Oxylipins derived from arachidonic acid (ARA) have been implicated in the development of colorectal adenomas and colorectal cancer. The primary purpose of this work was to determine the relationship between plasma levels of oxylipins and colorectal adenoma characteristics at study entry, as well as with the development of a new adenoma during follow-up within a Phase III adenoma prevention clinical trial with selenium (Sel). Secondarily, we sought to determine whether the selenium intervention influenced plasma oxylipin levels. Four oxylipins were quantified in stored plasma samples from a subset of Sel study subjects (n = 256) at baseline and at 12-months. There were significantly lower odds of an advanced adenoma at baseline with higher prostaglandin E₂ (PGE₂), with an OR (95% CI) of 0.55 (0.33–0.92), and with 5-hydroxyeicosatetraenoic acid (5-HETE) ((0.53 (0.33–0.94)); and of a large adenoma with higher PGE₂ ((0.52 (0.31–0.87)). In contrast, no associations were observed between any oxylipin and the development of a new adenoma during follow-up. Selenium supplementation was associated with a significantly smaller increase in 5-HETE after 12 months compared to the placebo, though no other results were statistically significant. The ARA-derived oxylipins may have a role in the progression of non-advanced adenoma to advanced, but not with the development of a new adenoma.

Drugs that inhibit cyclooxygenase (COX)-2 and the metabolism of arachidonic acid (ARA) to prostaglandin E₂ are potent anti-inflammatory agents used widely in the treatment of joint and muscle pain. Despite their benefits, daily use of these drugs has been associated with hypertension, cardiovascular and gastrointestinal toxicities. It is now recognized that ARA is metabolized to a number of bioactive oxygenated lipids (oxylipins) by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. Currently, the contribution of individual variability in ARA metabolism in response to the COX-2 inhibitors and potential adverse effects remains poorly understood. Using patient samples from the randomized, placebo-controlled phase III selenium/celecoxib (Sel/Cel) trial for the prevention of colorectal adenomatous polyps, we analyzed plasma concentrations of 74 oxylipins in a subset of participants who received celecoxib (n = 90) or placebo (n = 95). We assessed the effect of celecoxib (with and without low dose aspirin) on circulating oxylipins and systolic blood pressure (SBP). Individual CYP450- and LOX- but not COX-derived metabolites were higher with celecoxib than placebo (P<0.05) and differences were greater among non-aspirin users. LOX derived 5- and 8-HETE were elevated with celecoxib and positively associated with systolic blood pressure (P = 0.011 and P = 0.019 respectively). 20-HETE, a prohypertensive androgen-sensitive CYP450 metabolite was higher with celecoxib absent aspirin and was positively associated with SBP in men (P = 0.040) but not women. Independent of celecoxib or aspirin, LOX derived metabolites from ARA were strongly associated with SBP including 5- and 8-HETE. These findings support oxylipins, particularly the ARA LOX-derived, in blood pressure control and indicate that pharmacologic inhibition of COX-2 has effects on LOX and CYP450 ARA metabolism that contribute to hypertension in some patients.

Salivary gland hypofunction is an adverse side effect associated with radiotherapy for head and neck cancer patients. This study delineated metabolic changes at acute, intermediate, and chronic radiation damage response stages in mouse salivary glands following a single 5 Gy dose. Ultra-high performance liquid chromatography-mass spectrometry was performed on parotid salivary gland tissue collected at 3, 14, and 30 days following radiation (IR). Pathway enrichment analysis, network analysis based on metabolite structural similarity, and network analysis based on metabolite abundance correlations were used to incorporate both metabolite levels and structural annotation. The greatest number of enriched pathways are observed at 3 days and the lowest at 30 days following radiation. Amino acid metabolism pathways, glutathione metabolism, and central carbon metabolism in cancer are enriched at all radiation time points across different analytical methods. This study suggests that glutathione and central carbon metabolism in cancer may be important pathways in the unresolved effect of radiation treatment.

Aromatase inhibitor-induced arthralgia (AIA) comprises significant, activity-limiting musculoskeletal symptoms, including joint pain, myalgia, and joint stiffness. We conducted a prospective feasibility study in postmenopausal women diagnosed with early-stage (0–3) hormone receptor positive (HR+) breast cancer who were candidates for treatment with adjuvant AI therapy (n = 16). Tendons of the hands and wrists and the median nerve were imaged using gray-scale and power Doppler ultrasound (US) and US SWE. Arthralgia symptoms were evaluated using the Breast Cancer Prevention Trial (BCPT) Symptom Checklist musculoskeletal subscale (MS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and stiffness subscales. At baseline, there were significant differences in the SW velocities of tendons between dominant and nondominant hands. Increased velocity in 2 of 6 tendons and the median nerve was associated with greater pain at baseline, whereas slower velocity of the extensor digitorum tendon (suggesting decreased stiffness) was associated with a higher WOMAC stiffness score. Increased SW velocity (suggestive of increased stiffness) at baseline in the abductor pollicis longus tendon was associated with a worsening of all three pain and stiffness measures by 6 months. Future studies should evaluate SWE scores related to AIA outcomes in a larger sample size.

Celecoxib is among the more potent and better clinically studied, nonsteroidal anti-inflammatory drugs (NSAID) for use as a chemoprevention agent for colorectal cancer. Its use is associated with a 40% to 50% response rate for reduction in adenomatous polyps. However, rare serious cardiovascular effects and even death with celecoxib and other NSAIDs make it important to understand why some patients respond and others do not. Celecoxib is a selective inhibitor of COX-2. Its anticancer mechanism has largely been attributed to the inhibition of COX-2. Celecoxib also shows activity to induce apoptosis in cancer cells not expressing COX-2. This includes activity to upregulate 15-lipoxygenase-1 (15-LOX-1) independent of COX-2 and increase the synthesis of 13-S-hydroxyoctadecadienoic acid (13-S-HODE) from linoleic acid (LA) to downregulate PPAR-δ and induce apoptosis in colorectal cancer models. In examining the effect of celecoxib on 15-LOX-1 for reducing adenomatous polyps in patients with familial adenomatous polyposis (FAP), Yang and colleagues point out the potential importance of drug bioavailability in blood, normal, and neoplastic colorectal tissue in patient response. See related article, p. 217

While the COVID-19 pandemic continues to strain the healthcare system, it has also expanded telemedicine. There is a subset of hospitalized moderate to severe COVID-19 patients requiring oxygen but no other intervention. This is a retrospective study of patients ≥18 years with moderate to severe COVID-19 that participated in a home monitoring program with supplemental oxygen (HMP-O₂) ( N = 25). For study outcomes, HMP-O₂ participants were compared to patients meeting the same inclusion criteria but did not participate in the program ( N = 60). On average, the HMP-O₂ patients spent 5.8 days (±5.5 days) in the hospital compared to 8.12 days (±5.5 days) for non-program patients. This resulted in 19% cost-savings for HMP-O₂ patients. Lessons learned from this program can be applied to future HMPs for either COVID-19 or other conditions that would benefit from telecare.