinical relevance of these BRAF mutations in NSCLC is incompletely understood. Here we demonstrate that human NSCLC cells with BRAF^V600E, but not other BRAF mutations, initially are sensitive to BRAF-inhibitor treatment. However, these BRAF^V600E NSCLC cells rapidly acquire resistance to BRAF inhibition through at least one of two discrete molecular mechanisms: (i) loss of full-length BRAF^V600E coupled with expression of an aberrant form of BRAF^V600E that retains RAF pathway dependence or (ii) constitutive autocrine EGF receptor (EGFR) signaling driven by c-Jun–mediated EGFR ligand expression. BRAF^V600E cells with EGFR-driven resistance are characterized by hyperphosphorylated protein kinase AKT, a biomarker we validated in BRAF inhibitor-resistant NSCLC clinical specimens. These data reveal the multifaceted molecular mechanisms by which NSCLCs establish and regulate BRAF oncogene dependence, provide insights into BRAF–EGFR signaling crosstalk, and uncover mechanism-based strategies to optimize clinical responses to BRAF oncogene inhibition.The discovery of genetic alterations that drive tumor growth in a wide variety of tumor types and the development of targeted therapies acting against these oncogenic drivers have revolutionized the management of many cancer patients (1). Paradigmatic examples of the successful use of oncogene-targeted therapy include the identification and treatment of patients who have EGF receptor (EGFR)-mutant and ALK fusion-positive lung cancer with the tyrosine kinase inhibitors erlotinib and crizotinib, respectively, and of patients who have BRAF^V600E-melanoma with the selective BRAF kinase inhibitor vemurafenib. The clinical success of driver oncogene-targeted therapy arises because of tumor cell oncogene dependence that is established during tumorigenesis, but the mechanistic basis of this dependence remains incompletely understood. Filling this knowledge gap is critical, because the clinical success of driver oncogene-targeted therapies is limited by the almost inevitable escape from oncogene dependence and drug resistance that occur in patients with solid tumors, including lung cancer, the leading cause of cancer mortality worldwide (2, 3). The identification of the signaling events driving resistance provides insights into the molecular mechanisms underlying oncogene dependence and a rationale for mechanism-based polytherapy strategies to subvert resistance in patients (2, 4, 5).The BRAF gene is mutated in ∼7% of human cancers, including melanoma, colorectal, papillary thyroid, and NSCLC (6, 7). The BRAF^V600E variant is the most frequent mutant allele and has been used to match patients genetically to BRAF-inhibitor therapy. The clinical success and approval of the BRAF inhibitors vemurafenib and dabrafenib in BRAF^V600E melanoma have provided a rationale for testing BRAF inhibition in nonmelanoma patients whose tumors harbor BRAF mutations (8–10). The success of such efforts has been limited, with either BRAF-inhibitor treatment or downstream MAPK blockade failing to produce the desired clinical activity in patients with colorectal and thyroid cancers harboring BRAF^V600E; in both cases the failure is caused by intrinsic resistance (11–13). These observations indicate that tumor cell oncogene dependence is context specific and underscore the need to define the molecular events that regulate oncogene dependence in each tumor type to optimize clinical responses.Somatic mutations in BRAF (both V600E and non-V600E variants) are found in 6–8% of NSCLCs, accounting for more than 90,000 deaths annually worldwide. BRAF-mutant NSCLCs frequently harbor the V600E allele (∼55%); additional highly recurrent activating BRAF variants reported in NSCLC include G469A (∼35%) and D594G (∼10%) (14–17). The sensitivity of NSCLC cells across the spectrum of BRAF mutant alleles to BRAF-inhibitor treatment has not been characterized. Despite this uncertainty regarding allelotype specificity, the clinical efficacy of BRAF-inhibitor treatment in BRAF^V600E-melanoma has prompted a clinical trial testing the efficacy of BRAF-inhibitor treatment in patients with BRAF^V600E NSCLC. Given the emerging biological and clinical importance of mutant BRAF and the success (and limitations) of other oncogene-targeted therapies, including EGFR and ALK kinase inhibitors, in NSCLC patients, we sought to define the molecular basis of BRAF oncogene dependence in NSCLC. We investigated and uncovered critical events driving response and resistance to BRAF-inhibitor treatment in models of human BRAF-mutant NSCLC. Our findings provide insight into the regulation of BRAF oncogene dependence and reveal rational strategies for immediate clinical use to enhance patients’ responses to BRAF inhibitors.     

