Neuroinflammation in Chronic Systemic Symptoms (CSS)

Neuroinflammation in Chronic Systemic Symptoms (CSS): Proof-of-Concept Study Using PET and EEG/ERP Biomarkers

The purpose of the present research protocol is to investigate and identify translocator protein 18kDa, MRI DTI, and EEG/ERPs, markers of Chronic Systemic Symptoms (CSS).

Study Overview

• Status: Completed
• Conditions: Cancer; Chronic Pain; Chronic Disease; Cancer Head Neck; Chronic Inflammation; Neuroinflammatory Response

Detailed Description

In 2016, there were an estimated 15.5 million cancer survivors in the US, with a forecasted 20.3 million by 2026. Three percent of those survivors were treated for Head and neck cancers (HNC). This number is expected to rise due to increased long-term survival in patients with HPV associated oropharyngeal cancer. Increasing survivorship has generated a surge of interest in late effects of HNC therapy. Studies to date have largely focused on chronic effects stemming from local tissue damage. Recent data suggests that late systemic effects may be equally problematic. Chronic systemic symptoms (CSS) persist far longer than previously considered and are the source of significant function loss and detriment to quality of life. CSS include fatigue, neurocognitive dysfunction, centralized pain, mood disorders, sleep disturbances, and hypothalamic dysfunction manifested as thermal discomfort or hyperhidrosis. Systemic symptoms occur in clusters resulting in a heightened clinical impact. As with other critical illnesses, the trajectory of recovery from the systemic symptoms from cancer treatment is varied. Some patients will recover to baseline quickly post treatment while others display CSS that persist or worsen over time resulting in functional deficits, frailty, and an early aging phenotype which may impact survival. Survivors exhibiting a "slow burn" trajectory as manifested by persistent systemic symptom burden and worsening function over time, require extensive on-going long-term management. These patients often fail to return to work or previously held family roles. CSS may therefore be associated with greater economic cost than the initial treatment.

Work that spans a wide array of inflammatory disease processes (such as fibromyalgia, chronic fatigue syndrome, irritable bowel, etc.) demonstrate the presence of somatic, affective, and cognitive symptoms. Neuroinflammation is hypothesized to be the underlying cause of these symptoms and their manifestations. More specifically, peripheral injury/trauma/cancer release inflammatory mediators that activate glial components of peripheral and central cellular circuitry causing inflammation of the CNS. However, the concept that CSS is underlined by neuroinflammation is largely theoretical from disparate and indirect evidence. A gap in the evidence base suggests direct investigation of neuroinflammation in CSS patients in capturing a mechanistic marker is urgently needed in order to (1) present CSS as a diagnostic entity, (2) fully understand its neurobiological mechanism, and (3) test/develop appropriate treatments.

• Study Type: Observational
• Enrollment (Actual): 30

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

10x HNC patients will be recruited via Vanderbilt's Department of Otolaryngology.

10x Healthy controls will be recruited via VUMC recruitment listserv and ResearchMatch.

Description

• Inclusion Criteria for HNC patients:

  • Age ≥ 21
  • HNC of larynx, pharynx, oral cavity paranasal sinus, salivary gland, or unknown primary
  • Any histology of any epithelial origin
  • Completed therapy a minimum of 3 months prior to study entry
  • At least two systemic symptoms on the VHNSS-GSS subscale
  • Able to speak English to understand instructions and be able to provide informed consent

• Exclusion Criteria for HNC patients:

  • History of neurodegenerative disease, unrelated to cancer history/treatment
  • Alcohol/substance abuse/dependence within the last 6 months
  • Current or previous co-morbid bipolar disorder-, psychosis-, obsessive compulsive disorder-, eating disorders-, personality disorders-,
  • Neurological disorders unrelated to cancer and its treatment (e.g. ADHD, ASDs, epilepsy)
  • Learning difficulties.

