The impact of mitotane therapy on serum-free proteins in patients with adrenocortical carcinoma.

Introduction: Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal cortex. Whilst surgery is the preferred treatment, adjunctive therapy with mitotane may be offered post-surgically to minimise the risk of recurrence or, in the absence of surgery, to attenuate progression. Aim: The objective was to evaluate the effects of mitotane treatment on serum protein concentrations in patients treated for ACC with mitotane therapy and compare this to patients with other adrenal neoplasms and a normal pregnant cohort. Methods: Serum cortisol, thyroid function tests, adrenocorticotrophic hormone (ACTH), cortisol-binding globulin (CBG), thyroxine-binding globulin (TBG), gonadotrophins and androgens were measured on plasma and serum samples. Thirty-five patients with ACC were included, and mitotane levels were noted to be sub-/supra-therapeutic. Data were tested for normality, reported as mean ± s.d., and compared to other two cohorts using paired-sample t-test with a 5% P-value for significance and a 95% CI. Results: Patients on mitotane therapy had a higher mean serum CBG concentration compared to the adrenal neoplasm group (sub-therapeutic: 79.5 (95% CI: 33.6, 125.4 nmol/L), therapeutic: 85.3 (95% CI: 37.1-133.6 nmol/L), supra-therapeutic: 75.7 (95% CI: -19.3, 170.6 nmol/L) and adrenal neoplasm: 25.5 (95% CI: 17.5, 33.5 nmol/L). Negative correlations between serum cortisol and CBG concentration were demonstrated within the supra-therapeutic plasma mitotane and adrenal neoplasm groups. Conclusion: Patients with ACC and therapeutic plasma mitotane concentrations had higher serum CBG concentrations compared to those with adrenal neoplasms or pregnant women, and higher serum cortisol. Whilst there was no direct correlation with cortisol and mitotane level, the negative correlation of cortisol with CBG may suggest that the direct effect of mitotane in increasing cortisol may also reflect that mitotane has a direct adrenolytic effect.

A cytokine panel and procalcitonin in COVID-19, a comparison between intensive care and non-intensive care patients.

OBJECTIVES: Procalcitonin (PCT) is an acute-phase reactant with concentrations ≥0.5 µg/L indicative of possible bacterial infection in patients with SARS-CoV-2 infection (COVID-19). Some with severe COVID-19 develop cytokine storm secondary to virally driven hyper-inflammation. However, increased pro-inflammatory cytokines are also seen in bacterial sepsis. This study aimed to assess the clinical utility of a cytokine panel in the assessment of COVID-19 with bacterial superinfections along with PCT and C-reactive protein (CRP). METHODS: The retrospective analysis included serum cytokines (interleukins; IL-1ß, IL-6, IL-8 and tumour necrosis factor (TNFα)) measured using Ella™ (Bio-Techne, Oxford, UK) and PCT measured by Roche Cobas (Burgess Hill, UK) in patients admitted with COVID-19 between March 2020 and January 2021. Patients enrolled into COVID-19 clinical trials, treated with Remdesivir/IL-6 inhibitors were excluded. The cytokine data was compared between intensive care unit (ICU) patients, age matched non-ICU patients and healthy volunteers as well as ICU patients with high and normal PCT (≥0.5 vs. <0.5 µg/L). RESULTS: Cytokine concentrations and CRP were higher in COVID-19 patients (76; ICU & non-ICU) vs. healthy controls (n = 24), all p<0.0001. IL-6, IL-8, TNFα and were higher in ICU patients (n = 46) vs. non-ICU patients (n = 30) despite similar CRP. Among 46 ICU patients, the high PCT group (n = 26) had higher TNFα (p<0.01) and longer ICU stay (mean 47 vs. 25 days, p<0.05). There was no difference in CRP and blood/respiratory culture results between the groups. CONCLUSIONS: Pro-inflammatory cytokines and PCT were higher in COVID-19 patients requiring ICU admission vs. non-ICU admissions despite no difference in CRP. Furthermore, TNFα was higher in those with high PCT and requiring longer ICU admission despite no difference in CRP or rate of bacterial superinfection.

Immunometabolic analysis shows a distinct cyto-metabotype in Covid-19 compared to sepsis from other causes.

Background: In Covid-19, profound systemic inflammatory responses are accompanied by both metabolic risk factors for severity and, separately, metabolic mechanisms have been shown to underly disease progression. It is unknown whether this reflects similar situations in sepsis or is a unique characteristic of Covid-19. Aims: Define the immunometabolic signature of Covid-19. Methods: 65 patients with Covid-19,19 patients with sepsis and 14 healthy controls were recruited and sampled for plasma, serum and peripheral blood mononuclear cells (PBMCs) through 10 days of critical illness. Metabotyping was performed using the Biocrates p180 kit and multiplex cytokine profiling undertaken. PBMCs underwent phenotyping by flow cytometry. Immune and metabolic readouts were integrated and underwent pathway analysis. Results: Phopsphatidylcholines (PC) are reduced in Covid-19 but greater than in sepsis. Compared to controls, tryptophan is reduced in Covid-19 and inversely correlated with the severity of the disease and IFN-É£ concentrations, conversely the kyneurine and kyneurine/tryptophan ratio increased in the most severe cases. These metabolic changes were consistent through 2 pandemic waves in our centre. PD-L1 expression in CD8+ T cells, Tregs and CD14+ monocytes was increased in Covid-19 compared to controls. Conclusions: In our cohort, Covid-19 is associated with monocytopenia, increased CD14+ and Treg PD-L1 expression correlating with IFN-É£ plasma concentration and disease severity (SOFA score). The latter is also associated with metabolic derangements of Tryptophan, LPC 16:0 and PCs. Lipid metabolism, in particular phosphatidylcholines and lysophosphatidylcolines, seems strictly linked to immune response in Covid-19. Our results support the hypothesis that IFN-É£ -PD-L1 axis might be involved in the cytokine release syndrome typical of severe Covid-19 and the phenomenon persisted through multiple pandemic waves despite use of immunomodulation.