Background The TOPAZ‐1 phase III trial reported a survival benefit with the anti‐programmed death cell ligand 1 (anti‐PD‐L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer. The present study investigated the efficacy and safety of this new standard treatment in a real‐world setting. Methods The analysed population included patients with unresectable, locally advanced or metastatic adenocarcinoma of the biliary tract treated with durvalumab in combination with gemcitabine and cisplatin at 17 Italian centres. The primary endpoint of the study was progression‐free survival (PFS), whereas secondary endpoints included overall survival (OS), overall response rate (ORR) and safety. Unadjusted and adjusted hazard ratios (HRs) by baseline characteristics were calculated using the Cox proportional hazards model. Results From February 2022 to November 2022, 145 patients were enrolled. After a median follow‐up of 8.5 months (95% CI: 7.9–13.6), the median PFS was 8.9 months (95% CI: 7.4–11.7). Median OS was 12.9 months (95% CI: 10.9–12.9). The investigator‐assessed confirmed ORR was 34.5%, and the disease control rate was 87.6%. Any grade adverse events (AEs) occurred in 137 patients (94.5%). Grades 3–4 AEs occurred in 51 patients (35.2%). The rate of immune‐mediated AEs (imAEs) was 22.7%. Grades 3–4 imAEs occurred in 2.1% of the patients. In univariate analysis, non‐viral aetiology, ECOG PS >0 and NLR ≥3 correlated with shorter PFS. Conclusion The results reported in this first real‐world analysis mostly confirmed the results achieved in the TOPAZ‐1 trial in terms of PFS, ORR and safety.

Cerebrovascular control is carried out by multiple nonlinear mechanisms imposing a certain degree of coupling between mean arterial pressure (MAP) and mean cerebral blood flow (MCBF). We explored the ability of two nonlinear tools in the information domain, namely cross-approximate entropy (CApEn) and cross-sample entropy (CSampEn), to assess the degree of asynchrony between the spontaneous fluctuations of MAP and MCBF. CApEn and CSampEn were computed as a function of the translation time. The analysis was carried out in 23 subjects undergoing recordings at rest in supine position (REST) and during active standing (STAND), before and after surgical aortic valve replacement (SAVR). We found that at REST the degree of asynchrony raised, and the rate of increase in asynchrony with the translation time decreased after SAVR. These results are likely the consequence of the limited variability of MAP observed after surgery at REST, more than the consequence of a modified cerebrovascular control, given that the observed differences disappeared during STAND. CApEn and CSampEn can be utilized fruitfully in the context of the evaluation of cerebrovascular control via the noninvasive acquisition of the spontaneous MAP and MCBF variability.

The uncontrolled hyper-inflammation in critically ill patients with COVID-19 might be associated with a dysfunction of the cardiovascular regulatory mechanisms. In order to estimate the involvement of cardiovascular control in limiting the risk of mortality in COVID-19 patients we assessed the degree of asynchrony between heart period (HP) and systolic arterial pressure (SAP) variability at rest in supine condition (REST) and during an orthostatic challenge, namely the modified head-up tilt (MHUT), in 18 COVID-19 patients (age: 62 ± 10 yrs, 15 men) admitted in intensive care unit (ICU) for pneumonia. The patients were distinguished in two groups, i.e. survivors (SURVs) or non survivors (noSURVs) according to the outcome. Asynchrony between HP and SAP was assessed via a model-free nonlinear marker in the information domain, i.e. cross-sample entropy (CSampEn). Neither demographic indexes nor time domain markers could separate the two groups and this result held regardless of the experimental condition.Conversely, CSampEn could and, more precisely, noSURVs subjects had a significantly larger HP-SAP asynchrony when compared to SURVs in response to MHUT. We conclude that measures of the derangement of the cardiovascular control might be helpful to stratify the risk of mortality in COVID-19 critically ill patients.

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