局部晚期鼻咽癌患者外周血VEGF检测及意义

目的:研究血管内皮生长因子(vascular endothelium growth factor,VEGF)在局部晚期鼻咽癌患者外周血中的表达相,探讨VEGF与局部晚期鼻咽癌预后的关系,研究是否能预测局部晚期鼻咽癌患者的预后,或作为局部鼻咽癌治疗的靶分子,为寻找局部晚期鼻咽癌放化疗疗效的分子生物学评价指标提供依据。方法:选择57例局部晚期鼻咽癌患者,收集外周血标本,酶联免疫吸附实验(enzym-linked immunosorbent assay,ELISA)检测外周血中VEGF蛋白水平。结合临床病理特征和随访资料进行分析。结果:(1)局部晚期鼻咽癌患者外周血VEGF表达水平均与复发率、远处转移率有关(P0.05)。(2)局部晚期鼻咽癌患者外周血VEGF的表达水平与性别和年龄无关(P0.05)。(3)局部晚期鼻咽癌患者外周血VEGF的表达水平与生存率有关(P0.05)。结论:局部晚期鼻咽癌患者外周血中VEGF的表达水平对复发率、远处转移率和生存率有影响,提示VEGF在局部晚期鼻咽癌的侵袭转移中可能起协同作用;VEGF检测对筛选较高鼻咽癌转移风险的患者可能有更大的临床价值。     

新辅助化疗在局部晚期宫颈癌治疗中的疗效观察

目的：探讨新辅助化疗联合手术治疗较传统手术治疗Ib2、IIa2局部晚期宫颈癌的临床疗效。方法：选取2008年6月～2011年12月在黑龙江省哈尔滨医科大学附属第三医院初治宫颈癌患者120例,临床分期为Ib2期、IIa2期,术前均经病理证实为宫颈鳞癌,将其分为两组：研究组（新辅助化疗联合手术治疗组）;对照组（单纯手术治疗组）。研究组给予1～2个疗程的新辅助化疗后评估其化疗疗效,有效者化疗结束后行广泛性子宫切除＋盆腔淋巴结清扫术;对照组直接行手术治疗。结果：新辅助化疗能够使肿瘤体积较化疗前缩小或消失,临床有效率高达81.43%,从而降低了宫颈癌的临床分期,提高手术的切除率,扩大手术适应征,降低术后病理高危因素,同时手术治疗能保留卵巢功能,提高年轻宫颈癌患者生活质量。结论：术前新辅助化疗可以提高手术治疗局部晚期宫颈癌的临床疗效。     

放化疗与介入性动脉化疗治疗局部晚期宫颈癌的临床研究

目的:比较分析放化疗与介入性动脉化疗治疗局部晚期动脉宫颈癌的临床效果。方法:选择我院局部晚期宫颈癌患者97例,依据治疗方法分为常规组(行传统放化疗)55例和介入组(行介入性动脉化疗)42例。观察治疗后肿瘤大小、近期疗效、根治性手术率、术后并发症,对生活质量指数进行评分,评价两种方法的临床效果。结果:治疗后,两组患者近期疗效比较差异无统计学意义(P0.05);介入组肿瘤直径明显小于常规组,而根治性手术率明显高于常规组,差异均具有统计学意义(P0.05);介入组患者日常生活、健康、总体情况以及总的评分均明显高于常规组,差异具有统计学意义(P0.05),同时介入组并发症较少。结论:放化疗与介入性动脉化疗治疗局部晚期动脉宫颈癌近期临床疗效均较好,但介入性动脉化疗具有较高的根治性手术率以及生活质量,且并发症少。     

An Elevated Peripheral Blood Lymphocyte-to-Monocyte Ratio Predicts Favorable Response and Prognosis in Locally Advanced Breast Cancer following Neoadjuvant Chemotherapy

Purpose

Neoadjuvant chemotherapy (NCT) is a standard treatment option for locally advanced breast cancer. However, the lack of an efficient method to predict treatment response and patient prognosis hampers the clinical evaluation of patient eligibility for NCT. An elevated lymphocyte-to-monocyte ratio (LMR) has been reported to be associated with a favorable prognosis for certain hematologic malignancies and for nasopharyngeal carcinoma; however, this association has not been investigated in breast cancer. The purpose of this study was to evaluate whether pre-NCT LMR analysis could predict the prognosis of patients with locally advanced breast cancer.

