Background: Immune checkpoint inhibitor (ICI) use may be associated with diverse cardiovascular (CV) adverse events (AEs), but their baseline prevalence and incidence after ICI initiation are poorly known. We aimed to describe CV events using real-world hospital data from Belgian cancer patients. Materials and methods: Electronic health records (EHRs) from patients receiving at least one ICI between March 2017 and August 2022 at three Belgian hospitals were processed into an Observational Medical Outcomes Partnership Common Data Model warehouse. Structured data were enriched with unstructured data that were processed using a natural language processing (NLP) pipeline. We analyzed CV events from first ICI administration until last follow-up, identifying and validating the first detection of a CV event at the patient level. Results: We included 1571 patients (66% male, median age 67 years); CV events were detected in 196 (12.5%) patients [median (min-max) follow-up: 8 (0-63) months]. The CV AEs detected were heart failure (5.3%), atrial fibrillation (4.6%), myocardial infarction (2.0%), atrioventricular block (1.9%), myocarditis (1.2%), vasculitis (0.8%), pericarditis (0.4%), and Takotsubo cardiomyopathy (<0.3%). Median time (min-max) to onset ranged from 109 days (17-849 days) for myocarditis to 529 days (91-967 days) for Takotsubo cardiomyopathy. Conclusions: To our knowledge, this is the first study using a dataset enriched with NLP-processed EHRs that describes the frequency and onset time of CV events. CV event frequencies were higher than those reported in clinical trials, but similar to other real-world studies. However, we observed a later time to onset. Hence, clinicians should note that CV AEs can present in various ways and at any time during or after treatment.

Abstract Background Close monitoring of development of cardiovascular toxicity during anthracycline (AC) chemotherapy is crucial for early diagnosis and guidance of therapy. SerpinA3, a serine protease inhibitor, was recently described as prognostic marker for heart failure and elevated plasma levels are associated with increased mortality. The effect of AC on SERPINA3 levels in a cancer population has not been studied yet Purpose To investigate whether SERPINA3 plasma levels could serve as a marker for cancer therapy-related cardiac dysfunction and whether its levels are influenced by AC chemotherapy Methods Adult cancer patients requiring AC chemotherapy were enrolled between January 2020 and June 2022. Patients with a history of heart failure or prior cardiotoxicity were excluded. Measurement of cTnI and NT-proBNP and echocardiography (LVEF and GLS) were performed at four timepoints: before the start of AC (V1), directly after completion of chemotherapy (V2), 3 months thereafter (V3) and 1 year after V2 (V4). CTRCD was diagnosed according to the recent ESC guidelines. Results Fifty-one patients fulfilled inclusion criteria and agreed to participate in the study. Patients were on average 54 years old and the majority were female (80.4%). After anthracyclines, 38 patients developed asymptomatic CTRCD, graded as mild in 29 patients and moderate (LVEF 40-49%) in patients. SerpinA3 plasma levels at V3 were significantly higher in patients with moderate CTRCD (247.7; [196.4-428.9]) compared to patients with no CTRCD (142.7; [126.5-170.2]; p=0.004). In patients developing moderate CTRCD, a significant increase in SerpinA3 from baseline to V2 ( 209.0 [162.025-2.7]; 313.3 [212.6- 387.1, p=0.028) and remained elevated till V3 (247.7 [196.4-428.9], p=0.038). In patients with no CTRCD SerpinA3 showed an opposite trend with no significant difference at V2 compared to V1 (190.1 [165.2-230.5] vs 196.3 [170.8-297.1]; p= 0.972), but a subsequent significant decline from V2 to V3 (142.7 [126.5-170.2]; p=0.003). In patients with mild CTRCD a similar, but non-significant trend as in no CTRCD patients was seen(211.4 [167.8-302.6] vs 218.3 [171.9-277.7]; p=0.346 vs 167.5 [140.5-286.8]; p=0.122). These findings were confirmed by the absolute change in SerpinA3 from baseline to V4 which differed significantly in moderate CTRCD (+51.3; [7.1-176.4]) compared to both patients with no CTRCD (-47.5;[ -78.0- -35.4]; p=0.019) and patients with mild CTRCD (-52.0;[ -78.6- 32.8]; p=0.043). In patients with moderate CTRCD SerpinA3 values at V4 remained significantly elevated in patients without full cardiac recovery 1 year after the end of chemotherapy (4/5 patients; p=0.050). Conclusion SerpinA3 is increased after anthracycline chemotherapy in patients with moderate CTRCD. A lasting increase of serpinA3 was observed in in patients who did not show a complete recovery of cardiac function, potentially indicative of a worse cardiac prognosis.Figure 1Figure 2

