Management of immune-related adverse events resulting from immune checkpoint blockade

Introduction: Immune checkpoint inhibitors (ICI) are now a standard of care in the treatment of many cancers leading to durable responses in patients with metastatic disease. These agents are generally well tolerated but may lead to the occurrence of immune-related adverse events (irAEs). As any organ may be affected, clinicians should be aware of the broad range of clinical manifestations and symptoms and keep in mind that toxicities may occur late, at any point along a patient’s treatment course. Although the most common irAEs are rarely severe, some of them may be associated with great morbidity and even become life-threatening. The rate of occurrence, type and severity of irAEs may vary with the type of ICI; thus, grade 3 and 4 irAEs are reported in more than 55% of patients treated with the combination of ipilimumab 3 mg/kg and nivolumab 1 mg/kg.

Area covered: This review presents the management of irAEs resulting from checkpoint blockade, with a focus on rare irAEs.

Expert commentary: With the development of immuno-oncology and the expanding role of ICI, physicians have learnt to diagnose and treat most of the irAEs that can occur. This review provides an overview of current guidelines, previously published studies and our multidisciplinary team based practices.     

丘脑底核电刺激治疗苍白球毁损术后的帕金森病(12例报告)

目的探讨帕金森病(Parkinson's disease,PD)苍白球腹后部毁损术(posteroventral pallidotomy,PVP)后再行丘脑底核(subthalamic nucleus,STN)脑深部电刺激术(deep brain stimulation,DBS)的可行性、术中电生理学特点和治疗结果。方法应用MR和微电极记录技术进行靶点定位,对12例单侧PVP术后症状再次加重的PD患者实施STN-DBS手术,其中4例行毁损灶对侧的STN-DBS,8例行双侧STN-DBS。结果STN-DBS对本组12例PD患者症状有不同程度的改善,双侧STN-DBS的效果尤为明显,术后3个月的UPDRS运动及ADL评分较术前明显减少(P<0．05或0．01),美多巴的用量明显减少(P<0．01),无明显术后并发症。术中电生理记录显示毁损灶同侧的细胞放电明显低于正常情况。结论曾行单侧PVP的PD患者如面临二次手术,可以选择DBS手术,以双侧STN的DBS效果最好,可减少药物用量。     

Bilateral Implantation of Centromedian‐Parafascicularis Complex and GPi: A New Combination of Unconventional Targets for Deep Brain Stimulation in Severe Parkinson Disease

Objectives. Traditional deep brain stimulation (DBS) at the subthalamic nucleus (STN) has proved to be efficacious on core Parkinsonian symptoms. However, very disabling l ‐dopa–induced abnormal involuntary movements (AIMs) and axial signs are slightly affected, suggesting that we target less conventional targets. Our candidates for DBS were the globus pallidus internus (GPi) plus the intralaminar thalamic complex (Pf or CM), given its extensive functional links with basal ganglia nuclei. Materials and Methods. The routine utilization of our innovative stereotactic apparatus allows us to implant, at the same time, both the CM‐Pf complex together with the GPi in six Parkinson disease patients. Both intraoperative and postoperative neurophysiologic assessments helped us recognize functional subregions while optimizing implantation of electrodes. Unified Parkinson disease rating scale (UPDRS) motor scores, AIMs, and freezing were carefully blindly evaluated for each condition. Results. A significant amelioration of UPDRS scores was achieved by simultaneous activation of both targets. CM‐Pf activation was only slightly effective in reducing rigidity and akinesia, but more efficacious on freezing. Not surprisingly, AIMs were peculiarly decreased by the activation of the permanent electro‐catheter in the posteroventral GPi. Conclusions. These findings confirm that, in selected patients, it is conceivable to target structures other than the conventional STN in order to maximize clinical benefit.     