Methods

A retrospective cohort of 542 locally advanced breast cancer patients (T3/T4 and/or N2/N3 disease) receiving NCT followed by radical surgery was recruited between May 2002 and August 2011 at the Fudan University Shanghai Cancer Center. Counts for pre-NCT peripheral absolute lymphocytes and monocytes were obtained and used to calculate the LMR.

Results

Univariate and multivariate analysis revealed that higher LMR levels (≥4.25) were significantly associated with favorable DFS (P = 0.009 and P = 0.011, respectively). Additionally, univariate analysis revealed that a higher lymphocyte count (≥1.5×10⁹/L) showed borderline significance for improved DFS (P = 0.054), while a lower monocyte count (<0.4×10⁹/L) was associated with a significantly better DFS (P = 0.010).

Conclusions

An elevated pre-NCT peripheral LMR level was a significantly favorable factor for locally advanced breast cancer patient prognosis. This easily obtained variable may serve as a valuable marker to predict the outcomes of locally advanced breast cancer.     

脾切断流术围术期患者外周血淋巴细胞的变化及免疫功能的研究

目的:本实验旨在探讨脾切除门奇静脉断流术后患者外周血T淋巴细胞、B淋巴细胞、NK细胞的变化,评估患者的抗肿瘤免疫能力是否有所影响,及机体的免疫系统有何变化.方法:选择择期行脾切除门奇静脉断流术的肝硬化患者20名,给予全凭静脉麻醉.分别于麻醉前(T0)、切皮前(T1)、脾切除即刻(T2)、脾切除后1h(T3)、手术完毕(T4)、手术后1d(T5)、手术后7d(T6)时抽取病人外周静脉血2mL,采用流式细胞仪测定CD3+、CD4+、CD8+、CD19+B细胞、CD3-56+(NK细胞)绝对数量.结果:与麻醉前相比,切皮前CD3+T细胞、CD3+CD4+T细胞、CD3+CD8+T细胞、CD19+B细胞、NK细胞均明显的降低,而在脾脏切除即刻各系细胞又明显恢复,基本与麻醉前水平相当.然而随着手术继续,在脾脏切除后1h,仅B细胞低于术前,一直持续到手术完毕,但是,此时B细胞与麻醉前比已没有统计学差异.手术完毕时T、B细胞和NK细胞再次降低,但仍明显高于切皮前水平.手术后1d时,CD4+T细胞与NK细胞仍然低于麻醉前,CD3T细胞、CD3+CD8+T细胞和B细胞已经恢复到麻醉前水平.术后7d时,CD3+T细胞、CD3+CD4+T细胞、CD3+CD8+T细胞及B细胞不仅得到恢复,而且还比麻醉前明显升高,但是NK细胞仍与麻醉前的水平相当.结论:异丙酚联合瑞芬太尼麻醉对门脉高压患者行脾切除门奇静脉断流术患者的T、B淋巴细胞和NK细胞有快速、短期的降低作用,术后7d人体淋巴细胞数量不仅得到恢复,并且反馈性地升高,提示脾脏切除手术能够有效提升患者的免疫细胞数量.     

