European Journal of Clinical Investigation最新文献

Background: Approximately 10%-20% of prostate cancers progress to metastatic and castration-resistant forms (mCRPC). Radioligand (RLT) therapy with [¹⁷⁷Lu]Lu-prostate-specific membrane antigen (PSMA) is an approved treatment for metastasized mCRPC. Moreover, Actinium-225 (²²⁵Ac), an alpha-emitter isotope, has also been used to label PSMA and, recently, to treat mCRPC patients with encouraging results. However, robust clinical data on [²²⁵Ac]Ac-PSMA therapy and its comparison with [¹⁷⁷Lu]Lu-PSMA are still limited. Our aim was to evaluate the role of [²²⁵Ac]Ac-PSMA in treating mCRPC and compare it with conventional [¹⁷⁷Lu]Lu-PSMA therapy.

Methods: A systematic search was performed in PubMed, Web of Science, Scopus and the Cochrane Register of Controlled Trials from June 2023 to January 2024. This work was conducted in accordance with PRISMA guidelines.

Results: After screening and study selection according to PRISMA guidelines, 11 studies were included, 9 of which focused on [²²⁵Ac]Ac-PSMA only and two on tandem therapy ([²²⁵Ac]Ac-PSMA/[¹⁷⁷Lu]Lu-PSMA). Overall, the pooled proportion of PSA decline in patients was .85 (95% CI: .79-.91, p < .001); patients pretreated with [¹⁷⁷Lu]Lu-PSMA achieved a pooled proportion of PSA decline of .90 (95% CI: .82-.97, p < .001). In patients treated with tandem therapy, PSA decline was observed in approximately 90% of them, while PSA response rates above 50% ranged from 53.3% to 65%. Xerostomia was the most frequently reported side effect, along with anaemia, thrombocytopenia and nephrotoxicity.

Conclusions: Overall, the main results of our study showed that [²²⁵Ac]Ac-PSMA-617 had a significant therapeutic effect on mCRPC with an acceptable toxicity level. The latter, however, appears greater than with [¹⁷⁷Lu]Lu-PSMA-617. In future studies, an adequate analysis of the incidence of side effects associated with [²²⁵Ac]Ac-PSMA should be performed to evaluate the role of cumulative toxicity of earlier treatments and the higher frailty of heavily pretreated patients.

Background: The prediction of ischaemic stroke in patients with heart failure with reduced ejection fraction (HFrEF) but without atrial fibrillation (AF) remains challenging. Our aim was to evaluate the performance of machine learning (ML) in identifying the development of ischaemic stroke in this population.

Methods: We performed a post-hoc analysis of the WARCEF trial, only including patients without a history of AF. We evaluated the performance of 9 ML models for identifying incident stroke using metrics including area under the curve (AUC) and decision curve analysis. The importance of each feature used in the model was ranked by SAPley Additive exPlanations (SHAP) values.

Results: We included 2213 patients with HFrEF but without AF (mean age 58 ± 11 years; 80% male). Of these, 74 (3.3%) had an ischaemic stroke in sinus rhythm during a mean follow-up of 3.3 ± 1.8 years. Out of the 29 patient-demographics variables, 12 were selected for the ML training. Almost all ML models demonstrated high AUC values, outperforming the CHA₂DS₂-VASc score (AUC: 0.643, 95% confidence interval [CI]: 0.512-0.767). The Support Vector Machine (SVM) and XGBoost models achieved the highest AUCs, with 0.874 (95% CI: 0.769-0.959) and 0.873 (95% CI: 0.783-0.953), respectively. The SVM and LightGBM consistently provided significant net clinical benefits. Key features consistently identified across these models were creatinine clearance (CrCl), blood urea nitrogen (BUN) and warfarin use.

Conclusions: Machine-learning models can be useful in identifying incident ischaemic strokes in patients with HFrEF but without AF. CrCl, BUN and warfarin use were the key features.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a membrane protein that plays an important role in a variety of immune and non-immune functions. Such functions are regulated by its activity as a homophilic ligand but also through its ability to interact as a heterophilic ligand with various host proteins. These include CEACAM5, T cell immunoglobulin-mucin like protein-3 (TIM-3) and, potentially, protein death protein 1 (PD-1). Furthermore, CEACAM1 is targeted by various pathogens to allow them to invade a host and bypass an effective immune response. Clinically, CEACAM1 plays an important role in infectious diseases, autoimmunity and cancer. In this review, we describe the structural basis for CEACAM1 interactions as a homophilic and heterophilic ligand. We discuss the regulation of its monomeric, dimeric and oligomeric states in cis and trans binding as well as the consequences for eliciting downstream signalling activities. Furthermore, we explore the potential role of avidity in determining CEACAM1's activities.

Background: Chronic neuropathic pain (CNP) is a debilitating condition, often refractory to currently available drugs. Understanding biochemical alterations in peripheral tissues such as blood will be useful for understanding underlying pathophysiological processes relating to CNP.

