Neurologic Complications of Immune Checkpoint Inhibitors in Thoracic Malignancies

Immune checkpoint inhibitors (ICIs) have transformed the prognosis of cancers previously considered lethal. The spectrum of therapeutic indications is rapidly expanding, including the vast majority of thoracic malignancies. By enhancing the immune responses against cancer, the ICI treatments lead to the development of immune-related adverse events (irAEs) that may affect any organ. Severity varies from mild to fatal clinical manifestations. Neurologic involvement is relatively rare and highly heterogeneous, including central and peripheral nervous system diseases associated with neural-specific autoantibodies or not, central nervous system vasculitis, and granulomatous and demyelinating disorders. Symptoms often manifest within the first four cycles of treatment and can develop regardless of the class of ICI used. An unfavorable outcome is found in up to one-third of patients and is generally associated with the patients’ clinical characteristics (e.g., age, coexistence of systemic adverse events), cancer type (e.g., lung cancer versus other), and specific clinical setting (e.g., ICI treatment in patients with preexisting paraneoplastic neurologic autoimmunity, ICI rechallenge after a first neurologic irAE). Diagnosis should be suspected in patients with new-onset neurologic symptoms while on ICI treatment which are not explained by metastatic disease or other metabolic/infectious disorders. Recommended treatment is based on clinical severity and consists of ICI discontinuation with or without immunosuppressive/immunomodulatory therapy, although alternative approaches are reasonable depending on cancer status (e.g., aggressive immunosuppression without discontinuing ICI in patients with initial cancer response). Early recognition and appropriate treatment of these neurologic irAEs are crucial for improved patient outcomes and therapeutic planning.     

Imaging Features of Pulmonary Immune-related Adverse Events

Pulmonary immune-related adverse events represent rare but potentially severe side effects of immunotherapies. Diagnosis is often challenging, as symptoms and imaging features are not specific and may mimic other lung diseases, thus potentially delaying appropriate patient management. In this setting, an accurate imaging evaluation is essential for a prompt detection and correct management of these drug-induced lung diseases. The purpose of this article is to review the different types of pulmonary immune-related adverse events, describe their imaging characteristics on both high-resolution computed tomography and positron emission tomography/computed tomography and stress their underlying diagnostic challenge by presenting the mimickers.     

Timing of Uterine Artery Embolization for Leiomyoma during the Menstrual Cycle

PurposeTo investigate differences in outcomes of uterine artery embolization (UAE) for leiomyoma when performed during different phases of the menstrual cycle.Materials and MethodsIn this single-institution retrospective analysis, 111 premenopausal patients (median [range] age, 44 [33–52] years) undergoing UAE for symptomatic leiomyoma between June 2014 and February 2020 were included. Twenty-one patients underwent UAE in the menstrual phase (the early follicular phase), 27 in the late follicular phase, and 63 in the luteal phase. Baseline characteristics and technical and peri-procedural outcomes were compared among groups. Leiomyoma infarction on contrast-enhanced magnetic resonance imaging 1 week after UAE and 4-month outcomes, including changes in the Uterine Fibroid Symptom and Quality of Life questionnaire scores, the volume reduction rates of the uterus and largest leiomyoma, follicle stimulating hormone values, adverse events, and amenorrhea, were compared among groups.ResultsA 4-month follow-up was completed for all patients. No significant differences were observed among groups in baseline characteristics or technical and peri-procedural outcomes. There were no significant differences in the multivariate-adjusted 1-week infarction rates of all leiomyoma volumes (P = .161) or multivariate-adjusted 4-month outcomes, including changes in the Uterine Fibroid Symptom and Quality of Life questionnaire symptoms and total scores (P = .864 and P = .798, respectively), the volume reduction rates of the uterus and the largest leiomyoma (P = .865 and P = .965, respectively), and follicle stimulating hormone values (P = .186) among the groups. No significant differences were noted in the 4-month adverse events (P = .260) or amenorrhea (P = .793) among the groups.ConclusionsThe present study demonstrated no significant differences in the outcomes of UAE for leiomyoma when performed during different phases of the menstrual cycle.     