To bridge the gap between clinical trial patients and real-world populations, we conducted a comprehensive study in Belgium to characterize cancer patients treated with immune checkpoint inhibitors (ICIs), which have demonstrated survival advantages in various cancer types. Retrospective multicenter study in three Belgian hospitals, processing anonymized electronic health records including 10 data sources, using natural language processing (NLP) and machine learning. NLP model validation compared algorithm outputs to a physician-generated standard. The algorithm mapped 597 variables to SNOMED-CT, generating OMOP CDM databases, validated per hospital (federated), ensuring patient privacy. Cancer patients (≥18 years old, regardless of stage) receiving ICIs between March 2017 and August 2022 were included. Our study included 1,659 patients (median age [IQR]: 67 [60-74]); age categories: 2.4% (18-40 years), 6.1% (41-50), 17.8% (51-60), 35.1% (61-70), and 38.6% (>71). Most patients were male (65.9%). Current/former smokers totaled 43.2%, 18.6% were never smokers, and 38.2% had unknown smoking status. Alcohol abuse was observed in 10.8% of patients and negative/unknown in 89.2%. The most common ICI treatment (monotherapy or with other ICIs or antineoplastic drugs) was pembrolizumab (43.6%), followed by nivolumab (29.7%), atezolizumab (10.7%), ipilimumab (8.7%), durvalumab (4.2%), avelumab (2.1%), cemiplimab (0.8%) and dostarlimab (0.1%). Lung cancer was the most frequent cancer type (54.94%), followed by renal cancer (9.23%), bladder cancer (7.27%), melanoma (6.08%), and head and neck cancer (5.97%). Median overall survival by ICI ranged from 8 to 38 months. These initial findings highlight the feasibility of automatically extracting and locally validating federated hospital databases- an invaluable tool for real-world data on ICI-treated patients. Comparable datasets would require linking government databases, which cannot be done in a federated manner nor enriched with hospital-level data. Ongoing analyses will explore immune-related adverse events, comorbidities, tumor stage, anatomical pathology, and outcomes in various cancer types and treatment lines.

