Efficacy and Safety of Atezolizumab Plus Bevacizumab Following Disease Progression on Atezolizumab or Sunitinib Monotherapy in Patients with Metastatic Renal Cell Carcinoma in IMmotion150: A Randomized Phase 2 Clinical Trial

BackgroundThe use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively.ObjectiveTo evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC.Design, setting, and participantsIMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab.InterventionPatients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy.Outcome measurements and statistical analysisThe secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods.Results and limitationsFifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19–37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6–13.7) mo. The median event follow-up duration was 19.4 (12.9–21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors.ConclusionsThe atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC.Patient summaryPatients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.     

Normal sperm parameters per se do not reliably account for fertility: A case–control study in the real-life setting

A proportion of men are infertile despite having normal medical history/physical examination and normal semen analysis. We aimed to assess whether normal sperm parameters per se account for male factor fertility. 1,957 infertile men were compared with 103 age-comparable fertile controls. Semen analysis was based on 2010 World Health Organization reference criteria. Of all, 12.1% of infertile men and 40.8% of fertile men presented with normal sperm parameters. Among fertile men, 36.9% had isolated sperm abnormalities and 22.3% men showed two or more concomitant sperm abnormalities. Serum total testosterone was higher in infertile men with normal sperm parameters compared to those with ≥2 sperm abnormalities or azoospermia, but similar to those with isolated sperm abnormalities (p ≤ .001). Circulating hormones were similar among sperm parameters groups in fertile men. At multivariable analyses, testicular volume (OR 1.12, p ≤ .001) and FSH (OR 0.8, p ≤ .001) were associated with normal sperm parameters. Overall, the longer the infertility period, the greater the number of sperm parameters abnormalities (p < .01). In conclusion, we found that 12% of infertile men and only 41% of fertile men present with normal sperm parameters. Normal sperm parameters per se do not reliably account for fertility in the real-life setting.     

Expression of brain-derived neurotrophic factor in rapid ejaculator rats: A further study

Limited evidence has indicated that brain-derived neurotrophic factor (BDNF) may be involved in the neurobiology of premature ejaculation (PE). This study aimed to investigate BDNF levels in the central and peripheral nervous systems of a rapid ejaculation model. Eighteen male rats were selected and classified as ‘sluggish’, ‘normal’ and ‘rapid’ ejaculators on the basis of ejaculation frequency during copulatory behavioural tests. BDNF levels in specific brain regions, spinal cord and serum were determined by enzyme-linked immunosorbent assay (ELISA). Consistent with the results in PE patients, the concentration of serum BDNF decreased significantly from the sluggish rats to normal and rapid rats. Besides, in both brain regions and spinal cord, the sluggish group had the highest BDNF levels, while the rapid group had the lowest BDNF levels. Regression analyses of the expression of BDNF presented positive correlations between serum and brain (r = 0.958, p < .001), and between serum and spinal cord (r = 0.967, p < .001) respectively. Our findings suggested insufficient BDNF in the nervous system and serum may lead to rapid ejaculation. The current study adds to the evidence that BDNF is involved in the regulation of ejaculation.     

多西他赛+卡铂联合曲妥珠单抗方案对早期人表皮生长因子受体2阳性乳腺癌的新辅助治疗效果

目的探讨多西他赛+卡铂联合曲妥珠单抗(TCH)方案对早期人表皮生长因子受体2(HER2)阳性乳腺癌的新辅助治疗效果。方法回顾性分析2013年1月至2018年12月北京大学第一医院乳腺疾病中心经治的522例早期HER2阳性乳腺癌患者的临床资料,占同期收治早期浸润性乳腺癌患者的21.80%(522/2 394)。其中113例接受TCH方案进行新辅助治疗,年龄[M(QR)]52(13)岁(范围:23~69岁)。记录TCH方案新辅助治疗后病理完全缓解(pCR,ypT0N0M0期)的例数,采用Miller-Payne标准进行病理学评价。采用Kaplan-Meier法计算无病生存率和总体生存率,采用Log-rank检验比较组间生存差异。结果接受曲妥珠单抗规范治疗患者(294例)的无病生存率优于未规范治疗患者(177例)(84.4%比72.4%,χ²=4.095,P=0.046)。发生3~4级不良反应的患者占全部患者的15.9%(18/113),包括3~4级中性粒细胞减少12例,腹泻6例。31例患者获得pCR(ypT0N0M0),pCR率为27.4%(31/113)。pCR患者与非pCR患者的无病生存率和总体生存率无差异(91.8%比85.0%,92.5%比90.5%,P值均>0.05)。病理学评价为G4~5的患者无病生存率优于G1~3患者(89.6%比81.5%,χ²=5.340,P=0.021),而总体生存率的差异无统计学意义(91.4%比89.1%,χ²=1.008,P=0.315)。结论早期HER2阳性乳腺癌采用TCH方案行新辅助治疗的效果较好,新辅助治疗后病理学评价为G4~5的患者的无病生存率更高。     

Effects of cobalt and chromium ions on glycolytic flux and the stabilization of hypoxia‐inducible factor‐1α in macrophages in vitro

Implant wear and corrosion have been associated with adverse tissue reactions that can lead to implant failure. Wear and corrosion products are therefore of great clinical concern. For example, Co²⁺ and Cr³⁺ originating from CoCrMo‐based implants have been shown to induce a proinflammatory response in macrophages in vitro. Previous studies have also shown that the polarization of macrophages by some proinflammatory stimuli is associated with a hypoxia‐inducible factor‐1α (HIF‐1α)‐dependent metabolic shift from oxidative phosphorylation (OXPHOS) towards glycolysis. However, the potential of Co²⁺ and Cr³⁺ to induce this metabolic shift, which plays a determining role in the proinflammatory response of macrophages, remains largely unexplored. We recently demonstrated that Co²⁺, but not Cr³⁺, increased oxidative stress and decreased OXPHOS in RAW 264.7 murine macrophages. In the present study, we analyzed the effects of Co²⁺ and Cr³⁺ on glycolytic flux and HIF‐1α stabilization in the same experimental model. Cells were exposed to 6 to 24 ppm Co²⁺ or 50 to 250 ppm Cr³⁺. Glycolytic flux was determined by analyzing extracellular flux and lactate production, while HIF‐1α stabilization was analyzed by immunoblotting. Results showed that Co²⁺, and to a lesser extent Cr³⁺, increased glycolytic flux; however, only Co²⁺ acted through HIF‐1α stabilization. Overall, these results, together with our previous results showing that Co²⁺ increases oxidative stress and decreases OXPHOS, suggest that Co²⁺ (but not Cr³⁺) can induce a HIF‐1α‐dependent metabolic shift from OXPHOS towards glycolysis in macrophages. This metabolic shift may play an early and pivotal role in the inflammatory response induced by Co²⁺ in the periprosthetic environment.     

住院患者尊严现状及影响因素分析

目的 了解住院患者尊严期望现状,为针对性干预提供参考.方法 采用普通话版住院患者尊严量表对442例住院患者进行问卷调查.结果 住院患者尊严期望值为48.00(40.00,53.00)分,尊严满意度为71.00(61.00,75.00)分;回归分析结果显示,性别、家庭人均月收入、住院科室是住院患者尊严期望值影响因素(均P＜0.05);近年住院经历、经济负担、文化程度是住院患者尊严满意度影响因素(均P＜0.05).结论 住院患者尊严期望值处于中度水平,满意度较高.临床护士应根据不同尊严期望值和尊严满意度患者提供个性化和针对性干预,满足其尊严期望和尊严满意度.     

Takayasu’s arteritis occurring under TNF blockers in a patient with spondyloarthritis: is it an association or a paradoxical effect?

Coexistence of spondyloarthritis (SpA) and Takayasu’s arteritis is not a common finding, but such cases have been discussed, particularly in the context of choice of therapy. Inhibition of inflammation by tumor necrosis factor inhibitors (TNFi) is a key aspect of the treatment of SpA and also positive effects of such treatment in concomitant large vessel vasculitis have been reported. However, TNFi is also associated with the possibility of initiating vasculitis.The present article based on a case study and the available literature is an attempt to discuss coexistence of these two diseases and the impact of treatment with biological drugs from the anti-TNF group in the course of SpA with Takayasu’s arteritis.     

中药复方发明专利创造性审查的影响因素分析

目的 寻找中药复方发明专利创造性审查的关键影响因素并分析原因,为完善相关审查标准提供参考。方法 筛选驳回依据为创造性的中药复方发明专利复审决定,建立数据库,通过分类和单因素逻辑（Logistic）回归等方法分析影响因素。结果 中药复方专利创造性的审查标准受年度变化的影响明显。按要求补充实验数据、区别技术特征数量、复方的发明类型、审查员所引用的对比文件及公知常识情况均能提高专利复审的撤驳率。结论 我国尚未建立合理、统一、清晰的中药复方发明专利创造性审查标准,仍有待从多个方面进一步完善。     

基于转录组信息的甘松MADS-box转录因子家族分析

目的 基于转录组数据筛选鉴定分析甘松Nardostachys jatamansi MADS-box转录因子家族。方法 利用生物信息学的方法全面分析甘松MADS-box基因家族成员的蛋白理化性质、亚细胞定位、基因结构、导肽、信号肽及跨膜结构域、系统进化树。结果 在甘松转录组数据中共鉴定出20个MADS-box转录因子,含有90～365个氨基酸,相对分子质量在10 179.96～41 707.68,理论等电点范围为4.87～10.43,主要在细胞核表达,均含有MADS保守结构域,均不含信号肽、导肽以及跨膜结构域。系统发育分析表明甘松MADS蛋白主要属于TypeII型。结论 利用生物信息学分析手段,鉴定了甘松MADS-box家族转录因子,为甘松深入研究甘松MADS-box蛋白的生物学功能提供参考,为甘松的药用成分合成调控机制提供研究基础,为培育优质甘松新品种提供依据。