Pretreatment Glasgow Prognostic Score Correlated with Serum Histidine Level and Three-Year Mortality of Patients with Locally Advanced Head and Neck Squamous Cell Carcinoma and Optimal Performance Status

Abstract

Few prospective cohort trials have investigted the effect of pretreatment nutritional and inflammatory status on the clinical outcome of patients with cancer and optimal performance status and assessed the interplay between nutrition, inflammation, body composition, and circulating metabolites before treatment. Here, 50 patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC) and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2 were prospectively recruited along with 43 healthy participants. Before concurrent chemoradiotherapy, compared with healthy controls, the cancer group showed lower levels of histidine, leucine, and phenylalanine and had low values in anthropometric and body composition measurements; however, the group displayed higher ornithine levels, more malnutrition, and severe inflammation. Pretreatment advanced Glasgow prognostic score (1 and 2) status was the sole prognostic factor for 3-year mortality rate and was associated with age and serum histidine levels in patients with cancer. Thus, even at the same tumor stage and ECOG PS, patients with LAHNSCC, poor nutrition, and high inflammation severity at baseline may have inferior survival outcomes than those with adequate nutrition and low inflammation severity. Assessment of pretreatment nutritional and inflammatory status should be included in the enrollment criteria in future studies.

Keywords: Glasgow prognostic score; head and neck cancer; histidine; inflammation; metabolites; performance status.

Figure 1

Correlation matrices used to visualize the correlations of the pretreatment levels of metabolites, biochemical and anthropometric factors, NIBs, and DXA-derived parameters were obtained using Pearson correlation coefficient.

Figure 2

Four possible mechanisms responsible for serum levels of histidine, leucine, ornithine, and phenylalanine in patients with LAHNSCC before concurrent chemoradiotherapy. They include: amount of dietary intake (①), consumption in the neutralization against oxidative and pro-inflammatory stress (②), fuel provider for energy production (③), and nitric oxide synthase (NOS)–nitric oxide (NO) pathway (④). First, reduced dietary intake directly results in decreased serum levels of essential amino acids (histidine, leucine, and phenylalanine). Second, essential amino acids are delivered into cells via L-type amino acid transporter 1 (LAT1); once inside, they can neutralize the reactive oxygen species (ROS) and pro-inflammatory mediators using their antioxidative and anti-inflammatory activities or enter into the Krebs cycle for energy production to compensate calorie deficiency from inadequate food intake. Finally, ROS and pro-inflammatory mediators can stimulate thrombopoiesis from mature megakaryocytes in the bone marrow, inhibit lymphocyte differentiation and proliferation, and upregulate NOS and NO production. Produced NO can decrease ornithine decarboxylase (ODC) activity and increase the ornithine levels. The magnitude of oxidative stress and pro-inflammatory mediators are reciprocally regulated by cancer and immune cells, such as regulatory T cells (Treg), macrophages, and myeloid-derived suppressor cells (MDSC), within the tumor microenvironment and in the peripheral blood. ROS and pro-inflammatory mediators can reduce the function of phenylalanine hydroxylase (PAH) and prevent the conversion of phenylalanine to tyrosine. Tetrahydrobiopterin (BH4) and tetrahydrofolate (THF) are essential cofactors for the conversion of phenylalanine into tyrosine and histidine into glutamate, respectively.