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): 1.Flanders Research Foundation- FWO (doctoral research grant) 2.UZA Foundation-Wolvenbos Grant 2019 Background Anthracycline chemotherapy is a cornerstone in the treatment of several malignancies. However, it causes substantial toxicity, of which cardiotoxicity is the most frequent and most severe (1). Ideally, patients at risk for cardiotoxicity are identified prior to treatment, however, traditional patient- and treatment-related factors fail to fully predict the individual risk at the moment. Improved risk stratification for ANT-induced cardiotoxicity could possibly be reached by taking genetic risk factors into account. Purpose We assessed the prevalence of variants in genes encoding for cardiac proteins in the development of anthracycline-induced cardiotoxicity. Methods Patients presenting with early (< 1y) or late (> 1y) anthracycline-induced cardiotoxicity between 1995 and 2020 were included. Cardiotoxicity was defined as a decline in left ventricular ejection fraction (LVEF) to <50% and a ≥10% reduction from baseline by echocardiography. Genetic analysis was offered using a haloplex gene panel composed of 59 known cardiomyopathy-related genes. Variants were classified according to ACMG guidelines(2). Both variants of unknown significance (VUS, class 3) and likely pathogenic/pathogenic variants (class 4 and 5) were taken into account. Frequency of genetic variants was compared to a matched positive control cohort of patients with dilated cardiomyopathy (DCM). Results Forty-two patients that had developed cardiotoxicity (mean age at time of diagnosis 54yrs) fulfilled the inclusion criteria and agreed to genetic testing. The majority of patients had been treated for lymphoma (52.4%) or breast cancer (38.1%). Total equivalent dose of anthracyclines averaged 285.5 mg/m² doxorubicin. Patients showed an average reduction in LVEF of 27.1% (+- 10.1). In 18 patients (42.9 %), a variant could be identified; 15 patients carried a variant of unknown significance (VUS) and 3 carried a likely pathogenic variant. In total 29 variants different variants were identified in 18 distinct individuals. Genetic yield was independent of anthracycline-dose and the presence of other cardiovascular risk factors. The genetic yield in cardiotoxicity patients did not differ significantly from this in DCM-controls (18/42 VUS, 5/42 (likely) pathogenic variants, p = 0.19). After initiation of standard heart failure therapy, 6 (33.3%) of variant carriers showed incomplete recovery of cardiac function, compared to only 3 (12.5%) of patients who did not carry a variant (p=0.103). Conclusion Prevalence of genetic variants in anthracycline-induced cardiotoxicity is similar to that in isolated dilated cardiomyopathy. This finding supports a second-hit mechanism in which anthracycline chemotherapy, uncovers a genetically determined cardiomyopathy. As such, genetic variants in cardiomyopathy genes could improve individualized risk stratification prior to anthracycline chemotherapy and can assist in personalized prevention of this feared side effect of chemotherapy.

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Fund for Scientific Research (FWO) Flanders INSPIRE project (H2020-MSCA-ITN program) Background The chemotherapeutic doxorubicin (DOX) is frequently used to treat a wide variety of cancers, but the cardiotoxic side effects limits its clinical use in some patients. Additionally, DOX contributes to vascular toxicity, which may be an early manifestation of DOX-associated toxicity. Therefore, there is an interest to evaluate vascular function in patients receiving DOX-based treatment regimens. Purpose We aimed to assess arterial stiffness and endothelial dysfunction as potential markers of vascular toxicity in both DOX-treated cancer patients and a murine model. Methods Female breast cancer patients with a need for adjuvant or neoadjuvant DOX-based treatment were prospectively included. Chemotherapeutic regimen consisted of 12 weekly cycles of taxane treatment, followed by 4 cycles of DOX (and cyclophosphamide) treatment. Vascular function (endothelial function (FMD and RHI), arterial stiffness (Aix and cfPWV) and cardiac function (LVEF, hsTnI, NT-proBNP) were performed at baseline (T1), after completion of taxane treatment (T2) and after completion of DOX treatment (T3). In addition to the clinical study, male C57Bl6/J mice were intraperitoneally injected with 2 mg /kg (low dose) or 4 mg/kg DOX (high dose) once per week for 6 weeks. Arterial stiffness was assessed in vivo by measuring abdominal aorta pulse wave velocity (aaPWV) by high-frequency ultrasound imaging combined with ex vivo vascular function evaluation. Results Twenty patients (mean age 51.2 +/- 10.1 yrs) treated with DOX were included. After DOX treatment (T3 vs T2), left ventricular ejection fraction (LVEF) was decreased, while hsTnI and NT-proBNP levels were increased, indicating cardiotoxicity (Table 1). Likewise, LVEF was reduced in DOX-treated mice after 3 weeks, which persisted until the end of the treatment (6 weeks). In patients, RHI was impaired at T2 and T3 compared to T1, which indicates progressive endothelial dysfunction during treatment (Table 1). Consistent with these findings, DOX treatment in mice resulted in endothelial dysfunction, as evidenced by a lower basal nitric oxide (NO) index and reduced acetylcholine-induced endothelium-dependent vasorelaxation (Figure 1B & 1C). Finally, cfPWV was decreased at T2 and T3 compared to T1, even after correction for BP, suggesting rather an improvement of arterial stiffness (Table 1). Although DOX treatment in mice resulted in a similar trend towards lower aaPWV at the end of treatment (6 weeks), we observed an initial increase in aaPWV after 2 weeks (Figure 1A). Conclusion Collectively, these findings suggest that, apart from cardiotoxicity, DOX treatment results in early and consistent endothelial dysfunction, while evaluation of arterial stiffness may be time-sensitive. Hence, endothelial dysfunction may be a more reliable and sensitive marker than arterial stiffness to evaluate DOX-induced vascular toxicity in patients.

