Background:the study aims to evaluate whether high plasma trough levels of the kinase inhibitors (K.I.s) crizotinib, alectinib, osimertinib, dabrafenib, and trametinib were associated with a higher... Show moreBackground:the study aims to evaluate whether high plasma trough levels of the kinase inhibitors (K.I.s) crizotinib, alectinib, osimertinib, dabrafenib, and trametinib were associated with a higher risk of toxicity in non-small-cell lung cancer patients.Methods:In this retrospective cohort study, patients with non-small-cell lung cancer treated with the selected K.I.s were included if at least one plasma trough level at steady state (Cmin,ss) was available. Data were extracted from electronic medical records and laboratory databases. The high group for each K.I. was defined as 10% of patients with the highest first Cmin,ss. The remaining patients were placed in the non-high group. The frequency of dose-limiting toxicities (DLTs), defined as adverse events leading to dose reduction, dose interruption, or permanent discontinuation, was compared between the 2 groups.Results:A total of 542 patients were included in the different K.I. groups. A high Cmin,ss of crizotinib (n = 96), alectinib (n = 105), osimertinib (n = 227), dabrafenib (n = 52), and trametinib (n = 62) correlated with a Cmin,ss >= 490, >= 870, >= 405, >= 150, and >= 25 ng/mL, respectively. DLTs were more common in the alectinib high group than in the alectinib non-high group (64% vs. 29%, P = 0.036). Liver toxicity was observed in 4 (36%) patients in the high group and 5 (5%) patients in the non-high group (P = 0.007). For other K.I.s, no significant differences were observed in the frequency of DLTs between the high and non-high groups.Conclusions:For alectinib, high Cmin,ss was correlated with a higher risk of DLT. No differences in the frequency of DLTs were observed between the high and non-high groups for crizotinib, osimertinib, dabrafenib, and trametinib. Show less
Background: During the last decade Ebola virus has caused several outbreaks in Africa. The recombinant vesicular stomatitis virus-vectored Zaire Ebola (rVSVDGZEBOV-GP) vaccine has proved safe and... Show moreBackground: During the last decade Ebola virus has caused several outbreaks in Africa. The recombinant vesicular stomatitis virus-vectored Zaire Ebola (rVSVDGZEBOV-GP) vaccine has proved safe and immunogenic but is reactogenic. We previously identified the first innate plasma signature response after vaccination in Geneva as composed of five monocyte-related biomarkers peaking at day 1 post-immunization that correlates with adverse events, biological outcomes (haematological changes and viremia) and antibody titers. In this follow-up study, we sought to identify additional biomarkers in the same Geneva cohort and validate those identified markers in a US cohort. Methods: Additional biomarkers were identified using multiplexed protein biomarker platform O-link and confirmed by Luminex. Principal component analysis (PCA) evaluated if these markers could explain a higher variability of the vaccine response (and thereby refined the initial signature). Multivariable and linear regression models evaluated the correlations of the main components with adverse events, biological outcomes, and antibody titers. External validation of the refined signature was conducted in a second cohort of US vaccinees (n=142). Results: Eleven additional biomarkers peaked at day 1 post-immunization: MCP2, MCP3, MCP4, CXCL10, OSM, CX3CL1, MCSF, CXCL11, TRAIL, RANKL and IL15. PCA analysis retained three principal components (PC) that accounted for 79% of the vaccine response variability. PC1 and PC2 were very robust and had different biomarkers that contributed to their variability. PC1 better discriminated different doses, better defined the risk of fever and myalgia, while PC2 better defined the risk of headache. We also found new biomarkers that correlated with reactogenicity, including transient arthritis (MCP-2, CXCL10, CXCL11, CX3CL1, MCSF, IL-15, OSM). Several innate biomarkers are associated with antibody levels one and six months after vaccination. Refined PC1 correlated strongly in both data sets (Geneva: r = 0.97, P < 0.001; US: r = 0.99, P< 0.001). Conclusion: Eleven additional biomarkers refined the previously found 5- biomarker Geneva signature. The refined signature better discriminated between different doses, was strongly associated with the risk of adverse events and with antibody responses and was validated in a separate cohort. Show less
Introduction: The rVSVDG-ZEBOV-GP (Ervebo®) vaccine is both immunogenic and protective against Ebola. However, the vaccine can cause a broad range of transient adverse reactions, from headache to... Show moreIntroduction: The rVSVDG-ZEBOV-GP (Ervebo®) vaccine is both immunogenic and protective against Ebola. However, the vaccine can cause a broad range of transient adverse reactions, from headache to arthritis. Identifying baseline reactogenicity signatures can advance personalized vaccinology and increase our understanding of the molecular factors associated with such adverse events.Methods: In this study, we developed a machine learning approach to integrate prevaccination gene expression data with adverse events that occurred within 14 days post-vaccination.Results and Discussion: We analyzed the expression of 144 genes across 343 blood samples collected from participants of 4 phase I clinical trial cohorts: Switzerland, USA, Gabon, and Kenya. Our machine learning approach revealed 22 key genes associated with adverse events such as local reactions, fatigue, headache, myalgia, fever, chills, arthralgia, nausea, and arthritis, providing insights into potential biological mechanisms linked to vaccine reactogenicity. Show less