新辅助介入化疗可显著促进局部晚期宫颈癌治疗

本研究选择自2011年1月至2016年1月间在我院妇产科收治并确诊的90例肿瘤直径大于4 cm的Ⅰb～Ⅱb期宫颈癌患者作为研究对象,随机分为A组、B组和对照组,每组30例,A组患者手术前采用动脉介入新辅助化疗,B组患者手术前采用静脉介入新辅助化疗,对照组患者仅采用手术治疗,并对3组疗效及副作用进行了分析,采用免疫组化法检测治疗前后3组患者MMP-2、Fas和FasL细胞因子的表达情况,以探讨新辅助介入化疗在局部晚期宫颈癌治疗中的疗效。研究结果表明:A组(有效率=83.33%)和B组(有效率=73.33%)疗效显著高于对照组(p<0.05),并且A组疗效显著高于B组(χ~2=2.116, p=0.045);Ⅰb期有效率显著高于Ⅱa和Ⅱb,Ⅱa显著高于Ⅱb,鳞癌患者的化疗有效率显著高于腺癌,低分化宫颈癌患者有效率显著低于中分化和高分化(p<0.05);A组中共有14例出现化疗副作用,B组共有11例出现副作用,两组差异无统计学意义(p>0.05);MMP-2和FasL治疗后的阳性率在A组和B组中均较治疗前显著下降,而A组和B组中Fas阳性率治疗后较治疗前显著升高(p<0.05),而对照组中MMP-2、Fas和FasL治疗前后的阳性率差异均无统计学意义(p>0.05)。本研究的结论初步说明:新辅助介入化疗在局部晚期宫颈癌治疗中的效果显著,MMP-2、Fas和FasL细胞因子与宫颈癌肿瘤细胞密切相关。     

局部进展期胃癌术前动静脉结合化疗的疗效观察

目的:局部进展期胃癌,即使没有出现远处转移或腹膜种植,预后也极不理想.我们对局部进展期胃癌患者进行术前mECF方案的动静脉结合化疗,以评价其治疗疗效.方法:选取自2009年1月至2011年6月间我院局部进展期胃癌Ⅱ-ⅢC期患者38例,均由影像学确定淋巴结高度可疑转移或浸润、包绕主要血管结构,且没有发现远处转移或腹膜种植,进行2个周期的术前动静脉结合化疗后,行手术治疗.记录化疗毒性反应、临床、病理缓解率、手术并发症发生率和病死率以及1年无病生存率.结果:化疗毒性反应低,3级反应不超过10％,仅有1例出现4级反应,表现为腹泻、恶心和呕吐.38例患者中临床CR有6例,占15.8％,PR17例,占44.7％,NC13例(34.2％),PD2例(5.3％),RR为60.5％(23/38).全部患者均施行了手术,37例患者进行了根治性手术,R0切除率为97％.病理缓解率为5例完全缓解(13.2％),21例部分缓解(55.3％),8例轻微缓解(21.1％),4例未缓解(10.5％).手术并发症发生率为7.9％,无治疗相关死亡发生.1年无病生存率为81.6％.结论:局部进展期胃癌患者术前进行mECF方案的动静脉化疗毒性反应低,疗效理想,之后行手术完整切除后临床效果突出,是理想的治疗方法.     

Tumor Phosphatidylinositol-3-Kinase Signaling and Development of Metastatic Disease in Locally Advanced Rectal Cancer

Background

Recognizing EGFR as key orchestrator of the metastatic process in colorectal cancer, but also the substantial heterogeneity of responses to anti-EGFR therapy, we examined the pattern of composite tumor kinase activities governed by EGFR-mediated signaling that might be implicated in development of metastatic disease.

Patients and Methods

Point mutations in KRAS, BRAF, and PIK3CA and ERBB2 amplification were determined in primary tumors from 63 patients with locally advanced rectal cancer scheduled for radical treatment. Using peptide arrays with tyrosine kinase substrates, ex vivo phosphopeptide profiles were generated from the same baseline tumor samples and correlated to metastasis-free survival.

Results

Unsupervised clustering analysis of the resulting phosphorylation of 102 array substrates defined two tumor classes, both consisting of cases with and without KRAS/BRAF mutations. The smaller cluster group of patients, with tumors generating high ex vivo phosphorylation of phosphatidylinositol-3-kinase-related substrates, had a particularly aggressive disease course, with almost a half of patients developing metastatic disease within one year of follow-up.

