Immune-Related Adverse Events as Clinical Biomarkers in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors

Background

Immune checkpoint inhibitors (ICIs) are an important treatment for metastatic renal cell carcinoma (mRCC). These agents may cause immune-related adverse events (irAEs), and the relationship between irAEs and outcomes is poorly understood. We investigated the association between irAEs and clinical outcomes in patients with mRCC treated with ICIs.

Methods

We performed a retrospective study of 200 patients with mRCC treated with ICIs at Winship Cancer Institute from 2015 to 2020. Data on irAEs were collected from clinic notes and laboratory values and grades were determined using Common Terminology Criteria in Adverse Events version 5.0. The association with overall survival (OS) and progression-free survival (PFS) was modeled by Cox proportional hazards model. Logistic regression models were used to define odds ratios (ORs) for clinical benefit (CB). Landmark analysis and extended Cox models were used to mitigate lead-time bias by treating irAEs as a time-varying covariate.

Results

Most patients (71.0%) were male, and one-third of patients (33.0%) experienced at least one irAE, most commonly involving the endocrine glands (13.0%), gastrointestinal tract (10.5%), or skin (10.0%). Patients who experienced irAEs had significantly longer OS (hazard ratio [HR], 0.52; p = .013), higher chance of CB (OR, 2.10; p = .023) and showed a trend toward longer PFS (HR, 0.71; p = .065) in multivariate analysis. Patients who had endocrine irAEs, particularly thyroid irAEs, had significantly longer OS and PFS and higher chance of CB. In a 14-week landmark analysis, irAEs were significantly associated with prolonged OS (p = .045). Patients who experienced irAEs had significantly longer median OS (44.5 vs. 18.2 months, p = .005) and PFS (7.5 vs. 3.6 months, p = .003) without landmark compared with patients who did not.

Conclusion

We found that patients with mRCC treated with ICIs who experienced irAEs, particularly thyroid irAEs, had significantly improved clinical outcomes compared with patients who did not have irAEs. This suggests that irAEs may be effective clinical biomarkers in patients with mRCC treated with ICIs. Future prospective studies are warranted to validate these findings.

Implications for Practice

This study found that early onset immune-related adverse events (irAEs) are associated with significantly improved clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICIs). In this site-specific irAE analysis, endocrine irAEs, particularly thyroid irAEs, were significantly associated with improved clinical outcomes. These results have implications for practicing medical oncologists given the increasing use of ICIs for the treatment of mRCC. Importantly, these results suggest that early irAEs and thyroid irAEs at any time on treatment with ICIs may be clinical biomarkers of clinical outcomes in patients with mRCC treated with ICIs.

     

Shedding of proangiogenic microvesicles from hypertrophic scar myofibroblasts

Hypertrophic scars are a common complication of burn injuries and represent a major challenge in terms of prevention and treatment. These scars are characterized by a supraphysiological vascular density and by the presence of pathological myofibroblasts (Hmyos) displaying a low apoptosis propensity. However, the nature of the association between these two hallmarks of hypertrophic scarring remains largely unexplored. Here, we show that Hmyos produce signalling entities known as microvesicles that significantly increase the three cellular processes underlying blood vessel formation: endothelial cell proliferation, migration and assembly into capillary‐like structures. The release of microvesicles from Hmyos was dose‐dependently induced by the serum protein α‐2‐macroglobulin. Using flow cytometry, we revealed the presence of the α‐2‐macroglobulin receptor—low‐density lipoprotein receptor‐related protein 1—on the surface of Hmyos. The inhibition of the binding of α‐2‐macroglobulin to its receptor abolished the shedding of proangiogenic microvesicles from Hmyos. These findings suggest that the production of microvesicles by Hmyos contributes to the excessive vascularization of hypertrophic scars. α‐2‐Macroglobulin modulates the release of these microvesicles through interaction with low‐density lipoprotein receptor‐related protein 1.     

Whole‐exome sequencing and host cell reactivation assay lead to a diagnosis of xeroderma pigmentosum group D with mild ultraviolet radiation sensitivity

A case of xeroderma pigmentosum (XP) group D in a 39‐year‐old Japanese man is reported. The patient had suffered from moderate to severe solar sensitivity and freckle‐like pigmented macules in sun‐exposed areas since 6 years of age, and developed skin malignancies such as squamous cell carcinoma, actinic keratosis, Bowen’s disease and basal cell carcinoma. The minimal erythema dose for ultraviolet (UV) radiation was decreased with a delayed peak reaction. The level of unscheduled DNA synthesis of fibroblasts from the patient was 70% of normal, while they expressed POLH, a gene product responsible for the XP variant. Whole‐exome sequencing indicated that the patient harbored a homozygous mutation of c.1802G>T, p.Arg601Leu in ERCC2. A genetic complementation test was carried out by host cell reactivation assay, which showed that the patient’s fibroblasts recovered only when they were transfected with XPD cDNA, confirming the diagnosis of XP‐D. Arg601Leu mutation in ERCC2 may be related to mild UV radiation sensitivity and moderate skin lesions.     

