Key articles from international medical journals Prof. Oliver Reich Section editor Munich (DE)
oliver.reich@ klinikum-muenchen.de
Source: Biomarkers and clinical scores to aid the identification of disease severity and intensive care requirement following activation of an in-hospital sepsis code. Jaume Baldirà, Juan Carlos Ruiz‑Rodriguez, Darius Cameron Wilson, Adolf Ruiz‑Sanmartin, Alejandro Cortes, Luis Chiscano, Roser Ferrer‑Costa, Inma Comas, Nieves Larrosa, Anna Fàbrega, Juan José Gonzalez‑Lopez and Ricard Ferrer.
extreme caution should be used when considering treatment shifts based upon unvalidated surrogate endpoints.
Assoc. Prof. Francesco Sanguedolce Section editor Barcelona (ES)
Source: Intermediate clinical endpoints for surrogacy in localised prostate cancer: an aggregate meta-analysis. Gharzai LA, Jjang R, Wallington D et al. Lancet Oncol 2021; 22: 402-10.
fsangue@ hotmail.com
Ann Intensive Care 2020; 10:7. https://doi. org/10.1186/s13613-020-0625-5
Evaluation of biomarkers and clinical scores to aid the identification of disease severity and intensive care requirement for suspected sepsis Early diagnosis and treatment are mandatory for a successful outcome in sepsis. Few validated biomarkers or clinical score combinations exist which can discriminate between cases of infection and other non-infectious conditions following activation of an in-hospital sepsis code, as well as provide an accurate severity assessment of the corresponding host response. This study aimed to identify suitable blood biomarkers (MR-proADM (mid-regional proadrenomedullin), PCT (prolactin), CRP and lactate) or clinical score (SOFA and APACHE II) combinations to address this unmet clinical need. A prospective, observational study of patients activating the Vall d’Hebron University Hospital sepsis code (ISC) within the emergency department (ED), hospital wards and intensive care unit (ICU). Area under the receiver operating characteristic (AUROC) curves, logistic and Cox regression analysis were used to assess performance. One hundred and forty-eight patients met the Vall d’Hebron ISC criteria, of which 130 (87.8%) were retrospectively found to have a confirmed diagnosis of infection. Both PCT and MR-proADM had a moderate-to-high performance in discriminating between infected and non-infected patients following ISC activation, although the optimal PCT cut-off varied significantly across departments. Similarly, MR-proADM and SOFA performed well in predicting 28 and 90-day mortality within the total infected patient population, as well as within patients presenting with a community-acquired infection or following a medical emergency or prior surgical procedure. Importantly, MR-proADM also showed a high association with the requirement for ICU admission after ED presentation [OR (95% CI) 8.18 (1.75–28.33)] or during treatment on the ward [OR (95% CI) 3.64 (1.43–9.29)], although the predictive performance of all biomarkers and clinical scores diminished between both settings.
Investigators conclude that the individual use of PCT and MRproADM might help to accurately identify patients with infection and assess the overall severity of the host response… Investigators conclude that the individual use of PCT and MR-proADM might help to accurately identify patients with infection and assess the overall severity of the host response, respectively. In addition, the use of MR-proADM could accurately identify patients requiring admission to the ICU, irrespective of whether patients presented to the ED or were undergoing treatment on the ward. Initial measurement of both biomarkers might therefore facilitate early treatment strategies following activation of an in-hospital sepsis code. Finding the optimal biomarkers and clinical scores is an important research field also in urosepsis. Key articles
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New consensus-report on research priorities in sepsis Identification of intermediate clinical endpoints in localised prostate cancer The long natural history of localised prostate cancer poses challenges in clinical trials design to improve overall survival. In order to overcome this the international Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) working group established metastasis-free survival as a surrogate endpoint for overall survival for men with localised prostate cancer. However, 90% of the patients enrolled in the trials evaluated were treated with radiotherapy meaning the validity of this endpoint in surgical trials in unknown. This paper used a broader set of inclusion criteria to identify potential intermediate clinical endpoints for individual patient-level validation. In this meta-analysis eligible trials had to be randomised, therapeutic, reporting overall survival and at least one intermediate clinical endpoint, and with a sample size of at least 70 participants. Trials of metastatic disease were excluded. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure-free survival, progression-free survival, and metastasis-free survival.
… they showed that local failure did not correlate with overall survival in any of the subgroups examined. Having identified 4,221 studies, 75 randomised trials published between March 1986 and January 2020 were included. (53,631 patients) Median trial level follow-up was 9.1 years (IQR 5.7-10.6), medium age was 68.7 years (66.6-70.5) and median baseline PSA was 12.1 ng/ml (10.0-15.9 ng/ ml). Intermediate clinical endpoints that included biochemical failure had poor correlation of the treatment effect with overall survival. Correlation with local failure was also poor. Correlation of progression-free survival was moderate (R2 0.46 [95% CI 0.22-0.67]) and metastasis-free survival had the strongest correlation (R2 0.78 [95% CI 0.59-0.89]). Interestingly this held true in subgroup analysis irrespective of primary radical treatment. The same result was also seen when including only high-risk trials. More controversially they showed metastasis-free survival might not be a surrogate endpoint for radiotherapy-specific trials testing dose escalation, nodal irradiation, or hypofractionation. The goal of dose escalation is primarily to reduce local failure, and they showed that local failure did not correlate with overall survival in any of the subgroups examined. This finding could account for why dose-escalation trials to date, even those powered for overall survival, have not improved overall survival. For men with biochemical recurrence, it remains true that non-prostate cancer deaths are more frequent than dying from the disease. As a consequence, it may be true that intensification of treatment for biochemical recurrence may worsen other cause mortality and as a result obscure any correlation between biochemical recurrence and overall survival. This is especially likely to be true for treatments aimed at local control. As a result,
Urosepsis is a feared situation in urology and its prevention and treatment is of utmost importance. The objective of this report was to identify priorities for administrative, epidemiological and diagnostic research in sepsis. The report is a follow-up to a previous consensus statement about sepsis research by members of the Surviving Sepsis Campaign Research Committee, representing the European Society of Intensive Care Medicine and the Society of Critical Care Medicine. They addressed six questions regarding care delivery, epidemiology, organ dysfunction, screening, identification of septic shock, and information that can predict outcomes in sepsis.