Conclusion

High phosphatidylinositol-3-kinase-mediated signaling activity of the primary tumor, rather than KRAS/BRAF mutation status, was identified as a hallmark of poor metastasis-free survival in patients with locally advanced rectal cancer undergoing radical treatment of the pelvic cavity.     

Dacarbazine and the Agonistic TRAIL Receptor-2 Antibody Lexatumumab Induce Synergistic Anticancer Effects in Melanoma

Mapatumumab and lexatumumab (targeting death receptor 4 (DR4) and 5 (DR5), respectively) are agonistic TRAIL receptor antibodies that induce apoptosis in a wide range of cancer cells. The potency of mapatumumab and lexatumumab was assessed in mono therapy protocols, and the ability to sensitize for dacarbazine (DTIC) treatment was explored in ten different melanoma cell lines. Our data indicated that melanoma cell lines tend to be resistant to mapatumumab, most likely due to low expression of DR4, while a dose dependent response to lexatumumab was observed. Combining DTIC and lexatumumab induced an additive or synergistic effect on cell death in the various melanoma cell lines. The synergistic effect observed in the FEMX-1 cell line was related to enhanced cleavage of Bid in parallel with elevated expression of the pro-apoptotic proteins Bim, Bax and Bak. Furthermore, the anti-apoptotic proteins Bcl-XL, cIAP-1, XIAP and livin were down regulated. Cleavage of Bid and down regulation of cIAP-2 and livin were observed in vivo. Altogether, these data suggest a change in the balance between pro- and anti-apoptotic proteins favoring induction of apoptosis. In the more therapy resistant cell line, HHMS, no changes in the pro- and anti-apoptotic proteins were observed. FEMX-1 xenografts treated with DTIC and lexatumumab showed reduced growth and increased level of apoptosis compared to the control groups, providing arguments for further evaluation of this combination in melanoma patients.     

Clinical Efficacy of Chemotherapy Combined with Verapamil in Metastatic Colorectal Patients

In order to determine the clinical efficacy and adverse reactions of chemotherapy and verapamil infusion through a target artery to treat colorectal cancer patients with metastasis after failure with previous conventional treatments. Patients with metastatic colon cancer (n = 36) received an infusion of verapamil, interleukin-2, oxaliplatin (or hydroxy camptothecin or irinotecan hydrochloride), fluorouracil and calcium folinate through target artery using the Seldinger puncture technique. From the second day of infusion, the patients were treated with fluorouracil and calcium folinate via systematic intravenous injection for 2–3 days. Efficacy was evaluated after at least two treatment courses. The objective response including complete or partial response was 58.3% in the 36 patients; clinical benefit rate, evaluated by Karnofsky Performance Status score was 91.7%; by weight was 83.3%; by the amount of painkiller consumed was 80.6%. No patient experienced side effects associated with heart function. Post-treatment, the P–R period, Q–T period, QRS, and heart rate were not significantly different than before treatment. Liver function was significantly improved. Side effects of chemotherapy were minor in comparison to those observed with intravenous chemotherapy. Infusion of verapamil and chemotherapy directly into pelvic tumor tissue can increase treatment efficacy and has been shown to be a relatively safe technique.     

