JNNP:神经内分泌肿瘤与非神经内分泌肿瘤患者免疫检查点抑制剂相关神经病变的比较

2021-05-29 MedSci原创 MedSci原创

免疫检查点抑制剂(ICI)的适应症在过去几年中有了很大的扩展。本研究的目的是在神经内分泌肿瘤的癌症免疫治疗中,提供ICI相关神经病变(irNeuropathy)的临床表现、血清学关联和预后的最新信息。

免疫检查点抑制剂(ICI)的适应症在过去几年中有了很大的扩展。本研究的目的是在神经内分泌肿瘤的癌症免疫治疗中,提供ICI相关神经病变(irNeuropathy)的临床表现、血清学关联和预后的最新信息。在梅奥诊所接受评估的所有神经病变患者均通过电子病历搜索进行鉴定。排除服用ICIs前继发于细胞毒性化疗、放疗、糖尿病、结构性或压迫性病因的神经病变患者。临床表现,诊断结果,自身抗体谱和临床结果进行了审查。

20名患者(13名男性)患有神经病变。中位年龄为64岁(31-81岁)。两名患者(10%)在ICI开始前诊断为自身免疫性疾病;一个患有格雷夫斯病,另一个患有类风湿性关节炎。ICI方案包括程序性细胞死亡1受体(PD-1)或程序性死亡配体1抑制剂(n=15,75%)、细胞毒性T淋巴细胞抗原4(CTLA-4)抑制剂(n=2,10%)以及PD-1和CTLA-4的联合治疗(n=3,15%)。ICI周期的中位数和从ICI开始到出现神经病变症状的中位数时间分别为2.5个周期(范围1-20)和9周(范围1-56)。所有患者在诊断为神经病变后均停止ICIs。两名非神经内分泌患者在神经病变解除后重新接受不同类型的ICIs治疗;其中一名患者出现复发性ICI相关膈神经病变。

所有神经内分泌肿瘤患者(小细胞肺癌,n=3;梅克尔细胞癌(n=1)伴神经病变的患者肿瘤神经抗体(1型抗神经核抗体(ANNA1,抗Hu))呈血清阳性,n=2;CRMP5和浦肯野细胞抗体2型,n=1)。这些患者表现为感觉神经病变(n=3)和不对称轴索多神经根性神经病(n=1)。两名患者甚至在服用ICI之前就出现了轻微的神经病变症状(感觉异常、感觉共济失调)。其中一名患者(患者4)进行了肿瘤神经抗体检测,发现有ANA1,并在ICI前用静脉注射免疫球蛋白和甲基强的松龙进行治疗。神经病变症状在ICI开始后复发。ICI后有3例(75%)伴有中枢神经系统并发症。患者1和42有小脑功能障碍的体征和症状(在线补充表1)。患者2出现双侧中央暗点,3级视盘水肿,并在出现视神经病变的同时被诊断为视神经病变。

这些非神经内分泌肿瘤伴神经病变患者的临床表现在以前的研究中有报道。与神经病变相关的非神经内分泌恶性肿瘤包括黑色素瘤(n=9)、肾细胞癌(n=3)、肺/胃肠道/乳腺腺癌(n=3)和间皮瘤(n=1)。神经特异性抗体检测10例(血清7例,脑脊液3例),阴性9例(90%)。1例出现亚急性长度依赖性神经病变和束状突起的患者血清中检测到富含亮氨酸的胶质瘤-1-IgG灭活。最常见的神经病变表型是多神经根性神经病(n=7),其次是长度依赖性感觉运动周围神经病变(n=3),单侧/双侧膈神经病变(n=3),臂丛神经病变(n=2)和多发性单神经病变(n=1)。电诊断研究显示3名患者(18.8%)出现脱髓鞘,均为格林-巴利综合征(GBS)样表现。神经活检显示两名患者(12.5%)有坏死性血管炎的迹象,一名患者患有多发性单神经病变,另一名患者患有多神经根性神经病。

Figure 1

神经病变表现和结果

在神经内分泌肿瘤组中,轮椅依赖的频率也更常见(75%比12.5%,p=0.010)。尽管进行了积极的免疫治疗,但神经内分泌肿瘤患者的神经症状均无改善。而在伴有神经病变的非神经内分泌肿瘤患者中,免疫抑制治疗后,大多数患者的mRS(75%)和INCAT残疾(56%)评分有所改善。4例神经内分泌肿瘤伴神经病变患者中有2例死于进行性神经恶化,均在1年内死亡 神经病变发作后一个月。另外两名患者在随访28个月和6个月时仍有神经病变症状。在非神经内分泌肿瘤组中,在11个月的中位随访时间内报告了8例死亡,其中7例死于转移性疾病,1例死于ICI相关肝炎导致肝衰竭。

感觉神经病变和/或神经病变的胃轻瘫表现,仅见于队列中的神经内分泌肿瘤患者,模仿典型的副肿瘤性神经综合征(PNS)。其侵袭性病程和免疫抑制治疗的难治性也类似于PNS的长期结果。此外,所有发生神经病变的神经内分泌肿瘤患者至少有一种或多种肿瘤神经抗体呈血清阳性。相比之下,只有一个非神经内分泌肿瘤伴神经病变的患者检测到神经元细胞表面自身抗体,并且没有典型的PNS表现。在本研究中,非神经内分泌肿瘤患者的神经病变表现型与前面描述的相似。表现型是异质性的,包括GBS样表现、长度依赖性神经病变、臂丛神经病变和膈神经病变。此外,这些病例的免疫治疗反应和远期疗效也相对较好。

肿瘤神经抗体阳性的免疫性神经病可能是由于ICI刺激的针对肿瘤和神经细胞中表达的自身抗原的交叉反应性免疫反应引起的,类似于PNS的发病机制。另一方面,许多血清阴性的免疫性神经病可能是继发于ICI诱导的神经系统自身免疫潜在倾向的增强。随着ICI的应用和适应症的扩大,可能会遇到肿瘤神经抗体血清阳性的免疫性神经病,甚至在非神经内分泌肿瘤中也是如此。神经病变中神经特异性抗体的评估是重要的,尤其是与PNS典型相关的肿瘤。此外,在开始ICI治疗之前,考虑对无明确病因的神经病症状患者进行这些抗体的评估是必要的。这将有助于确定预先存在的副肿瘤性自身免疫,这可能会显著恶化后ICI。

本文的研究支持神经病变的表现和结果正在改变,因为ICI的适应症已经扩大到包括与PNS典型相关的肿瘤。在ICI开始前,识别提示已存在的副肿瘤性神经病变的临床特征和肿瘤神经自身抗体评估对于避免这些患者神经功能的不可逆衰退至关重要。

Chompoopong PZekeridou AShelly S, et al Comparison of immune checkpoint inhibitor-related neuropathies among patients with neuroendocrine and non-neuroendocrine tumours

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    2022-04-09 jklm09
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    2021-05-31 axin012
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