Metzemaekers, J.; Bouwman, L.; Vos, M. de; Nieuwenhuizen, K. van; Twijnstra, A.R.H.; Smeets, M.; ... ; Blikkendaal, M. 2023
STUDY QUESTION What is the additional value of the comprehensive complication index (CCI) and ClassIntra system (classification for intraoperative adverse events (ioAEs)) in adverse event (AE)... Show moreSTUDY QUESTION What is the additional value of the comprehensive complication index (CCI) and ClassIntra system (classification for intraoperative adverse events (ioAEs)) in adverse event (AE) reporting in (deep) endometriosis (DE) surgery compared to only using the Clavien-Dindo (CD) system? SUMMARY ANSWER The CCI and ClassIntra are useful additional tools alongside the CD system for a complete and uniform overview of the total AE burden in patients with extensive surgery (such as DE), and with this uniform data registration, it is possible to provide greater insight into the quality of care. WHAT IS KNOWN ALREADY Uniform comparison of AEs reported in the literature is hampered by scattered registration. In endometriosis surgery, the usage of the CD complication system and the CCI is internationally recommended; however, the CCI is not routinely adapted in endometriosis care and research. Furthermore, a recommendation for ioAEs registration in endometriosis surgery is lacking, although this is vital information in surgical quality assessments. STUDY DESIGN, SIZE, DURATION A prospective mono-center study was conducted with 870 surgical DE cases from a non-university DE expertise center between February 2019 and December 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS Endometriosis cases were collected with the EQUSUM system, a publicly available web-based application for registration of surgical procedures for endometriosis. Postoperative adverse events (poAEs) were classified with the CD complication system and CCI. Differences in reporting and classifying AEs between the CCI and the CD were assessed. ioAEs were assessed with the ClassIntra. The primary outcome measure was to assess the additional value toward the CD classification with the introduction of the CCI and ClassIntra. In addition, we report a benchmark for the CCI in DE surgery. MAIN RESULTS AND THE ROLE OF CHANCE A total of 870 DE procedures were registered, of which 145 procedures with one or more poAEs, resulting in a poAE rate of 16.7% (145/870), of which in 36 cases (4.1%), the poAE was classified as severe (>= Grade 3b). The median CCI (interquartile range) of patients with poAEs was 20.9 (20.9-31.7) and 33.7 (33.7-39.7) in the group of patients with severe poAEs. In 20 patients (13.8%), the CCI was higher than the CD because of multiple poAEs. There were 11 ioAEs reported (11/870, 1.3%) in all procedures, mostly minor and directly repaired serosa injuries. LIMITATIONS, REASONS FOR CAUTION This study was conducted at a single center; thus, trends in AE rates and type of AEs could differ from other centers. Furthermore, no conclusion could be drawn on ioAEs in relation to the postoperative course because the power of this database is not robust enough for that purpose. WIDER IMPLICATIONS OF THE FINDINGS From our data, we would advise to use the Clavien-Dindo classification system together with the CCI and ClassIntra for a complete overview of AE registration. The CCI appeared to provide a more complete overview of the total burden of poAEs compared to only reporting the most severe poAEs (as with CD). If the use of the CD, CCI, and ClassIntra is widely adapted, uniform data comparison will be possible at (inter)national level, providing better insight into the quality of care. Our data could be used as a first benchmark for other DE centers to optimize information provision in the shared decision-making process. STUDY FUNDING/COMPETING INTEREST(S) No funding was received for this study.The authors have no conflicts of interest to declare. Show less