Mutant KRAS is a druggable target for pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) represents an unmet therapeutic challenge. PDA is addicted to the activity of the mutated KRAS oncogene which is considered so far an undruggable therapeutic target. We propose an approach to target KRAS effectively in patients using RNA interference. To meet this challenge, we have developed a local prolonged siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against the mutated KRAS (siG12D LODER). The siG12D LODER was assessed for its structural, release, and delivery properties in vitro and in vivo. The effect of the siG12D LODER on tumor growth was assessed in s.c. and orthotopic mouse models. KRAS silencing effect was further assessed on the KRAS downstream signaling pathway. The LODER-encapsulated siRNA was stable and active in vivo for 155 d. Treatment of PDA cells with siG12D LODER resulted in a significant decrease in KRAS levels, leading to inhibition of proliferation and epithelial–mesenchymal transition. In vivo, siG12D LODER impeded the growth of human pancreatic tumor cells and prolonged mouse survival. We report a reproducible and safe delivery platform based on a miniature biodegradable polymeric matrix, for the controlled and prolonged delivery of siRNA. This technology provides the following advantages: (i) siRNA is protected from degradation; (ii) the siRNA is slowly released locally within the tumor for prolonged periods; and (iii) the siG12D LODER elicits a therapeutic effect, thereby demonstrating that mutated KRAS is indeed a druggable target.Pancreatic cancer is an aggressive disease that develops in a relatively symptom-free manner and in most cases, is already advanced at the time of diagnosis (1). It has one of the highest fatality rates of all cancers and is one of the leading causes of cancer-related deaths in the Western world (1, 2). Pancreatic ductal adenocarcinoma (PDA) is the most common pancreatic neoplasm, responsible for 95% of pancreatic cancer cases (3). Genetic alterations in the KRAS signaling pathway are involved in over 90% of pancreatic cancer cases (4–6). KRAS mutations were shown to be an early event in the development of pancreatic cancer (5, 7, 8).The most common KRAS mutation of the human pancreas adenocarcinoma is a gain-of-function substitution mutation of glycine at codon 12 to aspartate (G12D) (5, 9–11). Moreover, PDA cancer cell growth was shown to be dependent on the activity of the mutated KRAS (5, 11) and accordingly, silencing KRAS has proven effective in controlling pancreatic cell line proliferation (12). Here, we aimed to harness the advantages of siRNA technology as a therapeutic modality for pancreatic cancer.Parenteral controlled drug delivery systems are used to improve and advance the therapeutic effects of drug treatments by providing optimized local drug concentrations over prolonged periods of time, reduction of side effects, and cost reduction (13). A prominent method of controlling the release rate of a drug in a pharmaceutical dosage is to embed the active agent within a polymeric matrix (14, 15). The polymer must be biocompatible, and in the case of parenteral administration, preferably biodegradable, to avoid the need to remove empty remnants.In the present study, we exploited the slow-release characteristics of the biodegradable polymer matrix, which we named local drug eluter (LODER) for the treatment of solid tumors.     

Eradication of Helicobacter pylori infection

Eradication of Helicobacter pylori infection has become an important issue recently, because this bacterial species cluster can cause many gastrointestinal diseases. Elevated antibiotic resistance is related to an increasing failure rate of H. pylori eradication. Standard triple therapy is still the first-line therapy; however, according to the Maastricht IV Consensus Report, it should be abandoned in areas of high clarithromycin resistance. Alternative first-line therapies include bismuth-containing quadruple therapy, sequential, concomitant, and hybrid therapies. Quinolone-based triple therapy may be considered as first-line therapy in areas of clarithromycin resistance >15–20% and quinolone resistance <10%. Unique second-line therapy is still unclear, and bismuth-containing quadruple therapy or levofloxacin-based triple therapy can be used as rescue treatment. Third-line therapy should be under culture guidance to select the most effective regimens (such as levofloxacin-based, rifabutin-based, or furazolidone-based therapies). Antibiotics resistance, patient compliance, and CYP 2C19 genotypes could influence the outcome. Clinicians should use antibiotics according to local reports.     

Treating IPF—all or nothing? A PRO‐CON debate

The Idiopathic Pulmonary Fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. It is distinct from other idiopathic interstitial pneumonias by its histopathological pattern of usual interstitial pneumonia which is characterized by accumulation of fibroblasts, extracellular matrix and honeycombing. Inflammation is only scarce in true IPF. The use of anti-inflammatory therapy is still part of guidelines for IPF management, although not specifically recommended, because convincing evidence showing beneficial effects of this approach is lacking. This review provides a summary of important arguments PRO and CON using anti-inflammatory and anti-oxidant therapy for patients with IPF in form of a debate with a concluding statement of both positions at the end.     