Cardiovascular adverse events induced by immune checkpoint inhibitors (ICIs) have gained significant interest over the past decade due to their impact on short- and long-term outcomes. They were initially thought to be rare, but the increasing use of ICIs in the treatment of both advanced and early stages of various malignancies has resulted in a substantial increase in their incidence. Different guidelines have proposed screening measures for ICI-induced myocarditis by incorporating troponin measurements at baseline and during the first few weeks of treatment. However, no specific guidelines have been developed yet regarding the interpretation of an asymptomatic rise in troponins. This state-of-the art review aims to provide an overview of the clinical relevance of elevated troponins during checkpoint inhibition and recommendations on how to manage elevated troponin levels during ICI therapy.

Spinal cord injury can have widespread consequences beyond the disruption of sensory and motor functions. Injury at or above the sixth thoracic spinal cord segment frequently leads to dysregulation of the autonomic nervous system, which results in a syndrome called autonomic hyperreflexia or dysreflexia. It is a hypertensive crisis triggered by visceral or somatic stimuli below the level of the injury and caused by sympathetic spinal reflexes not modulated by regulatory centers in the brain. Patients with spinal cord injuries frequently undergo surgery for multiple reasons. Because of the potentially lethal complications of autonomic hyperreflexia, physicians, and in particular anaesthesiologists, must be aware of the underlying pathophysiological mechanisms and adequate perioperative management.

Introduction : Various drugs and physiologic disturbances affect the action of neuromuscular blocking agents. If some are ignored by the anesthesiologist, e.g. in the absence of monitoring of neuromuscular function, the patient may be at risk of potentially severe consequences related to postoperative residual curarization. Case presentation : A 67-year-old female patient underwent septoplasty under general anesthesia with basic monitoring (three-lead electrocardiogram, non-invasive blood pressure, end-tidal partial pressure of carbon dioxide and SpO2) and a monitoring of neuromuscular function using acceleromyography of the adductor pollicis. General anesthesia was induced with propofol and sufentanil. After neuromuscular monitoring calibration, a single dose of rocuronium was given. Thereafter the trachea was intubated and anesthesia was maintained with sevoflurane. One hundred and two minutes after the administration of rocuronium, a 1% lidocaine solution containing 5µg/mL epinephrine was injected under the mucosa of the nasal septum immediately before the incision. Two minutes after this injection, the train of four ratio was significantly reduced. It took about 13 minutes to recover to the value recorded before the submucosal injection. Conclusion : Epinephrine increases the degree of muscle relaxation achieved by rocuronium, even when neuro-muscular function is recovering. Monitoring is the only mean to rule out a risk of postoperative residual curarization, given the numerous medications and factors interfering with the action of neuromuscular blocking agents.

Background: Most trials testing phosphodiesterase 5 inhibitors (PDE5I) in heart failure with preserved ejection fraction (HFpEF) yielded a neutral outcome possibly because of low myocardial cyclic guanosine monophosphate (cGMP) content, which reduces effectiveness of PDE5I. Angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB) and statins (STAT) increase myocardial cGMP content through upregulated endothelial nitric oxide synthase. The acute and chronic effects on cardiac remodeling and dysfunction of PDE5I after optimized ACEI-ARB-STAT therapy were therefore evaluated.

Perioperative visual loss is a rare but devastating complication that may follow spine surgery in the prone position. So far, the incidence, mechanisms and risk factors have not been clearly established. Most commonly, the visual loss results from an ischemic optic neuropathy. We describe the case of a 68 year-old woman who underwent a lumbar laminectomy in the prone position. Upon recovery from anesthesia, the patient complained of total left blindness. This visual loss was, slowly and only partially, recovered after 72 hours. We discuss the most common causes of postoperative visual loss, the risk factors and preventive strategy.