A systematic review of health risks in human challenge trials published between 1980 and 2021 found no reported deaths or cases of permanent damage. Of challenged participants, 0.2% experienced... Show moreA systematic review of health risks in human challenge trials published between 1980 and 2021 found no reported deaths or cases of permanent damage. Of challenged participants, 0.2% experienced serious adverse events and no deaths were observed. Background: Few studies have assessed participant safety in human challenge trials (HCTs). Key questions regarding HCTs include how risky such trials have been, how often adverse events (AEs) and serious adverse events (SAEs) occur, and whether risk mitigation measures have been effective. Methods: A systematic search of PubMed and PubMed Central for articles reporting on results of HCTs published between 1980 and 2021 was performed and completed by 7 October 2021. Results: Of 2838 articles screened, 276 were reviewed in full. A total of 15 046 challenged participants were described in 308 studies that met inclusion criteria; 286 (92.9%) of these studies reported mitigation measures used to minimize risk to the challenge population. Among 187 studies that reported on SAEs, 0.2% of participants experienced at least 1 challenge-related SAE. Among 94 studies that graded AEs by severity, challenge-related AEs graded "severe" were reported by between 5.6% and 15.8% of participants. AE data were provided as a range to account for unclear reporting. Eighty percent of studies published after 2010 were registered in a trials database. Conclusions: HCTs are increasingly common and used for an expanding list of diseases. Although AEs occur, severe AEs and SAEs are rare. Reporting has improved over time, though not all papers provide a comprehensive report of relevant health impacts. We found very few severe symptoms or SAEs in studies that reported them, but many HCTs did not report relevant safety data. This study was preregistered on PROSPERO as CRD42021247218. Show less
Objectives: Six months after withdrawal of the HeartWare HVAD System (HVAD; Medtronic) from sale, approximately 4000 patients continue ongoing support with this device. In light of the diminishing... Show moreObjectives: Six months after withdrawal of the HeartWare HVAD System (HVAD; Medtronic) from sale, approximately 4000 patients continue ongoing support with this device. In light of the diminishing experience, this global consensus document summarizes key management recommendations. Methods: International experts with experience in the management of patients with ongoing HVAD support were invited to summarize key aspects of patient and pump management and highlight differences in the current HeartMate 3 (Abbott Laboratories) ventricular assist device. Clinicians from high-implanting HVAD sites reviewed current literature and reported experience to generate a consensus statement. Results: Specific guidelines to assist in the management of ongoing HVAD patients are developed. Key management protocols and helpful techniques developed from experienced clinicians are combined into a short guideline document. As experience with HeartMate 3 increases, key differences in approach to management are highlighted, where appropriate. Conclusions: With decreasing worldwide experience in the ongoing management of HVAD-supported patients, this consensus guideline provides a summary of best practice techniques from international centers. Differences in HeartMate 3 management are highlighted. Show less
Breeksema, J.J.; Kuin, B.W.; Kamphuis, J.; Brink, W. van den; Vermetten, E.; Schoevers, R.A. 2022
Introduction: Small-scale clinical studies with psychedelic drugs have shown promising results for the treatment of several mental disorders. Before psychedelics become registered medicines, it is... Show moreIntroduction: Small-scale clinical studies with psychedelic drugs have shown promising results for the treatment of several mental disorders. Before psychedelics become registered medicines, it is important to know the full range of adverse events (AEs) for making balanced treatment decisions. Objective: To systematically review the presence of AEs during and after administration of serotonergic psychedelics and 3,4-methyenedioxymethamphetamine (MDMA) in clinical studies. Methods: We systematically searched PubMed, PsycINFO, Embase, and ClinicalTrials.gov for clinical trials with psychedelics since 2000 describing the results of quantitative and qualitative studies. Results: We included 44 articles (34 quantitative + 10 qualitative), describing treatments with MDMA and serotonergic psychedelics (psilocybin, lysergic acid diethylamide, and ayahuasca) in 598 unique patients. In many studies, AEs were not systematically assessed. Despite this limitation, treatments seemed to be overall well tolerated. Nausea, headaches, and anxiety were commonly reported acute AEs across diagnoses and compounds. Late AEs included headaches (psilocybin, MDMA), fatigue, low mood, and anxiety (MDMA). One serious AE occurred during MDMA administration (increase in premature ventricular contractions requiring brief hospitalization); no other AEs required medical intervention. Qualitative studies suggested that psychologically challenging experiences may also be therapeutically beneficial. Except for ayahuasca, a large proportion of patients had prior experience with psychedelic drugs before entering studies. Conclusions: AEs are poorly defined in the context of psychedelic treatments and are probably underreported in the literature due to study design (lack of systematic assessment of AEs) and sample selection. Acute challenging experiences may be therapeutically meaningful, but a better understanding of AEs in the context of psychedelic treatments requires systematic and detailed reporting. Show less