• Inclusion Criteria for healthy controls:

  • Age ≥ 21
  • Able to speak English to understand instructions and be able to provide informed consent

• Exclusion Criteria for healthy controls:

  • History of HNC of larynx, pharynx, oral cavity paranasal sinus, salivary gland, or unknown primary
  • Alcohol/substance abuse/dependence within the last 6 months
  • Current or previous co-morbid bipolar disorder-, psychosis-, obsessive compulsive disorder-, eating disorders-, personality disorders-,
  • Neurological disorders (e.g. ADHD, ASDs, epilepsy)
  • Learning difficulties.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
HNC Patients w/ CSS; HNC survivor patients presenting high chronic systemic symptoms
Healthy Controls; Non-clinical controls
HNC Patients wo/ CSS; Patient Control - HNC survivor patients presenting no/low chronic systemic symptoms

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Positron Emission Tomography (PET)	Centralized Microglial Activation measured via mitochondrial translocator protein 18kDa (TSPO).	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EEG/ERP concomitant to working memory neurobehavioral task	Cognitive function as recommended by the International Cognition and Cancer Task Force (ICCTF)	12 months
EEG/ERP concomitant to sustained attention neurobehavioral task	Cognitive function as recommended by the International Cognition and Cancer Task Force (ICCTF)	12 months
Diffusion Tensor Imaging (DTI)	Diffusion coefficients as measure of cellular inflammation	12 months
Peripheral Cytokine and Chemokine Inflammation	Blood marker Interleukin-6 (IL-6)	12 months
Peripheral Cytokine and Chemokine Inflammation	Blood marker C reactive protein (CRP)	12 months
Peripheral Cytokine and Chemokine Inflammation	Blood marker nuclear factor (NF)-kB transcription factor	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Measure: Vanderbilt Head and Neck Symptom Survey (VHNSS) version 2.0 plus general symptom survey (GSS)	Validated tool to measure physical symptom burden and functional deficits related to head/neck cancer and its treatment.	12 months
Clinical Measure: Neurotoxicity Rating Scale (NRS)	37 item tool examining neurocognitive symptoms associated with neurotoxicity of medical treatment.	12 months
Clinical Measure: Central Sensitivity Inventory (CSI)	Two-part survey consisting of 35 questions. Part A aims to identify frequency of experienced systemic symptoms. Part B determines previous diagnosis of Central Sensitivity Syndromes or related disorders.	12 months
Clinical Measure: Pain Inventory (PI)	Diagram in which patients document specific areas of pain in the body, and rate pain intensity on a scale 1-10 in the past 3 months (i.e. with scores 3+ constituting chronic pain).	12 months
Clinical Measure: Patient Reported Outcomes Measurement Information System (PROMIS-29)	assesses 7 domains (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, participation in social roles/activities) using 5-point Likert scale, across 29-items.	12 months
Clinical Measure: • Behavior Rating Inventory of Executive Function - Adult version (BRIEF-A)	Measures nine non-overlapping theoretically and empirically derived clinical domains: Inhibit, Self-Monitor, Plan/Organize, Shift, Initiate, Task Monitor, Emotional Control, Working Memory, and organization of Materials.	12 months

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Collaborators: Vanderbilt-Ingram Cancer Center
• Investigators: Principal Investigator: Poppy Schoenberg, PhD, Osher Center for Integrative Medicine, VANDERBILT UNIVERSITY MEDICAL CENTER

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2021
• Primary Completion (Actual): December 7, 2021
• Study Completion (Actual): December 7, 2021

Study Registration Dates

• First Submitted: November 13, 2020
• First Submitted That Met QC Criteria: November 13, 2020
• First Posted (Actual): November 19, 2020

Study Record Updates

• Last Update Posted (Estimate): January 26, 2023
• Last Update Submitted That Met QC Criteria: January 23, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: PET; Cytokine; EEG/ERP; Neurophysiology; Chemokine; MRI/DTI; Molecular Radiology
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplasms by Site; Pain; Neurologic Manifestations; Disease Attributes; Head and Neck Neoplasms; Inflammation; Chronic Pain; Chronic Disease
• Other Study ID Numbers: IRB #202009

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

The PI will adhere to the NIH Sharing of Biomedical Research Resources: Guidelines for Recipients of NIH Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources.

1. Quality-controlled raw data as well as processed data used in publications will be de-identified before sharing upon "reasonable request". As described in the proposal, workflows and structure will be exactly described in reports and documented to allow precisely reproduce results from raw data and replicate methodology. Final data (computerized datasets with raw data and derived variables) that have not yet been published will be shared in a timely manner.
2. Software programs (i.e. experimental paradigm scripts produced for this study) and documentation will be made available for research purposes to replicate findings upon "reasonable request", and any software/script sharing requirements by journals.

• IPD Sharing Time Frame: 24 months
• IPD Sharing Supporting Information Type: Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No