The efficacy and toxicity of immune checkpoint inhibitors in a real-world older patient population

ImportanceImmunotherapy has emerged as an effective treatment option for the management of advanced cancers. The effects of these immune checkpoint inhibitors in the older patient population has not been adequately assessed.ObjectiveTo understand the impact of aging on CTLA-4 and PDL-1 inhibitors efficacy and immune-related adverse events (irAE) in the context of real-world management of advanced solid cancers.Design, Setting, and ParticipantsThis retrospective study involved all non-study patients with histologically-confirmed metastatic or inoperable solid cancers receiving immunotherapy at Kingston Health Sciences Centre. We defined ‘older patient’ as age ≥ 75. All statistical analyses were conducted under SPSS IBM for Windows version 24.0.Main Outcomes and MeasuresStudy outcomes included immunotherapy treatment response, survival, as well as number, type, and severity of irAEs.ResultsOur study (N = 78) had 29 (37%) patients age <65, 26 (33%) patients age 65–74, and 23 (30%) patients age ≥75. Melanoma, non-small cell lung cancer, and renal cell carcinoma accounted for 70%, 22%, and 8% of the study population, respectively. Distributions of ipilimumab (32%), nivolumab (33%), and pembrolizumab (35%) were similar in the study. The response rates were 28%, 27%, and 39% in the age <65, age 64–74, age ≥75 groups, respectively (P = 0.585). Kaplan-Meier curve showed a median survival of 28 months (12.28–43.9, 95% CI) and 17 months (0–36.9, 95% CI) in the age <65 and age 64–74 groups, respectively; the estimated survival probability did not reach 50% in the age ≥75 group (P = 0.319). There were no statistically significant differences found in terms of irAEs, multiple irAEs, severity of grade 3 or higher, types of irAEs, and irAEs resolution status when comparing between different age groups.Conclusion and RelevanceOur results suggest that patients age ≥75 are able to gain as much benefit from immunotherapy as younger patients, without excess toxicity. Our findings suggest that single agent immunotherapy is generally well-tolerated across different age groups with no significant difference in the type, frequency or severity of irAEs. Future studies evaluating aging and combination immunotherapy are warranted.     

Redox active or thiol reactive? Optimization of rapid screens to identify less evident nuisance compounds

Compounds that exhibit assay interference or undesirable mechanisms of bioactivity are routinely encountered in assays at various stages of drug discovery. We observed that assays for the investigation of thiol-reactive and redox-active compounds have not been collected in a comprehensive review. Here, we review these assays and subject them to experimental optimization to improve their reliability. We demonstrate the usefulness of our assay cascade by assaying a library of bioactive compounds, chemical probes, and a set of approved drugs. These high-throughput assays should complement the array of wet-lab and in silico assays during the initial stages of hit discovery campaigns to pursue only hit compounds with tractable mechanisms of action.     

子宫腺肌症对患者的心理影响及心理护理效果观察

目的 分析子宫腺肌症可能对患者造成的心理影响,探讨子宫腺肌症患者的心理护理方法,观察护理效果。方法 将62例子宫腺肌症患者随机分配为常规护理干预组和心理护理干预组,每组31例。对常规护理干预组患者,实施常规护理干预措施。对心理护理干预组患者,在常规护理干预措施的基础上,进一步对其实施针对性的心理护理干预措施。结果 心理护理干预组患者的焦虑自评量表(SAS)评分、抑郁自评量表(SDS)评分,以及睡眠质量自评量表(SRSS)各维度评分,都明显低于常规护理干预组,差异具有统计学意义。心理护理干预组患者的生活质量综合评定量表(GQOLI-74)各维度评分,要显著的高于常规护理干预组,差异同样具有统计学意义。结论 应重视并切实做好对子宫腺肌症患者的心理护理工作,这能够有效缓解患者的焦虑、抑郁情绪,提高患者的心理健康水平,改善患者的水平及生活质量。     

杨宇飞教授舌癌的中医康复治疗与验案两则＊

舌癌患者手术及放化疗后会出现构音障碍、吞咽困难、口腔黏膜炎、口干、营养不良等并发症，使患者生存质量下降，甚至导致肿瘤的复发转移，影响生存期，单一方法往往顾此失彼。依托于中国中医科学院西苑医院肿瘤康复基地，杨宇飞教授在国内外调研考察基础上，结合中国国情，构建了一种“门诊多学科肿瘤康复模式”，在舌癌康复方面，以患者为中心，以中医肿瘤内科为主导，多学科共同参与，结合康复科、口腔科、营养科、药剂科等各科优势，形成全程个体化规范序贯康复方案，对患者及早进行康复，在放疗前进行预防性干预尤其重要，使患者能够快速缓解手术和放疗的不良反应，患者获益明显。现取两个典型案例总结其舌癌多学科康复的经验，以期为舌癌的康复提供借鉴。     

Efficacy of percutaneous and transcutaneous tibial nerve stimulation in women with idiopathic overactive bladder: A prospective randomised controlled trial

