Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.     

Two-year results after combined phacoemulsification and iris-fixated phakic intraocular lens removal

Graefe's Archive for Clinical and Experimental Ophthalmology - To describe and present results after a technique for cataract surgery combined with explantation of an iris-fixated phakic...     

骨肉瘤差异表达基因的生物信息学分析及关键基因筛选

目的筛选成骨型骨肉瘤与正常成骨细胞的差异表达基因, 寻找成骨型骨肉瘤发生、发展的关键基因。方法从Gene Expression Omnibus(GEO)数据库获得正常成骨细胞和骨肉瘤组织的基因表达数据集GSE33382, 采用R语言的limma包筛选正常成骨细胞和成骨型骨肉瘤的差异表达基因, 对差异表达基因进行京都基因与基因组百科全书(KEGG)通路富集分析。采用String数据库构建蛋白交互网络, 应用Cytoscape软件的分子复合物检测(MCODE)插件筛选互作网络中的网络模块, 应用Cytoscape软件中的BiNGO模块对MCODE筛选得到的前3个主要模块所包含的差异表达基因进行基因本体(GO)富集分析。采用MCC算法筛选蛋白互作网络中前10个关键基因。从GEO数据库获得骨肉瘤的基因表达和生存数据集GSE39055, 采用Kaplan-Meier法进行生存分析。选取2005年1月至2015年12月福建医科大学附属第一医院收治的48例成骨型骨肉瘤患者的资料进行验证, 采用免疫组化法测定骨肉瘤组织中STC2蛋白的表达, 结合患者的临床资料进行生存分析。结果从GSE33382数据集...     

Opposing patterns in self-reported and measured physical activity levels in middle-aged adults

Physical activity brings significant health benefits to middle-aged adults, although the research to date has been focused on late adulthood. This study aims to examine how ageing affects the self-reported and accelerometer-derived measures of physical activity levels in middle-aged adults. We employed the data recorded in the UK Biobank and analysed the physical activity levels of 2,998 participants (1381 men and 1617 women), based on self-completion questionnaire and accelerometry measurement of physical activity. We also assessed the musculoskeletal health of the participants using the dual-energy X-ray absorptiometry (DXA) measurements provided by the UK Biobank. Participants were categorised into three groups according to their age: group I younger middle-aged (40 to 49 years), group II older middle-aged (50 to 59 years), and group III oldest middle-aged (60 to 69 years). Self-reported physical activity level increased with age and was the highest in group III, followed by group II and I (P?<?0.05). On the contrary, physical activity measured by accelerometry decreased significantly with age from group I to III (P?<?0.05), and the same pertained to the measurements of musculoskeletal health (P?<?0.05). It was also shown that middle-aged adults mostly engaged in low and moderate intensity activities. The opposing trends of the self-reported and measured physical activity levels may suggest that middle-aged adults over-report their activity level as they age. They should be aware of the difference between their perceived and actual physical activity levels, and objective measures would be useful to prevent the decline in musculoskeletal health.

     

Effect of iron deficiency without anaemia on days alive and out of hospital in patients undergoing valvular heart surgery

Comprehensive evidence regarding the treatment of non-anaemic iron deficiency in patients undergoing valvular heart surgery is lacking. This study aimed to investigate the association between non-anaemic iron deficiency and postoperative outcomes in these patients. We retrospectively analysed 321 patients of which 180 (56%) had iron deficiency (defined as serum ferritin < 100 ng.ml^-1 or < 300 ng.ml^-1 with transferrin saturation < 20%). While the iron-deficient group had lower pre-operative haemoglobin levels than the non-iron deficient group (median (IQR [range]) 134 (127–141 [120–172]) g.l^-1, 143 (133–150 [120–179]) g.l^-1, p = 0.001), there was no between-group difference in allogeneic red blood cell transfusion. Median (IQR [range]) days alive and out of hospital at postoperative day 90 was 1 day shorter in the iron-deficient group (80 (77–82 [9–85]) days vs. 81 (79–83 [0–85]) days, p = 0.026). In multivariable analysis, only cardiopulmonary bypass duration (p = 0.032) and intra-operative allogeneic red blood cell transfusion (p = 0.011) were significantly associated with reduced days alive and out of hospital at postoperative day 90. Iron deficiency did not exert any adverse influence on secondary outcomes except length of hospital stay. Our findings indicate that non-anaemic iron deficiency alone is not associated with adverse effects in patients undergoing valvular heart surgery when it does not translate into an increased risk of allogeneic transfusion.     

沙盘游戏疗法在肿瘤放疗患者中的应用

目的探讨沙盘游戏疗法对肿瘤放疗患者心理痛苦及生活质量的作用。方法采用便利抽样法,选取2019年1—12月于上海市质子重离子医院住院进行放疗的49例肿瘤患者为研究对象,采用分层随机分组方法,将患者随机分为对照组28例和试验组21例。对照组给予常规心理护理,试验组在此基础上给予沙盘游戏疗法。采用心理痛苦温度计和欧洲癌症研究与治疗组织生命质量核心量表中的5个功能维度比较两组患者干预前后的心理痛苦程度和生活质量水平。结果干预后,两组患者心理痛苦温度计得分均低于干预前,且试验组得分低于对照组,差异有统计学意义(P<0.01)。干预前后试验组患者的躯体功能、角色功能、认知功能、情绪功能、社会功能维度得分下降程度均小于对照组,差异有统计学意义(P<0.01)。结论沙盘游戏疗法对肿瘤放疗患者的心理痛苦和生活质量有一定改善作用。     

Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts

Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass.