Neuroinflammation in Chronic Systemic Symptoms (CSS)

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.

• 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.