BackgroundDifferent studies have reported the efficacy of percutaneous tibial nerve stimulation (PTNS) and transcutaneous tibial nerve stimulation (TTNS) in treating idiopathic overactive bladder (OAB). However, no study has compared the effectiveness of PTNS and TTNS added to bladder training (BT) in idiopathic OAB.ObjectiveTo compare the efficacy of PTNS and TTNS added to BT in women with idiopathic OAB.MethodsWe randomised 60 women with idiopathic OAB into 3 groups. Group 1 (n = 19) received BT, Group 2 (n = 19) received PTNS in addition to BT, and Group 3 (n = 20) received TTNS in addition to BT. PTNS and TTNS were performed 2 days a week, for 30 min a day, for a total of 12 sessions for 6 weeks. Patients were evaluated by incontinence severity (pad test), a 3-day voiding diary (frequency of voiding, incontinence episodes, nocturia and number of pads used), symptom severity, quality of life, treatment success (positive response rate), treatment satisfaction (Likert scale), discomfort level and preparation time for stimulation (sec).ResultsAt the end of treatment; severity of incontinence, frequency of voiding, incontinence episodes, nocturia, number of pads used, symptom severity and quality of life were significantly improved in Groups 2 and 3 versus Group 1 (P < 0.0167). Treatment success and treatment satisfaction were higher in Groups 2 and 3 than Group 1 (P < 0.001 and P < 0.0167, respectively). Level of discomfort was lower, treatment satisfaction was higher and preparation time for stimulation was shorter in Group 3 than Group 2 (P < 0.05).ConclusionBoth the PTNS plus BT and TTNS plus BT were more effective than BT alone in women with idiopathic OAB. These 2 tibial nerve stimulation methods had similar clinical efficacy but with slight differences: TTNS had shorter preparation time, less discomfort level and higher patient satisfaction than PTNS.     

凉血通瘀方干预高血压大鼠急性脑出血模型对脑组织中差异miRNA表达的影响＊

目的 研究凉血通瘀方对高血压大鼠急性脑出血模型脑组织miRNA表达的影响，对差异表达的miRNA靶基因进行分析，探索凉血通瘀方可能的药效机制。方法 将自发性高血压大鼠随机分成对照组（B）和实验组（C）。适应性饲养一周后，C组灌胃凉血通瘀方，B组灌胃等体积生理盐水，连续5天，每天1次。构建脑出血模型后收集脑组织，借助全转录组测序技术获得miRNA表达量，与miRBase数据库比对获取已知miRNA，使用miRDeep2预测新miRNA。差异分析软件为DESeq2，筛选阈值为|log₂FC| ≥1 并且P <0.05。对显著差异表达的miRNA进行靶基因预测，对靶基因进行GO功能、KEGG通路富集和PPI网络分析。结果 实验组和对照组对比，共发现21个显著差异表达的miRNA，上调有9个，下调有12个，共预测得到1243个有统计学意义的靶基因。GO富集分析发现，生物过程中突触囊泡分泌的调节、神经递质分泌的调节和神经递质运输的调节占前三位，神经元投射终点、全膜、质膜区域和细胞投射则是主要的细胞成分。分子功能分别为小GTPase绑定、底物特异性跨膜转运蛋白活性和离子跨膜转运体活性。通路分析结果显示，靶基因在癌证通路、pI3K-Akt信号通路、人类乳头瘤病毒感染、神经活性配体-受体相互作用和MAPK通路等分布广泛。采用STRING网站和Cytoscape软件，根据MCC算法筛选出ADRA2C、CASR、CCL28、CCR1、DRD2、GNAT3、GRM2、DYNC1LI1、GABBR1、GNAI1等核心靶基因。结论 凉血通瘀方对脑出血急性期鼠脑组织内miRNA的表达有重要影响；显著差异表达miRNAs可能通过靶向核心基因调控凉血通瘀方干预急性脑出血的病理过程及预后。     

Cardiac-type total anomalous pulmonary venous return is not benign

ObjectiveThe objective of this study was to investigate the association between morphological variation and postsurgical pulmonary vein (PV) stenosis (PPVS) in patients with cardiac total anomalous pulmonary venous connection (TAPVC).MethodsThis single-center, retrospective study included 168 pediatric patients who underwent surgical repair of cardiac TAPVC from 2013 to 2019 (connection to the coronary sinus [CS], n = 136; connection directly to the right atrium [RA], n = 32). Three-dimensional computed tomography modeling and geometric analysis were performed to investigate the morphological features; their relevance to the PPVS was examined.ResultsThe connection type had no association with PPVS (CS type: 18% vs right atrial type: 19%; P = .89) but there was a higher incidence of PPVS in patients with a single PV orifice than > 1 orifice (P < .001). Confluence-to-total PV area ratio (hazard ratio, 4.78, 95% CI, 1.86-12.32; P = .001) and length of drainage route (hazard ratio, 1.22; 95% CI, 1.14-1.31; P < .001) had a 4- and 1-fold increase in the risk for PPVS in the CS type after adjustment for age and preoperative pulmonary venous obstruction. In the right atrial type, those with anomalous PV return to the RA roof were more likely to develop PPVS than to the posterior wall of the RA (P < .001).ConclusionsThe number of inter-junction PV orifice correlated with PPVS development in cardiac TAPVC. The confluence-to-total PV ratio, length of drainage route, and anomalous PV return to the RA roof are important predictors for PPVS. Morphological subcategorization in this clinical setting can potentially assist in surgical decision-making.