复方鳖甲软肝片联合恩替卡韦对肺结核伴慢性乙肝患者肝纤维化的影响

目的探讨复方鳖甲软肝片联合恩替卡韦对肺结核伴慢性乙肝患者肝纤维化的影响。方法选择我院2018年1月至2019年10月收治的60例肺结核伴慢性乙肝患者,根据随机数字表法将其分为对照组和观察组,各30例。两组均实施常规抗结核治疗,在此基础上,对照组给予恩替卡韦,观察组给予恩替卡韦+复方鳖甲软肝片。比较两组的干预效果。结果治疗后,两组患者的血清HA、LN、PCⅢ、Ⅳ-C水平均较治疗前降低,且观察组低于对照组(P<0.05)。观察组的药物性肝损伤发生率低于对照组,病灶吸收率、空洞闭合率、HBV-DNA转阴率及HBeAg转阴率均高于对照组(P<0.05)。结论在肺结核合并慢性乙肝患者的治疗中联合应用恩替卡韦和复方鳖甲软肝片,可降低药物性肝损伤发生率,减轻肝纤维化程度,促使结核病灶吸收、肺部空洞闭合、乙肝病毒转阴。     

Prognostic value of red blood cell distribution width in patients with acute pulmonary embolism: A protocol for systematic review and meta-analysis

Background:Prior reports have suggested that the red blood cell distribution width (RDW) parameter could be measured as a prognostic indicator in pulmonary embolism (PE) patients, thereby helping to guide their care. However, no systematic analyses on this topic have been completed to date, and the exact relationship between RDW and PE remains to be fully clarified. We will therefore conduct a systematic literature review with the goal of defining the correlation between RDW and mortality in acute PE cases.Methods:The EMBASE, Web of Knowledge, PubMed, ClinicalTrials.gov, and Cochrane Library databases will be searched for all relevant studies published from inception through March 2021 using the following search strategy: (“red blood cell distribution width”) AND (“pulmonary embolism”). Two authors will independently identify eligible studies and extract data. The Q and I² statistics will be used to judge heterogeneity among studies.Results:This study will establish the relative efficacy of RDW as a metric for predicting PE patient mortality.Conclusions:This study will offer a reliable, evidence-based foundation for the clinical utilization of RDW as a tool for gauging mortality risk in acute PE patients.Ethics and dissemination:As this is a protocol for a systematic review of previously published data, no ethical approval is required. Electronic dissemination of study results will be done through a peer-review publication or represented at a related conference.     

小细胞肺癌患者外周血辅助性T细胞的表达情况及临床意义

目的研究小细胞肺癌(SCLC)患者外周血中辅助性T细胞1(Th1)、Th2、Th17及调节性T淋巴细胞(Treg)的表达情况,探讨其在SCLC进展中的作用。方法选择2016年1月至2018年4月本院收治的44例住院的SCLC患者(SCLC组)及24名健康者(对照组)作为研究对象。采用流式细胞法检测两组研究对象外周血中Th1、Th2、Th17及Treg细胞的表达情况,应用微量样本多指标流式蛋白定量技术(CBA)检测血清中的细胞因子IFN-γ、IL-17及IL-10的表达情况。结果SCLC组患者的外周血中Th1细胞、Th1/Th2、IFN-γ表达水平显著低于对照组,差异具有统计学意义(P<0.01)。SCLC组患者的外周血中Th2、Treg、Th17、Treg/Th17、IL-17、IL-10表达水平显著高于对照组,差异具有统计学意义(P<0.01)。结论SCLC患者外周血中Th1/Th2的降低、Treg/Th17的升高可能与SCLC的致病机理及预后密切相关,该结论将为SCLC的治疗提供新的思路。     

骨髓增生异常综合征患者移植前不同方案治疗对移植后结局影响的Meta分析

目的:系统性评价骨髓增生异常综合征（MDS）患者在异基因造血干细胞移植（allo-HSCT）前接受不同治疗方案对移植后长期复发及生存的影响。方法:检索Ovid、Cochrane Library、PubMed、Embase、中国期刊全文数据库、中文科技期刊数据库、万方数据库和中国生物医学文献数据库中从建库至2019年12月MDS患者行allo-HSCT前接受不同方案治疗的文献。对符合纳入标准的文献，由2名研究者按Cochrane系统评价方法，独立进行资料提取、质量评价并交叉核对。按治疗方法，将纳入文献中的病例分为去甲基化药物（地西他滨或阿扎胞苷）治疗组（去甲基化治疗组）和传统方案治疗组（包括化疗和支持治疗）（传统治疗组）。采用RevMan 5.3软件对各组总生存（OS）、复发、无复发死亡率（NRM）、无复发生存（RFS）进行分析。结果:共纳入10篇文献。Meta分析结果显示，传统治疗组中，化疗组与支持治疗组间3年OS率[44.6%（146/327）比35.5%（138/389）； OR=0.93，95% CI 0.38~2.27， P=0.87]、复发率[32.4%（106/327）比37.3%（145/389）； OR=1.00，95% CI 0.49~2.05， P=0.99]、NRM[26.3%（86/327）比27.0%（105/389）； OR=1.05，95% CI 0.75~1.49， P=0.77]、RFS率[9.2%（30/327）比12.6%（49/389）； OR=0.74，95% CI 0.26~2.10， P=0.57]差异均无统计学意义。去甲基化治疗组与传统治疗组间3年OS率[40.7%（165/405）比45.9%（290/632）； OR=0.98，95% CI 0.71~1.36， P=0.28]、复发率[32.6%（132/405）比38.3%（242/632）； OR=1.05，95% CI 0.79~2.05， P=0.25]、NRM[27.2%（110/405）比24.8%（157/632）； OR=0.81，95% CI 0.59~1.11， P=0.68]、RFS率[46.7%（189/405）比42.2%（267/632）； OR=0.84，95% CI 0.63~1.12， P=0.85]差异均无统计学意义。无论去甲基化治疗组与化疗组间、还是去甲基化治疗组与支持治疗组间，3年OS率、复发率、NRM、RFS率差异均无统计学意义（均 P>0.05）。 结论:MDS患者allo-HSCT前接受不同方案治疗对于移植后生存和复发均无明显影响。