Use of a novel physiologic measure for the assessment and monitoring of vincristine induced peripheral neuropathy (VIPN) in children and adolescents.

使用一种新的生理测量方法来评估和监测儿童和青少年长春新碱引起的周围神经病变（VIPN）。

• 批准号: 10547068
• 负责人: Julia Cole Finkel
• 金额: $ 39.67万
• 依托单位: ALGOMETRX, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547068
• 关键词: 6 year old; Acute Lymphocytic Leukemia; Adolescent; Adult; Affect; Aftercare; Age; Amyloid beta-Protein; Assessment tool; Axonal Transport; Child; Childhood; Chronic; Clinical; Clinical Research; Clinical Trials; Clinical assessments; Collaborations; Common Terminology Criteria for Adverse Events; Data; Detection; Development; Devices; Diagnosis; Diagnostic; Disease; Dose; Early Diagnosis; Early Intervention; Electric Stimulation; Enrollment; Fiber; Goals; Hospitals; Immunotherapy; Individual; Life; Maintenance; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Medical Device; Microtubules; Monitor; Morbidity - disease rate; Motor; Muscle Weakness; Nerve Fibers; Neuropathy; Nociception; Numbness; Painless; Participant; Pathway interactions; Patient Self-Report; Patients; Performance; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phase; Physiological; Population; Prevalence; Process; Public Health; Pupil; Quality of life; Reflex action; Reporting; Research; Risk Factors; Schedule; Sensory; Severities; Stimulus; Survival Rate; Survivors; Symptoms; Techniques; Technology; Testing; Time; Treatment Protocols; Upper Extremity; Validation; Vincristine; afferent nerve; chemotherapy; clinical care; holistic approach; improved; indexing; innovation; meetings; neurotoxicity; new technology; novel; novel strategies; painful neuropathy; pediatric patients; prevent; prototype; research study; response; risk minimization; standard of care; tool

In this application, we propose the examination of a novel physiologic measure of vincristine-induced peripheral neuropathy (VIPN) in pediatric patients. Establishment of such a measure will enable the objective characterization of both the positive and negative symptoms of neuropathy in pediatric patients treated with vincristine in order to enable early detection and management of the resulting morbidity. Acute lymphoblastic leukemia (ALL) is the most common childhood cancer but has a 90% 5-year survival rate in children due to current treatment protocols, of which vincristine is a critical component. Vincristine induces primarily a large fiber peripheral neuropathy by disrupting microtubule associated axonal transport. Clinically, this manifests as muscle weakness, loss of reflexes, neuropathic pain and loss of sensation. Clinical assessments and research of the prevalence and risk factors for vincristine neurotoxicity have been hampered by the differing sensitivities of neuropathy assessment tools. VIPN often manifests during treatment but can be present for years following therapy leading to a diminished quality of life. It is therefore imperative to develop a clinical tool to detect VIPN before the onset of overt symptoms. In this proposal, we define and assess a metric of VIPN, the Neuropathy Index, informed by a novel technology that can produce an objective assessment of nerve fiber sensitivity. This technology leverages our transformative finding that an innocuous, transcutaneous neuroselective electrical stimulus of each sensory nerve fiber type (C, Aδ and Aβ) induces a pupillary dilation (nPRD) response reflecting the sensitivity of the fiber. The nPRD responses of the three fiber types are compared to generate a composite index, Neuropathy Index, that will be used for the assessment of VIPN. To accomplish this, we propose the following aim: Aim 1: Assess the performance of a novel physiologic endpoint, the Neuropathy Index, for the characterization of nociceptive processing in patients with VIPN. We plan to enroll 20 patients ages 6y-18y diagnosed with ALL and receiving (or scheduled to receive) vincristine. We plan to collect data at regular intervals over the course of 8 months, which will allow us to measure different levels of VIPN severity. Participants will also be evaluated using the TNS©-PV. Using this approach, we plan to apply the Neuropathy Index (i.e., [AUCAδ-AUCAβ]/AUCC) to the data collected during each testing session. We then plan to compare the Neuropathy Index to the TNS-PV to determine the relationship between these two measures. We also plan to assess the reliability of the index via a test/retest paradigm and assess the patient reported acceptability of our test compared to that of the TNS-PV. Milestone: Demonstration of a relationship between the Index and the TNS-PV (a correlation of at least 0.7) and of reliability (a test- retest reliability coefficient of at least 0.58). Ultimately, the technology being developed in this application would enable early detection of VIPN, optimizing vincristine dosing for maximum disease response and early intervention with the goal of minimizing the risk of chronic functional deficits.

在本申请中，我们建议检查长春新碱诱导的一种新的生理测量方法 儿科患者的周围神经病变（VIPN）。制定这样的措施将有助于实现目标 接受治疗的儿科患者神经病阳性和阴性症状的特征 长春新碱，以便能够及早发现和管理由此产生的发病率。急性淋巴细胞性 白血病 (ALL) 是最常见的儿童癌症，但由于以下原因，儿童 5 年生存率高达 90% 目前的治疗方案，其中长春新碱是一个关键组成部分。长春新碱主要诱导大量 通过破坏微管相关的轴突运输来引起纤维周围神经病。在临床上，这表现为 肌肉无力、反射丧失、神经性疼痛和感觉丧失。临床评估和研究 不同的敏感性阻碍了长春新碱神经毒性的患病率和危险因素的研究 神经病评估工具。 VIPN 通常在治疗期间出现，但可能在治疗后持续数年 治疗导致生活质量下降。因此，开发一种检测 VIPN 的临床工具势在必行。 在出现明显症状之前。在本提案中，我们定义并评估了 VIPN（神经病）的指标 指数，采用新技术，可以对神经纤维敏感性进行客观评估。这 技术利用了我们的革命性发现，即一种无害的、经皮的神经选择性 每种感觉神经纤维类型（C、Aδ 和 Aβ）的电刺激都会引起瞳孔扩张 (nPRD) 反映光纤灵敏度的响应。比较三种光纤类型的 nPRD 响应 生成一个综合指数，即神经病变指数，用于评估 VIPN。为了完成 为此，我们提出以下目标： 目标 1：评估新的生理终点的表现，即 神经病变指数，用于表征 VIPN 患者的伤害感受处理。我们计划 招募 20 名年龄 6-18 岁、诊断患有 ALL 并正在接受（或计划接受）长春新碱的患者。我们计划 在 8 个月的时间内定期收集数据，这将使我们能够衡量不同的水平 VIPN 严重性。还将使用 TNS©-PV 对参与者进行评估。使用这种方法，我们计划应用 将神经病变指数（即 [AUCAδ-AUCAβ]/AUCC）与每次测试期间收集的数据进行比较。我们然后 计划将神经病变指数与 TNS-PV 进行比较，以确定两者之间的关系 措施。我们还计划通过测试/再测试范式评估该指数的可靠性，并评估患者 报告了我们的测试与 TNS-PV 相比的可接受性。里程碑：示范 该指数与 TNS-PV 之间的关系（相关性至少为 0.7）以及可靠性（测试- 重测信度系数至少为0.58）。最终，该应用中正在开发的技术 将能够早期发现 VIPN，优化长春新碱剂量以实现最大的疾病反应并尽早发现 干预的目的是尽量减少慢性功能缺陷的风险。