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.

在此应用中，我们提出了对长春新碱诱导的新生理测量的检查 小儿患者的周围神经病（VIPN）。建立这样的测量将使目标能够实现 在接受治疗的儿科患者中神经病的阳性和阴性症状的表征 vincristine是为了早期检测和管理由此产生的发病率。急性淋巴细胞 白血病（全部）是最常见的儿童癌症，但由于 当前的治疗方案，其中vincristine是关键组成部分。长春新碱主要引起大型 通过破坏微管相关的轴突转运，纤维周围神经病。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 敏感性的敏感性阻碍了长春新碱神经毒性的患病率和危险因素 神经病评估工具。 VIPN经常在治疗过程中表现出来，但可能存在多年 治疗导致生活质量降低。因此，必须开发一种临床工具来检测VIPN 在明显症状发作之前。在此提案中，我们定义和评估了VIPN的度量 索引，以一种新型技术为导致的，可以对神经纤维敏感性进行客观评估。这 技术利用了我们的变革性发现，这是无害的经皮神经选择性的 每种感觉神经纤维类型（C，Aδ和Aβ）的电刺激诱导瞳孔词典（NPRD） 反映纤维灵敏度的反应。比较了三种纤维类型的NPRD响应 为了生成一个复合指数，即神经病指数，该指数将用于评估VIPN。完成 这是我们提出以下目标：目标1：评估新型生理终点的性能， 神经病指数，用于表征VIPN患者的伤害性处理。我们计划 招募20名6Y-18岁的患者被诊断出患有所有人并接受（或计划接受）长春新碱。我们计划 在8个月的时间内定期收集数据，这将使我们能够测量不同的水平 VIPN的严重程度。参与者还将使用TNS©-PV进行评估。使用这种方法，我们计划申请 在每个测试过程中收集的数据，神经病指数（即[AUCAδ-AUCAβ]/AUCC）。然后我们 计划将神经病指数与TNS-PV进行比较，以确定这两者之间的关系 措施。我们还计划通过测试/重新测试范式评估指数的可靠性，并评估患者 与TNS-PV相比，我们的测试可接受性。里程碑：演示 指数与TNS-PV（至少为0.7的相关性）与可靠性之间的关系（测试 - 重新测试系数至少为0.58）。最终，在本应用程序中开发的技术 将能够早期检测VIPN，优化vincristine剂量以最大程度的疾病反应和早期 干预措施的目的是最大程度地减少慢性功能缺陷的风险。