Methods: We collected blood from two independent cohorts of CNP and pain-free controls (CNP n = 129/Controls n = 127) in the UK and Ireland to investigate the relationship between CNP-associated molecular/biochemical alterations and a range of clinical and pain metric parameters. Multiple statistical comparisons were conducted on the data, with selected variables included in one or more of the intended inferential analyses (six models).

Results: Gene expression analysis showed that choline phosphotransferase (CHPT1) was increased (p < .001) in the CNP group compared to controls. The levels of phosphatidylcholine, a metabolite of CHPT1 in the Kennedy Pathway, were significantly (p = .008) decreased in the plasma of patients with CNP. Given the relationship between the Kennedy pathway and endocannabinoids, plasma endocannabinoids and related N-acylethanolamines were quantified in clinical samples by HPLC-Tandem Mass Spectrometry. Plasma levels of the endocannabinoid 2-arachidonoylglycerol were higher in CNP samples compared to controls, and in the statistical models applied, 2-arachidonoylglycerol significantly increased the odds of CNP (p < .001). The expression of genes related to the synthesis and catabolism of endocannabinoids also corroborated the increased plasma 2-arachidonoylglycerol levels in patients with CNP.

Conclusions: Endocannabinoid levels, expression of genes related to endocannabinoid metabolism, age, sex, depression and anxiety state together were strong predictors of CNP. The observed molecular changes indicate that lipid metabolism is altered in CNP and thus may represent a viable target for novel analgesics or biomarker development.

Aim: Vascular endothelial growth factor (VEGF) is linked to inflammation and angiogenesis, indicating a possible role in inflammatory bowel disease (IBD) and its main clinical manifestations, Crohn's disease (CD) and ulcerative colitis (UC). This systematic review and meta-analysis investigated studies assessing circulating VEGF concentrations in IBD patients and healthy controls, considering the effect of IBD type, sample type and geographical location.

Methods: A systematic search identified 18 studies (28 group comparators) investigating 1741 IBD patients and 1291 controls. Data were extracted and analysed using standardized mean differences (SMD) with 95% confidence intervals (CI).

Results: VEGF concentrations were significantly higher in IBD patients (SMD = .71, 95% CI .38 to 1.04; p < .001). UC patients showed higher VEGF concentrations than CD patients. Serum samples indicated significant VEGF elevations, unlike plasma samples. Significant VEGF increases were observed in studies conducted in Western Europe and Asia, but not in Eastern Europe. No significant differences were found between active and inactive disease.

Conclusions: VEGF concentrations are elevated in IBD patients, with variations by disease type, sample type and geography. However, VEGF is not a reliable marker of disease activity. Future research should standardize methods and explore regional influences to enhance VEGF's clinical utility as a biomarker of IBD.

Background: The global pandemic of coronavirus disease 2019 (COVID-19) represented a major public health concern. Growing evidence shows that plasma of COVID-19 patients contains large numbers of circulating extracellular vesicles (cEVs) that correlate with disease severity and recovery. In this study, we sought to characterize the longitudinal cEV signature in critically ill COVID-19 patients during hospitalization and its relation to mortality risk.

Methods: cEVs were quantitatively and phenotypically analysed in hospitalized non-surviving COVID-19 patients at baseline (n = 42) and before exitus (n = 40) and in 40 healthy volunteers as a reference group by high sensitivity nano flow cytometry using specific markers for parental cell sources and activation.

Results: Levels of cEV subtypes differed between patients with severe COVID-19 and healthy subjects, specifically those from platelets and endothelial, inflammatory and viral infected cells, which associate to high mortality risk. In the longitudinal analysis from baseline to the time point immediately preceding death, no changes were found for platelet, pan-leukocyte, and lung epithelial cell-shed cEVs, while endothelial cell releases of EVs (eEVs) significantly differed. Vascular endothelial growth factor receptor 2-positive eEVs were significantly increased before death compared to admission whereas endoglin and E-selectin-containing eEVs did not change. Conversely, lymphocyte (ℓEV), monocyte, macrophage, pericyte and progenitor cell-derived cEVs displayed significant reductions before exitus. Noteworthy, levels of CD45⁺/CD3⁺-ℓEVs were significantly associated to the patient's survival time.

Conclusions: An evolving cEV profile able to discriminate prompt risk of death during hospitalization has been defined suggesting a role for circulating and vascular cell-derived EVs in COVID-19 pathogenesis.

Background: The role of sex in choosing between coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) for unprotected left main coronary artery (ULMCA) disease has gained interest.

Methods: Randomized controlled trials and adjusted observational studies comparing PCI versus CABG in ULMCA patients with outcomes by sex were included. The primary endpoint was major adverse cardiovascular events (MACE), with secondary endpoints being all-cause mortality and repeated revascularization.