The document provides a framework for priorities in research to address the 6 most important questions… Six questions from the Scoring/Identification and Administration sections of the original Research Priorities publication were explored in greater detail to better examine the knowledge gaps and rationales for questions that were previously identified. The document provides a framework for priorities in research to address the following questions: (1) What is the optimal model of delivering sepsis care? (2) What is the epidemiology of sepsis susceptibility and response to treatment? (3) What information identifies organ dysfunction? (4) How can we screen for sepsis in various settings? (5) How do we identify septic shock? (6) What in-hospital clinical information is associated with important outcomes in patients with sepsis? The group concludes that there is substantial knowledge of sepsis epidemiology and ways to identify and treat sepsis patients, but many gaps remain. Areas of uncertainty identified in this manuscript can help prioritise initiatives to improve understanding of individual patients and demographic heterogeneity with sepsis and septic shock, biomarkers and accurate patient identification, organ dysfunction, and ways to improve sepsis care. The present report provides guidance also for research on urosepsis.
Source: The Surviving Sepsis Campaign: research priorities for the administration, epidemiology, scoring and identification of sepsis. Nunnally ME, Ferrer R, Martin GS, Martin-Loeches I, Machado FR, De Backer D, et al. Intensive care medicine experimental. 2021;9(1):34 https://doi.org/10.1186/s40635-021-00400-z
Can we develop further bespoke treatments for men with mCRPC? Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous lethal disease characterised by variable sensitivity to androgenreceptor signalling pathway therapy. All patients ultimately develop treatment-resistant, lifethreatening disease. One mechanism of resistance to androgen deprivation is activation of the PI3K/
AKT pathway Furthermore, the PTEN tumour suppressor is functionally lost in approximately 40–50% of patients with mCRPC. PTEN loss activates AKT signalling, leading to tumour growth and cell proliferation, worse outcomes, and reduced benefit from androgen-receptor pathway blockade. Ipatasertib is a selective ATP-competitive small-molecule inhibitor of all three isoforms of AKT. It has been evaluated both as a single agent and in combination studies using dual AKT and androgen-receptor pathway blockade with ipatasertib and abiraterone and was shown to be feasible with manageable side-effects. This study assesses whether the combination is more effective than abiraterone alone. Patients with previously untreated asymptomatic or mildly symptomatic mCRPC were recruited. Previous chemotherapy for metastatic hormonesensitive prostate cancer was permitted, provided it was initiated no more than 6 months after the time of first castration treatment, and that the patient had not progressed during chemotherapy or within 3 months after completion of chemotherapy. All patients were required to have a valid prostate cancer tumour PTEN immunohistochemistry result, using archival or newly collected tumour samples. Next-generation sequencing to detect PTEN status or PIK3CA/AKT1/PTEN alteration was also done using the FoundationOne CDx next-generation sequencing assay. 1,611 patients were screened and 1,101 (68%) were enrolled and assigned 1:1 to placebo-abiraterone versus ipatasertib-abiraterone. 521 patients had PTEN loss by immunohistochemistry and were equally split between the groups. In the intention to treat analysis median progression free survival was 16.6 months in the placebo-abiraterone group and 19.2 months in the ipatasertib-abiraterone group (HR 0.84 [95% CI 0.71-0.99] p = 0.043; ns at a = 0.01). In the patients with PTEN loss, median progression-free survival was 16.5 months in the placebo-abiraterone group and 18.5 months in the ipatasertib-abiraterone group (HR 0.77 [95% CI 0.61-0.98] p = 0.034; significant at a = 0.04). Adverse events leading to discontinuation of treatment occurred in 5% of the placeboabiraterone group and 21% of the ipatasertibabiraterone group, suggesting there is a balance between clinical benefit and quality of life.
… it is the first randomised phase III trial in this setting to report a combination treatment suggesting there may be a benefit for other combinations. This study is significant in two ways. Firstly, it demonstrates that targeting the AKT pathway may have a role in mCRPC for men with PTEN loss, although further follow-up is required to demonstrate if this results in improved overall survival. It is also not clear what is the best test to determine what is clinically significant PTEN loss. In addition, it is the first randomised phase III trial in this setting to report a combination treatment suggesting there may be a benefit for other combinations.
Source: Ipatasertib plus abiraterone and prednisolone in metastatic castrationresistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial. Sweeney C, Bracarda S, Sternberg CN, et al. Lancet 2021; 398: 131-42.
EAU EU-ACME Office
European Urology Today
August/September 2021