等电聚焦电泳分析红细胞Gd(-)壮族富宁型〔Gd(-)Zhuang-Funing〕

本文采用聚丙烯酰胺凝胶等电聚焦电泳(IEF),借助园盘电泳仪的简易装置,对正常 B 型G6PD 及变异型 G6PD 进行分析,获得了满意效果。     

敌枯双慢性毒性实验的病理形态学研究——实验大鼠脏器组织病理变化

将150只SD大鼠随机地分成Ⅰ,Ⅱ,Ⅲ,Ⅳ四个实验组和一个对照组(Ⅴ)。实验组敌枯双剂量分别为1.0,0.2,0.05及0.01mg/kg,均用去离子水配成相应浓度的染毒水,由动物自由摄取,对照组摄入去离子水。于实验第29.5,55周分两批处死。经组织病理学检查,结果发现:敌枯双可引起甲状腺滤泡上皮细胞萎缩甚至脱屑,其发生率(Ⅲ组为63.64%)与对照组(0%)比较差异有高度显著性(P<0.01);睾丸曲细精管各级生精细胞减少、萎缩甚至完全消失,其发生率(Ⅳ组为58.33%)与对照组(8.33%)比较差异有显著性(P<0.01);对心肌、肝组织也有不同程度的损伤.     

胚鼠黑质细胞悬液移植于帕金森病模型鼠侧脑室的实验研究

将胚鼠中脑腹侧组织制成细胞悬液移植于帕金森病(PD)模型鼠侧脑室,动态观察受体鼠在移植前后的行为变化。移植后16周应用诱发荧光及免疫细胞化学等方法,对移植物在受体鼠脑内的存活及生长情况进行了研究。结果,受体鼠旋转行为明显改善,侧脑室内可见黄绿色荧光细胞及酪氨酸羟化酶(TH)免疫反应阳性细胞,有的发出突起伸向室管膜及迁于尾核区.提示:移植的胚鼠黑质细胞生长良好,似作为触液神经元发挥其作用。     

人参茎叶总皂甙对实验性小鼠生殖细胞遗传物质损伤的影响

本文采用小鼠精原细胞姐妹染色单体互换（ＳＣＥ）实验方法，研究了人参茎叶总皂甙（ＧＮＳ）对丝裂霉素Ｃ（ＭＭＣ）引起的小鼠精原细胞遗传物质损伤的影响。结果表明，ＧＮＳ不能诱发小鼠精原细胞ＳＣＥ，而且在腹腔注射ＭＭＣ的同时给予ＧＮＳ，可使ＭＭＣ诱发的小鼠精原细胞ＳＣＥ频率明显降低。为此，我们认为ＧＮＳ对小鼠生殖细胞遗传物质具有保护作用。     

乳腺癌层粘连蛋白的免疫组织化学研究

本研究应用层粘连蛋白（ＬＮ）抗体，对２７例乳腺癌、５例乳腺良性病变进行了免疫组织化学研究。结果发现乳腺良性病变时，ＬＮ以均匀完整的线型阳性反应显示在乳腺导管及小叶基膜处。乳腺癌时，ＬＮ的染色表现为癌细胞胞浆内弥漫状阳性反应。２７例乳腺癌中，癌细胞ＬＮ染色强度不同，伴有转移的乳腺癌ＬＮ染色多数较强，强度在＋＋～的为７／１２（５８．３％）；不伴有转移的病例，ＬＮ染色多数较浅或为阴性，强度在＋＋～＋＋＋的病例为３／１５（２０％）。说明癌细胞内源性ＬＮ染色强弱与肿瘤转移密切相关，内源性ＬＮ的合成可能改变肿瘤细胞的浸润活性。     

重庆市新生儿高胆红素血症患儿G6PD基因突变类型及临床特点

目的研究重庆市新生儿黄疸儿G6PD三种常见基因突变与其临床表现特点之间的关系。初步估计其基因突变频率并探讨其临床意义和遗传学特征。方法应用突变特异性扩增系统(ARMS)法,检测54例重庆市新生儿黄疸儿的G6PD基因突变类型。结果检出G1388A突变39例(72%),G1376T突变8例(15%),未定型者7例(13%)。未检出G95A。结论本研究首次对重庆市新生儿黄疸儿进行G1388A、G1376T和A95G突变检测。提示G1388A和G1376T为重庆市新生儿黄疸儿G6PD缺乏症基因突变的主要类型。ARMS法是一种简便、快速、经济的检测G6PD已知基因突变的方法。本研究发现这两种突变类型仅见于中国人和华裔人群,具有遗传学及临床意义。