Background The clinical presentation of COVID-19 in patients admitted to hospital is heterogeneous. We aimed to determine whether clinical phenotypes of patients with COVID-19 can be derived from clinical data, to assess the reproducibility of these phenotypes and correlation with prognosis, and to derive and validate a simplified probabilistic model for phenotype assignment. Phenotype identification was not primarily intended as a predictive tool for mortality. MethodsIn this study, we used data from two cohorts: the COVID-19@Spain cohort, a retrospective cohort including 4035 consecutive adult patients admitted to 127 hospitals in Spain with COVID-19 between Feb 2 and March 17, 2020, and the COVID-19@HULP cohort, including 2226 consecutive adult patients admitted to a teaching hospital in Madrid between Feb 25 and April 19, 2020. The COVID-19@Spain cohort was divided into a derivation cohort, comprising 2667 randomly selected patients, and an internal validation cohort, comprising the remaining 1368 patients. The COVID-19@HULP cohort was used as an external validation cohort. A probabilistic model for phenotype assignment was derived in the derivation cohort using multinomial logistic regression and validated in the internal validation cohort. The model was also applied to the external validation cohort. 30-day mortality and other prognostic variables were assessed in the derived phenotypes and in the phenotypes assigned by the probabilistic model. Findings Three distinct phenotypes were derived in the derivation cohort (n=2667)-phenotype A (516 [19%] patients), phenotype B (1955 [73%]) and phenotype C (196 [7%])-and reproduced in the internal validation cohort (n=1368)phenotype A (233 [17%] patients), phenotype B (1019 [74%]), and phenotype C (116 [8%]). Patients with phenotype A were younger, were less frequently male, had mild viral symptoms, and had normal inflammatory parameters. Patients with phenotype B included more patients with obesity, lymphocytopenia, and moderately elevated inflammatory parameters. Patients with phenotype C included older patients with more comorbidities and even higher inflammatory parameters than phenotype B. We developed a simplified probabilistic model (validated in the internal validation cohort) for phenotype assignment, including 16 variables. In the derivation cohort, 30-day mortality rates were 2•5% (95% CI 1•4-4•3) for patients with phenotype A, 30•5% (28•5-32•6) for patients with phenotype B, and 60•7% (53•7-67•2) for patients with phenotype C (log-rank test p<0•0001). The predicted phenotypes in the internal validation cohort and external validation cohort showed similar mortality rates to the assigned phenotypes (internal validation cohort: 5•3% [95% CI 3•4-8•1] for phenotype A, 31•3% [28•5-34•2] for phenotype B, and 59•5% [48•8-69•3] for phenotype C; external validation cohort: 3•7% [2•0-6•4] for phenotype A, 23•7% [21•8-25•7] for phenotype B, and 51•4% [41•9-60•7] for phenotype C).Interpretation Patients admitted to hospital with COVID-19 can be classified into three...

BackgroundAgents targeting the vascular endothelial growth factor receptor (VEGF) pathway may induce many toxicities. The European Medicines Agency (EMA) recommended a starting dose of 5 mg twice daily in renal cell carcinoma.PurposeTo describe the data regarding the effectiveness and safety of therapy with axitinib in patients with advanced renal cell carcinoma treated in our hospital.Material and methodsRetrospective observational study that included all patients treated with axitinib until October 2015. The variables collected using electronic medical records were: sex, age, location of metastases, therapeutic positioning, ECOG Scale, initial dose, dosage adjustment, progression free survival (PFS), grounds for suspension-interruption and clinical variables associated with adverse effects.Results26 patients were included, with a mean age of 64.55 years (±12.71); 54.85% were men. The diagnosis in 80.77% of patients was clear cell renal cell carcinoma, and metastatic lesions were located mainly in the lungs (69.23%), bones (53.85%), lymph nodes (38.46%) and liver (34.61%).The median number of lines of treatment was 3 (range 2–6). The median of the ECOG Scale was the same at the beginning and end of the study (ECOG=0). 64.54% of patients began treatment with a dose of 10 mg/day axitinib and median PFS was 11 months (95% confidence interval 6.673 to 15.327).Regarding the safety profile, 88.46% suffered an adverse reaction associated with axitinib, including: general disorders (60.87%), gastrointestinal (52.17%), vascular (47.82%) and skin (34.78%), increase in TSH (26.09%) and cardiac (17.39%). 19.23% of patients experienced dose reduction at some time during treatment due to drug intolerance and gastrointestinal upset (42.86%) being the main cause. Temporary interruption of treatment was observed in 57.69% of patients associated with axitinib, and 15.37% of treatments were suspended indefinitely because of side effects (one case with severe congestive heart failure and another with renal impairment). The rest of the suspensions were for clinical progression of the disease.ConclusionOnly half of the patients began treatment at a dose of 10 mg/day, as recommended by the EMA.Median PFS in our patients was similar to that of clinical trials.Nearly 3 of 4 patients treated with axitinib experienced adverse effects that led to a temporary or permanent suspension of treatment. Therefore, the role of the pharmacist may be of special interest for the provision of special pharmaceutical care in drugs with a safety profile as relevant as axitinib.References and/or AcknowledgementsPhase 3 AXIS trial.No conflict of interest.

BackgroundIn Cushing’s syndrome (CS), when surgery is unsuccessful or contraindicated, ketoconazole is the drug most frequently used to treat hypercortisolism.In July 2013, European Medicines Agency announced their negative risk-benefit assessment of oral ketoconazole as treatment of fungal infections, because it can cause liver damage and drug interactions due to cytochrome P450 inhibition. Ketoconazole was suspended as an antifungal in the European Union, but compassionate use is authorised for CS.PurposeTo analyse the hormonal effects and tolerance of ketoconazole in CS over the last year.Material and methodsNine patients [32–83 years old] were treated in hospital. All patients were retrospectively studied with a follow-up of 26 months; their treatment had lasted from 12 days–25 years. One patient had ectopic ACTH production, two had pituitary adenoma, and six had adrenal neoplasia. Four patients had previously had surgery, but it was not effective in two cases. The dose of ketoconazole was between 200–1,200 mg/day.Liver tests checked: transaminases, total bilirubin and alkaline phosphatase. Hormonal control was observed with Nugent’s test and 24 h urinary free cortisol. The patient’s current treatment was noted to check for drug interactions.ResultsAll patients were checked. No adrenal insufficiency was observed. Liver function tests were normal. Five patients stopped ketoconazole: two for surgery; two died of metastatic cancer; and one because of a potential drug interaction with calcium antagonism. 77.8% of the patients had some possible drug interactions, but only one stopped ketoconazole. Other interactions were with drugs metabolised by CYP450; or with proton pump inhibitors which reduce the pH-dependent absorption of ketoconazole. These problems were solved by changing the dose of the drugs concerned.ConclusionKetoconazole seems to be a safe and efficacious treatment in CS. However, it is necessary to perform a bigger study to get significant conclusions.ReferenceFeelders RA, Hofland LJ, de Herder WW. Medical treatment of Cushing’s syndrome: adrenal-blocking drugs and ketoconazole. Neuroendocrinology 2010;92(Suppl 1):111–15No conflict of interest.

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