Annemieke M. Peters van Ton

Mitotane is an adrenolytic drug with cytotoxic effects, registered for the treatment of advanced adrenocortical carcinoma (ACC), a rare but aggressive tumour type with a poor prognosis despite treatment. Recently, the oral multi‐kinase inhibitor cabozantinib has shown promising results as a potential second‐line treatment option. Unfortunately, first‐line mitotane therapy complicates subsequent treatments due to its strong and long‐lasting inducing effects on drug‐metabolizing enzymes resulting in persistent subtherapeutic concentrations. This is also relevant for subsequent cabozantinib treatment, and therefore only patients with mitotane concentration ≤2 mg/L were eligible to enter the cabozantinib study. However, ACC is often too aggressive to await mitotane effects to diminish. In this case report, we describe different pharmacokinetic interventions to potentiate cabozantinib efficacy in a patient with rapidly progressive ACC who had persistent subtherapeutic cabozantinib concentrations after previous mitotane treatment. First, we recommended co‐administration with a high‐fat meal and grapefruit juice to increase cabozantinib absorption. Second, we aimed to reduce cabozantinib clearance through co‐administration of the CYP3A4 inhibitor cobicistat (150 mg once daily). Pharmacokinetic sampling revealed that cobicistat enhanced cabozantinib absorption, but had insufficient impact on metabolic enzymes and thereby failed to normalize the mitotane‐induced clearance of cabozantinib. Therefore, doubling the dose is deemed necessary in order to reach therapeutic cabozantinib concentrations. Our findings suggest that an aggressive approach, combining pharmacokinetic boosting, dose escalation and frequent pharmacokinetic monitoring is required to prevent undertreatment and toxicity. By mitigating mitotane‐induced subtherapeutic concentrations, this pharmacokinetic strategy may facilitate more effective use and earlier initiation of cabozantinib as second‐line treatment in ACC.

Fecal calprotectin (FC), chitinase 3-like-1 protein (CHI3L1), S100A12 and osteoprotegerin (OPG) are biomarkers of intestinal inflammation. This cross-sectional study aimed to evaluate these biomarkers in a cohort of children with Crohn’s disease (CD) and compare them with other measures of disease activity. Stool samples from children with CD were used to measure FC, CHI3L1, S100A12 and OPG by enzyme-linked immunosorbent assay. Serum inflammatory markers were measured and pediatric CD disease activity index (PCDAI) scores calculated. The simple endoscopic score for CD (SES-CD) was reported for a subgroup who underwent ileocolonoscopy corresponding with the stool samples. Sixty-five children were recruited. Children in clinical remission had lower FC and CHI3L1 levels than those with active disease (FC: 277 vs. 1648 µg/g, p = 0.012; CHI3L1: 23 vs. 227 ng/g, p = 0.013). FC levels differed between patients with clinically active or inactive isolated ileal CD. Although FC and CHI3L1 levels correlated strongly (r = 0.83), none of the fecal markers correlated well with serum markers. Only FC and OPG correlated with SES-CD scores (r = 0.57 and r = 0.48, respectively). In conclusion, FC correlated with both endoscopic and clinical disease activity and was the only biomarker that differentiated between active and inactive ileal CD. CHI3L1 also predicted clinical disease activity and correlated highly with FC. Further investigation of the role of CHI3L1 is required.

OBJECTIVES: Given the strong association between systemic inflammation and cognitive decline, we aimed to determine whether nonneurologic infections are associated with accelerated cognitive decline and structural changes in the brain using pre- and post-infection neuropsychologic assessments and repeated brain MR images. DESIGN: Additional analysis of the prospective observational Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort study. SETTING: Single-center study at the Radboud university medical center, Nijmegen, The Netherlands, between January 2006 and September 2015. PATIENTS: Five-hundred three participants (50–85 yr old) with cerebral small vessel disease were included and followed for 9 years. MEASUREMENTS AND MAIN RESULTS: Participants underwent repeated cognitive measurements and brain MRI. Infectious events were collected. Sepsis episodes were analyzed, and additionally, patients were stratified in three groups: having had a severe infectious episode (e.g., sepsis or hospitalization for infection), a mild, or no infectious episode. Development of dementia, trajectories of cognition, and structural brain changes on MRI in the subsequent follow-up periods were compared between the groups. Complete infectious data were available from 331 patients (mean age 64 ± 8 yr, 57% males). Twenty-nine participants (9%) suffered from a sepsis episode, 69 (21%) from a severe, 201 (61%) from a mild, and 61 (18%) had no infectious episode during follow-up. After correction for age, baseline cognition, and brain volume, each sepsis episode remained associated with an 82% increased risk to develop dementia within the follow-up period (hazard ratio, 1.82; 95% CI, 1.07–3.10; p = 0.027). Infections had no effect on the trajectory of structural changes to the brain after correction for baseline differences. CONCLUSIONS: In this 9-year observational follow-up study, sepsis episodes were associated with subsequent development of dementia. Nonneurologic infections had no effect on the trajectory of structural cerebral changes.

Introduction: Postoperative cognitive dysfunction occurs frequently after coronary artery bypass grafting (CABG). The underlying mechanisms remain poorly understood, but neuroinflammation might play a pivotal role. We hypothesise that systemic inflammation induced by the surgical trauma could activate the innate immune (glial) cells of the brain. This could lead to an exaggerated neuroinflammatory cascade, resulting in neuronal dysfunction and loss of neuronal cells. Therefore, the aims of this study are to assess neuroinflammation in vivo presurgery and postsurgery in patients undergoing major cardiac surgery and investigate whether there is a relationship of neuroinflammation to cognitive outcomes, changes to brain structure and function, and systemic inflammation. Methods and analysis: The FOCUS study is a prospective, single-centre observational study, including 30 patients undergoing elective on-pump CABG. Translocator protein (TSPO) positron emission tomography neuroimaging will be performed preoperatively and postoperatively using the second generation tracer ¹⁸ F-DPA-714 to assess the neuroinflammatory response. In addition, a comprehensive cerebral MRI will be performed presurgery and postsurgery, in order to discover newly developed brain and vascular wall lesions. Up to 6 months postoperatively, serial extensive neurocognitive assessments will be performed and blood will be obtained to quantify systemic inflammatory responses and peripheral immune cell activation. Ethics and dissemination: Patients do not benefit directly from engaging in the study, but imaging neuroinflammation is considered safe and no side effects are expected. The study protocol obtained ethical approval by the Medical Research Ethics Committee region Arnhem-Nijmegen. This work will be published in peer-reviewed international medical journals and presented at medical conferences. Trial registration number: NCT04520802 .