两种多西他赛联合化疗方案在局部进展期胃癌术后辅助化疗中的疗效评价

摘要 目的：探讨两种多西他赛联合化疗方案在局部进展期胃癌术后辅助化疗中的疗效和安全性,并分析其对患者生活质量的影响。方法：回顾性分析2015年11月至2018年11月期间本院收治的50例胃癌根治术后病理分期为IIA-IIIC期患者的临床资料,所有患者行多西他赛联合方案辅助化疗。根据不同的多西他赛联合用药方案将患者分为两组：一组为多西他赛联合顺铂、氟尿嘧啶的三药静脉联合腹腔化疗方案（DCF组）,共计20例患者;另一组为多西他赛联合奥沙利铂的两药静脉化疗方案（DP组）,共计30例患者。分析经两种辅助化疗方案治疗后患者的2年无复发生存时间（RFS）、2年总生存时间（OS）、生活质量及不良反应。结果：DCF组2年RFS率、OS率较DP组升高（P<0.05）;DCF组患者出现复发转移的时间明显长于DP组（P<0.05）;两组复发转移部位发生率比较无统计学差异（P>0.05）;化疗后2周,DCF组生活质量改善情况优于DP组（P<0.05）;两组不良反应均可控,患者可耐受,两组不良反应的发生率比较无差异（P>0.05）。结论：两种多西他赛联合化疗方案应用于局部进展期胃癌术后辅助化疗均安全有效,采用三药静脉联合腹腔化疗有助于降低复发转移风险,提高患者的生活质量。     

术前调强放疗联合替吉奥化疗对局部晚期直肠癌患者的疗效回顾分析

目的:探讨术前调强放疗联合替吉奥化疗对局部晚期直肠癌患者的疗效。方法:回顾性分析2012年12月至2014年12月我院收治的局部晚期直肠癌患者90例进行研究,根据治疗方法分为三组:A组(n=30)给予术前调强放疗联合替吉奥化疗治疗,B组(n=30)仅给予术前调强放疗治疗,C组(n=30)给予替吉奥化疗治疗。比较三组患者的总有效率,血清TPS、CYFRA21-1水平变化情况,1年、2年、3年复发、转移、生存率,保肛率及不良反应发生情况。结果:A组总有效率86.68%显著高于对照B组的46.67%和C组的50.00%,差异显著(P0.05);治疗前,三组TPS、CYFRA21-1水平无显著差异(P0.05);治疗后,三组TPS、CYFRA21-1水平均显著下降,且A组低于B组和C组(P0.05);三组患者1年、2年复发、转移情况无显著差异;A组3年复发、转移情况均显著低于B组和C组(P0.05);三组患者1年、2年生存率无显著差异;A组3年生存率均显著高于B组和C组(P0.05);三组患者发生恶心呕吐、白细胞减少等并发症发生情况无显著差异;A组保肛率均显著高于B组和C组(P0.05)。结论:采用术前调强放疗联合替吉奥化疗治疗局部晚期直肠癌疗效好于术前放疗。     

The Predicted Impact of Ipilimumab Usage on Survival in Previously Treated Advanced or Metastatic Melanoma in the UK

Background

Evaluating long-term prognosis is important for physicians, patients and payers. This study reports the results of a model developed to predict long-term survival for UK patients receiving second-line ipilimumab.

Methods

MDX010-20 trial data were used to predict survival for ipilimumab versus UK best supportive care. Two aspects of this analysis required novel approaches: 1) The overall survival Kaplan–Meier data shape is unusual: an initial steep decline is observed before a ‘plateau’. 2) The need to extrapolate beyond the trial end (4.6 years). Based upon UK clinician advice, a three-part curve fit was used: from 0–1.5 years, Kaplan–Meier data from the trial; from 1.5–5 years, standard parametric curve fits; after 5 years, long-term data from the American Joint Committee on Cancer registry.

Results

This approach provided good internal validity: low mean absolute error and good match to median and mean trial data. Lifetime predicted means were 2.77 years for ipilimumab and 1.07 for best supportive care, driven by increased long-term survival with ipilimumab.

Conclusion

To understand the full benefit of treatment and to meet reimbursement requirements, accurate estimation of treatment benefit is key. Models, such as the one presented, can be used to extrapolate beyond trials.     