Results: Ten studies (3 randomized, 7 observational) involving 22,141 ULMCA disease patients (13,411 PCI, 8730 CABG) with a median 5-year follow-up were included. Among males, PCI was associated with a higher risk of MACE (HR 1.18, 95% CI 1.01-1.38), while no significant difference was seen in females. However, moderator analysis showed no significant interaction between sex and revascularization strategy for MACE (p for interaction .422). No differences in all-cause mortality were observed between PCI and CABG for either sex. Repeated revascularization risk was significantly higher with PCI for both sexes (HR 3.51, 95% CI 2.21-5.59 in males and HR 4.20, 95% CI 2.57-6.87 in females).

Conclusions: In males with ULMCA disease, CABG was associated with a lower risk of MACE compared to PCI, while no significant differences were seen in females. The lack of a significant interaction between sex and revascularization strategy suggests that these findings may not reflect true sex-based effect modification. PCI was linked to a higher risk of repeated revascularization in both sexes compared to CABG.

Trial registration: The protocol was registered in the PROSPERO International Prospective Register of Systematic Reviews (ID: CRD42024537726).

Background: Anticoagulation therapy in patients with atrial fibrillation (AF) and concomitant cancer can be challenging due to the significantly increased risk of both embolism and bleeding. Moreover, the benefits and risks of vitamin K antagonists (VKA, eg. warfarin) versus non-vitamin K antagonist oral anticoagulants (NOACs) in such patients are less well understood.

Methods: From the prospective, global, multi-centered Global Registry on Long-Term Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), we characterized these patients according to their history of prior cancer when enrolled. All patients received anticoagulant therapy. The primary outcome was the composite of all-cause mortality, stroke, transient ischemic attack, systemic embolism. The secondary endpoints were all-cause mortality, cardiovascular death, stroke, major bleeding and thromboembolism during the 3 years follow-up period. Cox regression analyses were used to calculate the hazard ratio (HR) and confidence interval (CI) following propensity score matching (PSM).

Results: Overall, among 16,700 patients enrolled in Phase III in GLORIA-AF, 1725 (10%) patients had concomitant cancer(s) at enrolment. After PSM, the primary outcome occurred in 250 (14.8%) of patients with cancer(s) and 160 (9.3%) without cancer(s) (HR, 1.62 [95% CI, 1.33-1.97], p < .001) during the 3 years follow-up period. The risk of all-cause mortality was significantly higher in patients with cancer(s) versus non- cancer(s) (HR, 1.71 [95% CI, 1.37-2.12], p < .001). In patients with cancer(s), after PSM, the use of NOACs was associated with reduced risk of the primary outcome compared with that of VKA (HR, .69 [95% CI, .49-.99], p = .043), as well as a lower risk of thromboembolism (HR, .49 [95% CI, .24-1.00], p = .051), but the risk of major bleeding was not significantly different (HR, .87 [95% CI, .48-1.56], p = .635). Subgroup analysis in patients with cancers showed a reduced risk of major bleeding with NOACs compared with VKA (HR, .18 [95% CI, .04-.8], p = .024) in patients with coronary artery disease (CAD). For the main cancer subtypes (genitourinary, breast, gastrointestinal, haematological and skin), the trends for the risk of primary outcome were consistently favouring NOACs compared with VKA without any significant interaction among these five cancers.

Conclusions: Cancer is a common comorbidity in patients with AF and is associated with increased risk of composite of all-cause mortality and thromboembolism. Compared with VKA, NOACs was associated with a lower risk of composite events and showed an advantage in lower risk of thromboembolism, as well as a reduced risk of major bleeding when CAD was also present.

Background: Preload insufficiency is an underrecognized cause of exercise intolerance identified during invasive cardiopulmonary exercise testing, and defined hemodynamically by decreased biatrial filling pressures, cardiac output, and oxygen consumption (V̇O₂) at peak effort. Patients with preload insufficiency, however, typically present with symptoms of dyspnea on exertion, and/or exercise intolerance at submaximal efforts, particularly when performing activities of daily living. The cardiopulmonary hemodynamics and physiology at submaximal work levels of preload insufficiency have not been previously investigated. We hypothesized that preload insufficiency hemodynamics exist along a continuum, with submaximal exercise values reflecting peak exercise cardiopulmonary hemodynamics.

Methods: We compared submaximal cardiopulmonary hemodynamics, measured at anaerobic threshold, between preload insufficiency patients and age-matched controls referred for dyspnea but with normal exercise responses.

Results: Our study included 66 patients: 41 with preload insufficiency and 25 controls. Preload insufficiency patients exhibit significantly reduced V̇O₂, watts, and METS at submaximal levels compared to controls, alongside earlier anaerobic threshold achievement and similar heart rates at anaerobic threshold.

Conclusions: These findings underscore the profound impact of preload insufficiency on submaximal exercise capacity, emphasizing the importance of its recognition and management. This insight sets the stage for further investigations into interventions targeting preload insufficiency at submaximal exercise levels to enhance both exercise performance and quality of life.