Immune Checkpoint Inhibitor Toxicities

Immune checkpoint inhibitors are molecules that increase the endogenous immune response against tumors. They have revolutionized the field of oncology. Since their initial approval for the treatment of advanced melanoma, their use has expanded to the treatment of several other advanced cancers. Unfortunately, immune checkpoint inhibitors have also been associated with the emergence of a new subset of autoimmune-like toxicities, known as immune-related adverse events. These toxicities differ depending on the agent, malignancy, and individual susceptibilities. Although the skin and colon are most commonly involved, any organ may be affected, including the liver, lungs, kidneys, and heart. Most of these toxicities are diagnosed by excluding other secondary infectious or inflammatory causes. Corticosteroids are commonly used for treatment of moderate and severe immune-related adverse events, although additional immunosuppressive therapy may occasionally be required. The occurrence of immune-related toxicities may require discontinuation of immunotherapy, depending on the specific toxicity and its severity. In this article, we provide a focused review to familiarize practicing clinicians with this important topic given that the use of immune checkpoint inhibitors continues to increase.     

A DNA vaccine expressing an optimized secreted FAPα induces enhanced anti-tumor activity by altering the tumor microenvironment in a murine model of breast cancer

Cancer-associated fibroblasts (CAFs), major components of the tumor microenvironment (TME), promote tumor growth and metastasis and inhibit the anti-tumor immune response. We previously constructed a DNA vaccine expressing human FAPα, which is highly expressed by CAFs, to target these cells in the TME, and observed limited anti-tumor effects in the 4T1 breast cancer model. When the treatment time was delayed until tumor nodes formed, the anti-tumor effect of the vaccine completely disappeared. In this study, to improve the safety and efficacy, we constructed a new FAPα-targeted vaccine containing only the extracellular domain of human FAPα with a tissue plasminogen activator signal sequence for enhanced antigen secretion and immunogenicity. The number of CAFs was more effectively reduced by CD8⁺ T cells induced by the new vaccine. This resulted in decreases in CCL2 and CXCL12 expression, leading to a significant decrease in the ratio of myeloid-derived suppressor cells in the TME. Moreover, when mice were treated after the establishment of tumors, the vaccine could still delay tumor growth. To facilitate the future application of the vaccine in clinical trials, we further optimized the gene codons and reduced the homology between the vaccine and the original sequence, which may be convenient for evaluating the vaccine distribution in the human body. These results indicated that the new FAPα-targeted vaccine expressing an optimized secreted human FAPα induced enhanced anti-tumor activity by reducing the number of FAPα⁺ CAFs and enhancing the recruitment of effector T cells in the 4T1 tumor model mice.     

高转换型肾性骨病中骨保护素及其配体的表达和形态计量学观察

目的 观察高转换型肾性骨病中骨保护素及其配体 (OPG，RANKL)的表达，并与骨形态计量学指标进行相关分析。 方法 选择10例慢性肾衰尿毒症患者和3例正常人进行髂骨活检术，获得骨组织标本。采用免疫组化方法检测OPG和RANKL蛋白质的表达。采用全自动图像分析系统进行骨组织形态计量学测定。结果 10例慢性肾衰尿毒症患者经骨病理学检查证实均为高转换型骨病，以破骨细胞活化形成骨吸收陷窝伴或不伴骨矿化不全为特点。免疫组化显示尿毒症患者骨组织中以RANKL阳性表达为主。与正常对照相比，RANKL阳性表达细胞数目显著增加，OPG阳性表达细胞数目显著减少。尿毒症患者RANKL的阳性表达细胞数目与骨吸收面积和破骨细胞数目呈显著正相关。结论 高转换型肾性骨病中，PTH的溶骨作用可能是通过OPG/RANKL/RANK系统介导的。     