Evaluation of Neoadjuvant Chemotherapy Response in Women with Locally Advanced Breast Cancer Using Ultrasound Elastography

PURPOSE: Ultrasound elastography is a new imaging technique that can be used to assess tissue stiffness. The aim of this study was to investigate the potential of ultrasound elastography for monitoring treatment response of locally advanced breast cancer patients undergoing neoadjuvant therapy. METHODS: Fifteen women receiving neoadjuvant chemotherapy had the affected breast scanned before, 1, 4, and 8 weeks following therapy initiation, and then before surgery. Changes in elastographic parameters related to tissue biomechanical properties were then determined and compared to clinical and pathologic tumor response after mastectomy. RESULTS: Patients who responded to therapy demonstrated a significant decrease (P < .05) in strain ratios and strain differences 4 weeks after treatment initiation compared to non-responding patients. Mean strain ratio and mean strain difference for responders was 81 ± 3% and 1 ± 17% for static regions of interest (ROIs) and 81 ± 3% and 6 ± 18% for dynamic ROIs, respectively. In contrast, these parameters were 102±2%, 110±17%, 101±4%, and 109±30% for non-responding patients, respectively. Strain ratio using static ROIs was found to be the best predictor of treatment response, with 100% sensitivity and 100% specificity obtained 4 weeks after starting treatment. CONCLUSIONS: These results suggest that ultrasound elastography can be potentially used as an early predictor of tumor therapy response in breast cancer patients.     

DCs-CIK细胞免疫治疗联合化疗对转移性前列腺癌患者免疫功能及生活质量的影响

目的:探讨DCs-CIK细胞免疫(Dendritic cells-Cytokine induced killer cells,DCs-CIK)治疗联合化疗对转移性前列腺癌患者免疫功能及生活质量的影响。方法:选择106例确诊转移性前列腺癌患者随机分为观察组与对照组,每组各53例,对照组采用多西他赛联合表阿霉素~+泼尼松化疗方式进行治疗,观察组在此基础上给予DC-CIK细胞免疫治疗。比较两组患者治疗前后外周血CD3~+、CD3~+CD4~+、CD3~+CD8~+、CD3-CD56~+、CD4~+CD8~+、自然杀伤细胞(NK)、自然杀伤T细胞(NKT)表达水平;使用QLQ-C30问卷评价患者治疗前后生活质量的变化情况,观察并比较患者治疗过程中发生的不良反应情况。结果:组观察组患者治疗总有效率达73.58%远高于对照组41.51%水平(p0.05);观察组患者治疗后外周血CD3~+、CD3~+CD4~+、CD3~+CD8~+、CD3-CD56~+、CD4~+CD8~+、NK、NKT表达水平明显好于对照组(p0.05);观察组患者躯体功能、角色功能、情绪功能、认知功能、社会功能各项指标得分明显好于对照组(p0.05);两组患者接受治疗后,均有部分患者出现恶心呕吐、脱发、白细胞减少、血小板减少或肝功受损,其中观察组患者出现恶心呕吐、白细胞减少的人数明显少于对照组(p0.05)。结论:DCs-CIK细胞免疫治疗联合化疗有助于转移性前列腺癌患者的治疗,在明显改善患者免疫能力的同时有效改善患者生活质量,具有重要的临床指导意义。     

Peripheral Immune Cell Gene Expression Changes in Advanced Non-Small Cell Lung Cancer Patients Treated with First Line Combination Chemotherapy

Introduction

Increasing evidence has shown that immune surveillance is compromised in a tumor-promoting microenvironment for patients with non-small cell lung cancer (NSCLC), and can be restored by appropriate chemotherapy.

Methods

To test this hypothesis, we analyzed microarray gene expression profiles of peripheral blood mononuclear cells from 30 patients with newly-diagnosed advanced stage NSCLC, and 20 age-, sex-, and co-morbidity-matched healthy controls. All the patients received a median of four courses of chemotherapy with cisplatin and gemcitabine for a 28-day cycle as first line treatment.