肺癌免疫治疗导致甲状腺功能异常

免疫疗法治疗恶性肿瘤近年来取得前所未有的进展，迎来肿瘤治疗的新时代。免疫治疗在肿瘤患者的持续应答时间比放化疗的更持久。随着免疫治疗在临床上的广泛应用，免疫相关不良反应（immune-related adverse events，irAEs）也越来越多的被发现。irAEs主要累及皮肤、胃肠道、肝脏和内分泌系统,而自身免疫性甲状腺功能紊乱是最常见的irAEs之一。本文就肺癌免疫治疗导致的甲状腺功能异常不良事件作一综述。     

Hepatic Artery Infusion Chemotherapy Using Fluorouracil,Leucovorin, and Oxaliplatin versus Transarterial Chemoembolization as Initial Treatment for Locally Advanced Hepatocellular Carcinoma: A Propensity Score–Matching Analysis

PurposeTo compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with a modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) regimen with that of transarterial chemoembolization as a locoregional treatment for patients with locally advanced hepatocellular carcinoma (HCC).MethodsThis retrospective study included adult patients with locally advanced HCC who received first-line treatment with either HAIC-mFOLFOX or conventional transarterial chemoembolization monotherapy from January 2015 to December 2016. The outcomes, including tumor response rates, evaluated via imaging assessment using the modified response evaluation criteria in solid tumors; overall survival; progression-free survival; and safety, were compared. The propensity score–matching methodology was used to reduce the influence of confounding factors on the outcomes.ResultsThe study included 131 patients with locally advanced HCC who underwent transarterial chemoembolization and 101 who received HAIC-mFOLFOX as initial treatment. After propensity score matching (n = 67 in each group), patients who received HAIC-mFOLFOX had a higher objective response rate (43.3% vs 13.4%, P = .001), longer median overall survival (13.9 vs 6.0 months, P < .001), and longer median progression-free survival (6.4 vs 2.8 months, P = .001) than those who underwent transarterial chemoembolization. The survival benefit with HAIC-mFOLFOX was strengthened in patients with HCC with vascular invasion (hazard ratio: 0.379; 95% confidence interval: 0.237–0.607). HAIC-mFOLFOX was associated with lower incidences of severe adverse events (8.9% vs 22.9%) and liver toxicity than transarterial chemoembolization.ConclusionsCompared with transarterial chemoembolization, HAIC-mFOLFOX is a potentially safer and more effective locoregional therapy for patients with locally advanced HCC.     

Is weight-based IV dosing of trastuzumab preferable to SC fixed-dose in some patients? A systematic scoping review

Trastuzumab, a key treatment for HER2-positive breast cancer, is available in weight-based IV and fixed-dose (600 mg) SC formulations. While the Phase 3 HannaH trial indicated non-inferiority of the SC formulation, there is some concern that the target plasma concentration may not be reached in overweight/obese patients whereas low-body-weight patients may be at risk of toxicity.This scoping review evaluated whether overweight/obese patients are at risk of below-target exposure with fixed-dose SC trastuzumab, whether low-body-weight patients are at risk of increased toxicity, especially cardiotoxicity, and whether IV and SC trastuzumab are equivalent in terms of treatment-emergent adverse events (TEAEs) (e.g. infections). Thirty-seven publications that met the eligibility criteria were included.Body weight is not an important determinant of exposure to trastuzumab at steady state (i.e. pre-dose cycle 8); however, real-world evidence suggests that the target concentration (20 μg/mL) may not be reached with the first SC dose in overweight/obese patients. There is no evidence that low-body-weight patients are at increased risk of cardiotoxicity with SC trastuzumab, although this may be confounded by the higher rate of cardiovascular comorbidities in overweight patients. In Phase 3 trials, SC trastuzumab was associated with higher rates of ISRs, ADAs and SAEs, the latter often requiring hospitalization and occurring during adjuvant treatment when patients are not burdened by chemotherapy.The route of administration of trastuzumab (IV vs SC) in different treatment settings should be discussed with the patient, taking into account the risks and benefits associated with each route.     