异丙酚和异氟醚对非体外循环搭桥术患者围术期细胞因子的影响

目的:研究异丙酚和异氟醚对非体外循环搭桥术患者围术期炎性与抗炎性细胞因子平衡的影响。方法:择期非体外循环搭桥患者50例,随机分为2组。异丙酚组微量泵输入剂量为4～6mg·kg-·1h-1,异氟醚组吸入浓度为1%～1.5%。检测诱导前、打开心包、旁路血管开放30min,术后2h、24h血清白细胞介素6(IL-6)、白细胞介素10(IL-10)和肿瘤坏死因子α(TNF-α)的浓度。结果:2组患者旁路血管开放后IL-6浓度较术前升高(P<0.01),术后2h达高峰;术后2h异氟醚组高于异丙酚组(P<0.05)。IL-10浓度变化趋势与IL-6相似,旁路血管开放后、术后2h和24h异丙酚组高于异氟醚组(P<0.05)。2组患者TNF-α水平均无显著变化。结论:异丙酚麻醉促进IL-10的产生,抑制IL-6的产生,控制术中应激反应异丙酚优于异氟醚。     

旋转铰链型与单纯铰链型膝关节肿瘤假体置换的临床比较研究

目的 研究膝关节肿瘤保肢手术两种假体置换的术后效果及其比较.方法 随访我院1999年6月2006年3月治疗的72例膝关节肿瘤患者，失访9例，余63例中40例采用单纯铰链型假体置换(A组)，23例采用旋转铰链型假体置换（B组）63例随访时间9月~8年平均3年9个月，按MSTS膝关节评分标准、ambulation scores、关节屈伸度及感染、复发、手术时间进行评估。结果：A组：手术时间2.6625±0.3362h，复发5例，转移死亡3例，感染2例； B组：手术时间2.5722±0.2878h，复发3例，转移死亡2例，感染2例 。B组1例术后发生旋转轴聚乙烯轴套断裂关节脱位，再次手术更换轴套后未再出现并发症，两组无假体松动病例。两组手术时间无统计学意义；去除复发及转移死亡病例后,剩50例, A组32例， MSTS评分平均23.0/30分。 B组18例，MSTS评分平均23.7/30分。两组MSTS评分p>0.05，无统计学意义；ambulation scores各分项总分均p<0.05，有统计学意义．两组关节伸直时为0°或接近0°,屈曲度A组119.3750±17.49°，B组125.0000±15.34°，无统计学意义（p>0.05）。结论： 1. 按ambulation scores标准，在步行舒适度和快速步行方面，旋转型铰链假体置换组与单纯铰链型假体置换比较有统计学意义；2.而MSTS标准则未能体现出两组术后功能方面的统计学意义，因此ambulation scores较MSTS评分更灵敏，更适合对膝关节保肢术后功能评价；3.两组在手术时间、术后临床屈伸功能及并发症方面，如复发、感染，未见显著差别，单纯铰链型不会出现脱位，而可旋转铰链型假体有脱位的可能。     

hTERT启动子调控hNIS基因介导肺癌细胞碘摄取和131I治疗的实验研究

目的 构建含人端粒酶反转录酶(hTERT)核心启动子调控的人钠/碘同向转运体(hNIS)基因重组腺病毒,并靶向转染至肺癌A549细胞中特异性表达.探讨hTERT启动子调控的hNIS基因介导放射性碘治疗肿瘤的可能性.方法 应用AdEasy系统构建重组腺病毒Ad-hTERT-hNIS,同时构建巨细胞病毒(CMV)启动子调控的hNIS重组腺病毒Ad-CMV.hNIS作为阳性对照,不含hNIS的重组腺病毒Ad-CMV作为阴性对照.应用反转录.聚合酶链反应(RT-PCR)方法验证hTERT在转染肿瘤细胞中的转录活性,摄碘实验检测表达的hNIS蛋白功能,细胞克隆形成实验评价131I对转染肿瘤细胞的毒性作用.结果 成功构建重组腺病毒Ad-hTERT-hNIS、Ad-CMV-hNIS及Ad-CMV,并经PCR验证正确.RT-PCR证实hNIS cDNA能从Ad-hTERT-hNIS转染的细胞中扩增出来.Ad-hTERT-hNIS和Ad-CMV-hNIS转染的肺癌A549细胞摄碘能力比阴性对照组Ad-CMV转染的细胞分别提高了23和31倍,且摄碘能力可以被NaClO4抑制.Ad-hTERT-hNIS和Ad-CMV-hNIS转染的肺癌A549细胞均可被131I杀死,2组细胞成活率分别为(31.2±1.45)%和(23.6±4.08)%,而阴性对照组和未转染病毒组分别为(89.0 ±2.99)%和(91.2 ±4.63)%.结论 hTERT启动子调控的hNIS重组腺病毒转染肿瘤细胞后,应用131I治疗有望成为一种新的基因靶向治疗手段.     