Despite major improvements in outcome for patients with heart failure and a reduced ejection fraction (HFREF), the prognosis in heart failure with preserved ejection fraction (HFPEF) has remained unaltered during the past few decades. Moreover, the incidence of HFPEF has increased and currently HFPEF accounts for 50% of all heart failure cases. It therefore constitutes a considerable burden on health-care services. The pathophysiological mechanisms leading to HFPEF are still not clear. The HFPEF phenotype is thought to be the result of the interplay of diastolic left ventricular dysfunction, systolic left ventricular dysfunction, vascular stiffening and vasomotor or chronotropic insufficiency. The diagnosis of HFPEF has improved as a consequence of the 2007 ESC guidelines, but it is still a matter of debate. Echocardiography is a corner stone in the diagnosis, but unfortunately it has some shortcomings. With a better knowledge of the pathophysiological mechanisms, the diagnostic criteria can be refined and a more important role for biomarkers is likely. Therapeutic options in HFPEF have been disappointing with neutral outcomes of the large clinical trials with ACE-inhibitors, angiotensin receptor blockers and beta blockers. Better insight into the pathophysiology and improved diagnostic criteria will probably pave the way for future studies with drugs that tackle the mechanisms underlying HFPEF. The purpose of this review is to discuss the literature on pathophysiology, diagnosis and therapeutic interventions in HFPEF.

Glanzmann thrombasthenia (GT) is a rare autosomal recessive disorder characterized by a deficiency or functional defect of platelet glycoprotein (GP) IIb/IIIa. Physiologically, this platelet receptor mediates aggregation of activated platelets by binding the adhesive proteins, fibrinogen, von Willebrand factor (VWF) and fibronectin. This facilitates attachment and aggregation of platelets at sites of vascular injury. We reported the management of a pterional meningioma resection in a patient with Glanzmann thrombasthenia, with recombinant factor VIIa (rFVIIa - NovoSeven) as haemostatic agent. A 48-year-old woman suffering from Glanzmann thrombasthenia was scheduled for spheno-orbital meningioma en plaque surgery. Because of repeated platelet transfusions, this patient developed isoantibodies against missing GPIIbIIIa and alloantibodies against Human Leukocyte Antigen (HLA) leading to refractoriness to platelet transfusions. We observed that Novoseven offered sufficient haemostasis conditions. Therefore, we noticed a deep vein thrombosis. This imposed us to use low weight molecular heparin despite recent surgery.

A new Bifidobacterium species is described based on the study of ten Gram-positive strains with fructose-6-phosphate phosphoketolase activity. They are part of a phenotypic group comprising 141 strains isolated from raw milk and raw milk cheeses in French raw milk cheese factories. This group was separated by a numerical analysis based on API 50CH, API 32A tests and growth at 46 degrees C. A strong similarity of 16S rRNA sequences (99.8%) was shown between strain FR62/b/3(T) and Bifidobacterium psychraerophilum LMG 21775(T). However, low DNA-DNA relatedness was observed between their DNAs (31%). The new isolates are able to grow at low temperatures (all ten strains up to 5 degrees C) and strain FR62/b/3(T) grows under aerobic conditions, as does B. psychraerophilum. However, contrary to B. psychraerophilum, they do not ferment L-arabinose, D-xylose, arbutin or melezitose, but they do acidify lactose. The DNA G+C content of FR62/b/3(T) is 56.4mol%. Therefore, the name Bifidobacterium crudilactis sp. nov. is proposed, with its type strain being FR62/b/3(T) (=LMG 23609(T)=CNCM I-3342(T)).

Department of Anesthesiology and Intensive Care Medicine, University Hospital, University of Liège, Liège, Belgium

Rousseau, A. F.1; Lecoq, J. P.1; Carlier, A.2; Deleuze, J. P.2; Dubuisson, A.2; Lamy, M.1; Franssen, C.1 Author Information