Results

Sixty-nine differentially expressed genes between the patients and controls, and 59 differentially expressed genes before and after chemotherapy were identified. The IL4 pathway was significantly enriched in both tumor progression and chemotherapy signatures. CXCR4 and IL2RG were down-regulated, while DOK2 and S100A15 were up-regulated in the patients, and expressions of all four genes were partially or totally reversed after chemotherapy. Real-time quantitative RT-PCR for the four up-regulated (S100A15, DOK2) and down-regulated (TLR7, TOP1MT) genes in the patients, and the six up-regulated (TLR7, CRISP3, TOP1MT) and down-regulated (S100A15, DOK2, IL2RG) genes after chemotherapy confirmed the validity of the microarray results. Further immunohistochemical analysis of the paraffin-embedded lung cancer tissues identified strong S100A15 nuclear staining not only in stage IV NSCLC as compared to stage IIIB NSCLC (p = 0.005), but also in patients with stable or progressive disease as compared to those with a partial response (p = 0.032). A high percentage of S100A15 nuclear stained cells (HR 1.028, p = 0.01) was the only independent factor associated with three-year overall mortality.

Conclusions

Our results suggest a potential role of the IL4 pathway in immune surveillance of advanced stage NSCLC, and immune potentiation of combination chemotherapy. S100A15 may serve as a potential biomarker for tumor staging, and a predictor of poor prognosis in NSCLC.     

The Efficacy and Safety of Icotinib in Patients with Advanced Non-Small Cell Lung Cancer Previously Treated with Chemotherapy: A Single-Arm,Multi-Center,Prospective Study

Background

Icotinib is a small molecule targeting epidermal growth factor receptor tyrosine kinase, which shows non-inferior efficacy and better safety comparing to gefitinib in previous phase III trial. The present study was designed to further evaluate the efficacy and safety of icotinib in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy.

Methods

Patients with NSCLC progressing after one or two lines of chemotherapy were enrolled to receive oral icotinib (125mg tablet, three times per day). The primary endpoint was progression-free survival. The secondary endpoints included overall survival, objective response rate, time to progression, quality of life and safety.

Results

From March 16, 2010 to October 9, 2011, 128 patients from 15 centers nationwide were enrolled, in which 124 patients were available for efficacy evaluation and 127 patients were evaluable for safety. The median progression-free survival and time to progression were 5.0 months (95%CI 2.9–6.6 m) and 5.4 months (95%CI 3.1–7.9 m), respectively. The objective response rate and disease control rate were 25.8% and 67.7% respectively. Median overall survival exceeded 17.6 months (95%CI 14.2 m-NA) according to censored data. Further follow-up of overall survival is ongoing. The most frequent treatment-related adverse events were rash (26%, 33/127), diarrhea (12.6%, 16/127) and elevation of transaminase (15.7%, 20/127).

Conclusions

In general, this study showed similar efficacy and numerically better safety when compared with that in ICOGEN trial, further confirming the efficacy and safety of icotinib in treating patients with advanced NSCLC previously treated with chemotherapy.

Trial Registration

ClinicalTrials.gov NCT02486354     

不同化疗方案对晚期非小细胞肺癌患者骨髓抑制及免疫功能的影响

目的:探讨不同化疗方案对晚期非小细胞肺癌患者骨髓抑制及免疫功能的影响。方法:选取2011年1月至2013年12月收治的130例晚期非小细胞肺癌患者,按照知情同意原则随机分为三组:NP(长春瑞滨+顺铂)组45例、GP(吉西他滨+顺铂)组43例、TP(紫杉醇+顺铂)组42例,分别于化疗前及化疗2个周期后检测患者的骨髓抑制及免疫水平。结果:三种化疗方案进行治疗后骨髓抑制水平由高到低排列为GP组、TP组、NP组,差异有统计学意义(P0.05);GP组血小板减少发生率高于其他两组,TP组白细胞下降发生率高于其他两组,差异有统计学意义(P0.05);三组患者化疗后的免疫功能指标均较化疗前低,差异有统计学意义(P0.05)。三种化疗方案进行治疗后免疫功能抑制水平由高到低排列为GP组、TP组、NP组,差异有统计学意义(P0.05)。结论:GP组患者血小板下降更明显,TP组白细胞下降更为明显,NP组对骨髓抑制及免疫功能抑制较缓和,更适于老年人,因此临床选择化疗方案时要综合考虑患者骨髓状况、免疫功能情况及年龄等。     