Background: Residual risk of ischemic stroke despite anticoagulation in patients with atrial fibrillation (AF) represents a significant clinical issue that remains unaddressed. We aimed to evaluate... Show moreBackground: Residual risk of ischemic stroke despite anticoagulation in patients with atrial fibrillation (AF) represents a significant clinical issue that remains unaddressed. We aimed to evaluate the incidence and risk factors for residual adverse events in AF. Methods and Results: Using data from phase II/III of the prospective GLORIA-AF (Global Registry on Long-Term Oral Anti-thrombotic Treatment in Patients With Atrial Fibrillation) registry, we studied anticoagulated patients with newly diagnosed AF and an increased risk of stroke (CHA(2)DS(2)-VASc >= 1). The primary outcome of interest was ischemic stroke. Secondary outcomes were all-cause death, cardiovascular death and myocardial infarction. A total of 22 410 patients were included; median age 65 (interquartile range 71-78) and 10 044 (44.8%) were female. During a median follow-up period of 3.0 (interquartile range 2.2-3.1) years, the incidence of ischemic stroke was 0.60 (95% CI, 0.54-0.67) per 100-PYs, all-cause death 3.22 (95% CI, 3.08-3.37) per 100-PYs, cardiovascular death 1.08 (95% CI, 1.00-1.16) per 100-PYs and myocardial infarction 0.59 (95% CI, 0.53-0.66) per 100-PYs. Using multivariable Cox proportional hazards analysis, independent predictors of residual ischemic stroke were age (HR 1.05 [95% CI, 1.03-1.07]), diabetes (HR 1.42 [95% CI, 1.08-1.87]), prior thromboembolism (HR 2.27 [95% CI, 1.73-2.98]) and use of antiarrhythmic drugs (HR 0.66 [95% CI, 0.47-0.92]). The incidence of ischemic stroke was comparable among patients treated with nonvitamin K antagonist oral anticoagulants versus vitamin K antagonist; however, there were differences in the independent predictors between both groups. Conclusions: Patients with AF remain at significant residual risk of developing complications including ischemic stroke despite anticoagulation therapy. Further efforts among these patients should be directed at the management of modifiable risk factors that contribute to this risk. Show less
Verhagen, M.J.; Vos, M.S. de; Smaggus, A.; Hamming, J.F. 2022
Objective Efforts to study morbidity and mortality conferences (M&MC) are hampered by the lack of rigorous instruments to assess the effectiveness of the conferences for the purpose of quality... Show moreObjective Efforts to study morbidity and mortality conferences (M&MC) are hampered by the lack of rigorous instruments to assess the effectiveness of the conferences for the purpose of quality improvement and medical education. This might limit further advancement of the practice. The aim of this scoping review was to determine commonly used effectiveness measures of M&MC in the literature. Method A scoping review was performed of quantitative, qualitative, and mixed methods studies of M&MC, using databases from PubMed, Emcare, Embase, Web of Science, and the Cochrane library. Studies were included if an outcome was described after a general evaluation or an intervention to M&MC. Study quality was assessed with the Quality Assessment Tool for Studies with Diverse Designs. Results A total of 43 articles were included in the review. The majority used a quantitative (n = 23) or mixed (n = 17) design, with surveys as the most frequent method used for data collection (n = 29). The overall Quality Assessment Tool for Studies with Diverse Designs scores were modest (64%). Outcome measures used to evaluate the effectiveness of M&MC were clustered in the following categories: "participant experiences," "characteristics of the meeting," "medical knowledge," "actions for improvement," and "clinical outcomes." Conclusions This review found a wide variety of effectiveness measures for M&MC. Rather than using isolated measures, approaches that combine multiple effectiveness measures could offer a more comprehensive assessment of M&MC. Although there was a preference for quantitative metrics, this fails to seize the opportunity of qualitative methods to yield insights into sociological purposes of M&MC, such as building professional identities and safety culture. Show less
Aims: Major adverse event (MAE) rates during left ventricular assist device (LVAD) therapy in advanced heart failure (HF) patients are high, and impair quality of life and survival. Prediction and... Show moreAims: Major adverse event (MAE) rates during left ventricular assist device (LVAD) therapy in advanced heart failure (HF) patients are high, and impair quality of life and survival. Prediction and risk stratification of MAEs in order to improve patient selection and thereby outcome during LVAD therapy is therefore warranted. Circulating natriuretic peptides (NPs) are strong predictors of MAEs and mortality in chronic HF patients. However, whether NPs can identify patients who are at risk of MAEs and mortality or tend toward myocardial recovery after LVAD implantation is unclear. The aim of this systematic review is to analyze the prognostic value of circulating NP levels before LVAD implantation for all-cause mortality, MAEs and myocardial recovery after LVAD implantation.Methods and Results: Electronic databases were searched