Thalamic deep brain stimulation for Tourette Syndrome: A naturalistic trial with brief randomized,double-blinded sham-controlled periods

BackgroundThere is still a lack of controlled studies to prove efficacy of thalamic deep brain stimulation for Tourette's Syndrome.ObjectivesIn this controlled trial, we investigated the course of tic severity, comorbidities and quality of life during thalamic stimulation and whether changes in tic severity can be assigned to ongoing compared to sham stimulation.MethodsWe included eight adult patients with medically refractory Tourette's syndrome. Bilateral electrodes were implanted in the centromedian-parafascicular-complex and the nucleus ventro-oralis internus. Tic severity, quality of life and comorbidities were assessed before surgery as well as six and twelve months after. Short randomized, double-blinded sham-controlled crossover sequences with either active or sham stimulation were implemented at both six- and twelve-months’ assessments. The primary outcome measurement was the difference in the Yale Global Tic Severity Scale tic score between active and sham stimulation. Adverse events were systematically surveyed for all patients to evaluate safety.ResultsActive stimulation resulted in significantly higher tic reductions than sham stimulation (F = 79.5; p = 0.001). Overall quality of life and comorbidities improved significantly in the open-label-phase. Over the course of the trial two severe adverse events occurred that were resolved without sequelae.ConclusionOur results provide evidence that thalamic stimulation is effective in improving tic severity and overall quality of life. Crucially, the reduction of tic severity was primarily driven by active stimulation. Further research may focus on improving stimulation protocols and refining patient selection to improve efficacy and safety of deep brain stimulation for Tourette's Syndrome.     

帕博丽珠单抗治疗晚期黑色素瘤的不良事件及相关性分析

背景与目的:免疫检查点抑制剂(immune checkpoint inhibitor,ICI)已成为肿瘤治疗的重要手段,然而伴随其显著疗效的是药物相关不良反应。观察帕博丽珠单抗在晚期黑色素瘤治疗中的安全性;初步探讨程序性死亡[蛋白]-1(programmed death-1,PD-1)单抗不良事件发生的预测因子及与疗效的相关性。方法:收集2016年8月-2017年7月期间在北京大学肿瘤医院入组一项"帕博丽珠单抗作为二线治疗中国局部晚期或转移性黑色素瘤的Ⅰb期临床研究(Keynote-151)"的54例患者的临床资料,包括性别、年龄、疾病分期、原发部位、既往化疗史、美国东部肿瘤协作组(Eastern Cooperative Oncology Group,ECOG)评分及基线外周血细胞计数,以及药物治疗相关不良事件和疗效相关信息。不良事件根据通用不良事件术语标准(Common Terminology Criteria Adverse Events,CTCAE)4.03版评价,疗效根据实体肿瘤疗效评价标准(Response Evaluation Criteria in Solid Tumors,RECIST)1.1标准评估。结果:帕博丽珠单抗在晚期黑色素瘤治疗中不良事件发生率达88.9%(48/54),严重不良事件发生率为13.0%(7/54),无死亡病例;肝毒性是导致中断和终止用药的主要原因;分析严重不良事件的发生与所观察各项临床特征及实验室检查指标之间均无显著相关性;不良事件的发生与疗效相关分析提示白癜风(P=0.001)和甲状腺功能异常(P=0.007)与疗效相关。结论:帕博丽珠单抗治疗晚期黑色素瘤不良反应发生率较高,但以1~2级为主,耐受性较好;肝毒性对试验药物应用影响最大;白癜风和甲状腺功能异常均可能是疗效较好的预测因子。