胰腺癌治疗进展

胰腺癌是高度恶性的消化系统肿瘤，约90%起源于腺管上皮的导管腺癌，其发病率和死亡率近几年明显上升，5年生存率<6%，是预后最差的恶性肿瘤之一。该病早期确诊率较低，手术死亡率较高。男女发病率之比约为(1.5～2)∶1，其治疗方案由单一手术治疗转为多学科综合治疗。近几年内外科治疗方案并无太多新的突破，分子靶向治疗的热度逐年上升，其重要性也越来越引起专家的重视，部分治疗靶点已经应用于临床，并取得可喜的治疗效果。     

Endoscopic alcohol injection therapy of giant gastric leiomyomas: an alternative method to surgery

Leiomyomas are the most common benign mesenchymal tumours of the upper gastrointestinal tract. They rarely cause symptoms when they are smaller than 5 cm in diameter. Observation with repeated endoscopies is recommended in asymptomatic patients with small lesions. Surgical resection remains the main therapy option for symptomatic and complicated patients. The treatment of esophageal leiomyoma has been enhanced by improvements in diagnostic and therapeutic endoscopic techniques; however, the same cannot be said for gastric leiomyoma management. The present article describes the management of two cases involving giant gastric leiomyomas that were  successfully treated using endoscopic injection of alcohol. To the authors' knowledge, the present study is the first report of the treatment of such hemorrhagic gastric tumours using this alternative and low-cost technique. Endoscopic local ethanol injection may be the treatment of choice in carefully selected patients with hemorrhagic leiomyomas of the upper gastrointestinal tract.     

The Steroid-Sparing Effect of Long-Term Plasmapheresis in Pemphigus: An Update

Abstract: Glucocorticoids and immunosuppressive agents can induce remission in most pemphigus patients, but mortality remains at 5 to 15% as a result of side effects. We reviewed the adjunctive effect of long-term plasmapheresis in 8 pemphigus patients. Four cases had been resistant to conventional therapy. One or 2 large-volume plasmapheresis treatments were given monthly over 5 to 141 months. All patients, were in clinical remission within 2 months. Relapses seldom occurred: the patients stayed in remission 90% (40–94) (median, ranges) of the period. In all cases the daily dose of glucocorticoid was reduced. The prednisone level could be decreased from 38 (15–80) mg/day to 7.5 (2.5–35) mg/day (p = 0.002). The overall level of other immunosuppressive agents remained unchanged, except in 1 patient for whom cyclosporine was introduced. This indicates that long-term plasmapheresis could have a steroid-sparing effect and clinical efficacy in pemphigus.—     

肥胖症的药物治疗现状与展望

肥胖是一个严重的公众健康问题，人们迫切希望能有安全、有效的减肥药物。目前用于减肥的药物主要有两类：即西布曲明和赛尼可，前者主要抑制食物的摄取，后者抑制脂肪的吸收。由于对复杂的体重调节机制的认识越来越深入，很多新的减肥药物正在研制过程之中。目前正在研究的具有较大潜力的减肥药物共有30余种，其中研究较多的有瘦素、黑皮质素受体激动剂、神经肽Y拮抗剂、β3肾上腺素能受体激动剂、胰高血糖素样肽－1激动剂以及激活或增加解偶联蛋白表达的药物。     

四联疗法与序贯疗法在幽门螺杆菌根除补救治疗中的疗效比较

[目的]比较四联疗法与序贯疗法在幽门螺杆菌(Hp)根除补救治疗中的疗效及安全性,旨在寻找一种有效、安全、经济的补救治疗方案。[方法]将首次根除Hp治疗失败的90例慢性胃炎患者,随机分为四联疗法组和序贯疗法组,每组45例。四联疗法组患者治疗方案为埃索美拉唑、枸橼酸铋钾、阿莫西林、莫西沙星,疗程14d。序贯疗法组患者治疗方案为前5d给予埃索美拉唑、阿莫西林;后5d给予埃索美拉唑、克拉霉素、奥硝唑。所有患者在疗程结束停药4周后行14 C尿素呼气试验检测Hp。比较2组患者治疗前后的不良反应。[结果]四联疗法组Hp根除率(91.1%)显著高于序贯疗法组(75.6%),差异有统计学意义(P<0.05)。2组不良反应均很轻微,组间不良反应发生率比较差异无统计学意义(P>0.05)。[结论]对于Hp补救治疗,四联疗法较序贯疗法疗效更好,且不良反应小,患者依从性好,值得在临床上推广。