同种异体骨支撑架微创治疗股骨头坏死的临床研究

目的应用改良髓芯减压术结合同种异体骨支撑架加自体骨和脱钙骨基质（decalcified bone matrix，DBM）治疗早期股骨头坏死，探索早期股骨头坏死的微创治疗方法。方法2004年1月～2005年4月，23例24个髋关节采用经大转子下通过股骨颈钻隧道至股骨头骨坏死区，将装有自体松质骨和DBM的同种异体骨支撑架经隧道拧入骨坏死区直至软骨下骨约5mm处，隧道远端用自体髂骨填塞。观察手术前后Harris评分变化、x线影像学表现及是否需进一步治疗。结果本组所有患者均获得随访，平均随访19（12—27）个月，以最后一次随访资料作为最终评价依据。Harris评分，术前优良率为43．5％（10／23）。术后优良率为91．3％（21／23）。22侧髋关节影像学表现保持稳定，无明显并发症发生。结论同种异体骨支撑架植入结合自体松质骨和DBM治疗成人股骨头坏死，增加了股骨头负重区软骨下骨的机械支撑，成骨作用强，有利于股骨头坏死的修复与重建，同时，不破坏患者股骨头本身的血液供应，创伤小，操作简单，值得临床推广使用。     

Thyroid Artery Erosion by Esophageal Cancer: Management with Interventional Radiology

Management of upper gastrointestinal bleeding because of erosion of vessels by esophageal cancer may be challenging. We present herein the angiographic images of a 49-year-old patient who was admitted with massive bleeding from a tumor-eroded inferior thyroid artery. Attempts to control the bleeding by means of flexible endoscopy and insertion of a Sengstaken–Blakemore tube had failed. The diagnosis was impressively demonstrated by multislice computed tomography with intravenous contrast in the arterial phase and multiplanar reconstructions (computed tomography angiography) and by digital subtraction angiography. The bleeding was successfully treated with superselective catheterization and coiling of the eroded vessel.     

腮腺多形性腺瘤与沃辛瘤MRI表现对照分析

目的:探讨磁共振成像检查对腮腺多形性腺瘤与沃辛瘤的鉴别诊断价值。方法:回顾分析经病理证实的8例腮腺多形性腺瘤及10例腮腺沃辛瘤的磁共振成像检查表现,并作统计学处理。结果:腮腺多形性腺瘤为单侧腮腺单发病灶(8/8),沃辛瘤可单侧单发(5/10),亦可双侧或多发(5/10)(P<0.05);沃辛瘤多位于腮腺浅叶(13/17),腮腺多形性腺瘤可位于浅叶(6/8),亦可位于深叶或占据深浅叶(2/8)(P<0.05);多形性腺瘤在T2WI中以高信号多见(5/8),沃辛瘤以等信号或低信号为主(17/17)(P<0.05);性别分布上腮腺多形性腺瘤女性多见(6/8),沃辛瘤男性多见(7/10)(P<0.05);年龄分布上沃辛瘤为50岁以上者多见(6/10),多形性腺瘤中50岁以上与50岁以下者分布相近,各为4例(P<0.01)。结论:磁共振成像检查的特征表现和临床资料相结合对腮腺多形性腺瘤与沃辛瘤可正确诊断。