Absence of HIV-1 Evolution in the Gut-Associated Lymphoid Tissue from Patients on Combination Antiviral Therapy Initiated during Primary Infection

Mucosal mononuclear (MMC) CCR5+CD4+ T cells of the gastrointestinal (GI) tract are selectively infected and depleted during acute HIV-1 infection. Despite early initiation of combination antiretroviral therapy (cART), gut-associated lymphoid tissue (GALT) CD4+ T cell depletion and activation persist in the majority of HIV-1 positive individuals studied. This may result from ongoing HIV-1 replication and T-cell activation despite effective cART. We hypothesized that ongoing viral replication in the GI tract during cART would result in measurable viral evolution, with divergent populations emerging over time. Subjects treated during early HIV-1 infection underwent phlebotomy and flexible sigmoidoscopy with biopsies prior to and 15–24 months post initiation of cART. At the 2^nd biopsy, three GALT phenotypes were noted, characterized by high, intermediate and low levels of immune activation. A representative case from each phenotype was analyzed. Each subject had plasma HIV-1 RNA levels <50 copies/ml at 2^nd GI biopsy and CD4+ T cell reconstitution in the peripheral blood. Single genome amplification of full-length HIV-1 envelope was performed for each subject pre- and post-initiation of cART in GALT and PBMC. A total of 280 confirmed single genome sequences (SGS) were analyzed for experimental cases. For each subject, maximum likelihood phylogenetic trees derived from molecular sequence data showed no evidence of evolved forms in the GALT over the study period. During treatment, HIV-1 envelope diversity in GALT-derived SGS did not increase and post-treatment GALT-derived SGS showed no substantial genetic divergence from pre-treatment sequences within transmitted groups. Similar results were obtained from PBMC-derived SGS. Our results reveal that initiation of cART during acute/early HIV-1 infection can result in the interruption of measurable viral evolution in the GALT, suggesting the absence of de-novo rounds of HIV-1 replication in this compartment during suppressive cART.     

Modulation of Cell Signaling Networks after CTLA4 Blockade in Patients with Metastatic Melanoma

Background

The effects on cell signalling networks upon blockade of cytotoxic T lymphocyte-associated antigen-4 (CTLA4) using the monoclonal antibody tremelimumab were studied in peripheral blood mononuclear cell (PBMC) samples from patients with metastatic melanoma.

Methodology/Principal

Findings Intracellular flow cytometry was used to detect phosphorylated (p) signaling molecules downstream of the T cell receptor (TCR) and cytokine receptors. PBMC from tremelimumab-treated patients were characterized by increase in pp38, pSTAT1 and pSTAT3, and decrease in pLck, pERK1/2 and pSTAT5 levels. These changes were noted in CD4 and CD8 T lymphocytes but also in CD14 monocytes. A divergent pattern of phosphorylation of Zap70, LAT, Akt and STAT6 was noted in patients with or without an objective tumor response.

Conclusions/Significance

The administration of the CTLA4-blocking antibody tremelimumab to patients with metastatic melanoma influences signaling networks downstream of the TCR and cytokine receptors both in T cells and monocytes. The strong modulation of signaling networks in monocytes suggests that this cell subset may be involved in clinical responses to CTLA4 blockade.

Clinical Trial Registration

clinicaltrials.gov; Registration numbers {"type":"clinical-trial","attrs":{"text":"NCT00090896","term_id":"NCT00090896"}}NCT00090896 and {"type":"clinical-trial","attrs":{"text":"NCT00471887","term_id":"NCT00471887"}}NCT00471887