for studies analyzing circulating NP in adults with advanced HF before LVAD implantation in relation to mortality, MAEs, or myocardial recovery after LVAD implantation. Twenty-four studies published between 2008 and 2021 were included. Follow-up duration ranged from 48 hours to 5 years. Study sample size ranged from 14 to 15,138 patients. Natriuretic peptide levels were not predictive of all-cause mortality. However, NPs were predictive of right ventricular failure (RVF) and MAEs such as ventricular arrhythmias, moderate or severe aortic regurgitation, and all-cause rehospitalization. No relation between NPs and myocardial recovery was found.Conclusion: This systematic review found that NP levels before LVAD implantation are not predictive of all-cause mortality after LVAD implantation. Thus, NP levels may be of limited value in patient selection for LVAD therapy. However, NPs help in risk stratification of MAEs and may be used to identify patients who are at risk for RVF, ventricular arrhythmias, moderate or severe aortic regurgitation, and all-cause rehospitalization after LVAD implantation. Show less
For the treatment of Covid-19 patients with remdesivir, poor renal and liver function were both exclusion criteria in randomized clinical trials and contraindication for treatment. Also,... Show moreFor the treatment of Covid-19 patients with remdesivir, poor renal and liver function were both exclusion criteria in randomized clinical trials and contraindication for treatment. Also, nephrotoxicity and hepatotoxicity are reported as adverse events. We retrospectively reviewed renal and liver functions of Covid-19 103 patients who received remdesivir in the 15 days after treatment initiation. Approximately 20% of the patient population met randomized clinical trial exclusion criteria. In total, 11% of the patients had a decrease in estimated glomerular filtration rate >10 mL/min/1.73m(2). Also, 25 and 35% had increased alanine transaminase and aspartate transaminase levels, respectively. However, serious adverse events were limited. Therefore, based on these preliminary results, contraindications based on kidney and liver function should not be absolute for remdesivir treatment in patients with Covid-19 if these functions are monitored regularly. A larger patient cohort is warranted to confirm our results. Show less
Ooijevaar, R.E.; Nood, E. van; Goorhuis, A.; Terveer, E.M.; Prehn, J. van; Verspaget, H.W.; ... ; Keller, J.J. 2021
Fecal microbiota transplantation (FMT) has become a well-established treatment for recurrent Clostridioides difficile infection (rCDI). While short-term outcomes and adverse events relating to FMT... Show moreFecal microbiota transplantation (FMT) has become a well-established treatment for recurrent Clostridioides difficile infection (rCDI). While short-term outcomes and adverse events relating to FMT have been well documented, there still is a paucity of data with regard to long-term safety. In this report, we describe the long-term follow-up of the prospective cohort of the first randomized controlled trial of FMT for rCDI, and review the existing literature. A total of 34 patients were treated with FMT for rCDI. Seven patients were still alive after a follow-up of more than 10 years and three patients were lost to follow-up. None of the 34 patients had experienced a new-onset autoimmune, gastrointestinal, or malignant disorder during follow-up. We did not find any deterioration or amelioration of pre-existing medical conditions. Furthermore, no deaths directly attributable to FMT could be identified. These findings are in accordance with the data in available literature. In conclusion, no long-term adverse events or complications directly attributable to FMT were found in our prospective cohort. Review of the available literature does not point to long-term risks associated with FMT in this elderly population, provided that carefully screened fecal suspensions are being used. No firm conclusion on the long-term safety of FMT in younger patients could be drawn. Show less
Toxicity of immune checkpoint inhibitors such as ipilimumab and nivolumab is likely associated with clinical efficacy. In this study, we aim to evaluate this association for pembrolizumab. To this... Show moreToxicity of immune checkpoint inhibitors such as ipilimumab and nivolumab is likely associated with clinical efficacy. In this study, we aim to evaluate this association for pembrolizumab. To this end, data of 147 patients included in the Dutch cohort of the Pembrolizumab Expanded Access Program were collected. All data were collected prospectively. Patients with adverse events (AEs) at any time during therapy showed a higher chance of achieving disease control compared with patients without AEs (low-grade AEs vs. no AEs: odds ratio=12.8, P=0.0002, high-grade AEs vs. no AEs: odds ratio=38.5, P=0.0001) according to a multivariate logistic regression analysis. In addition, Cox regression analysis showed a lower risk of death (hazard ratio: 0.51, 95% confidence interval: 0.28-0.97) and disease progression (hazard ratio: 0.54, 95% confidence interval: 0.30-0.98) over time for patients with high-grade AEs at any time during therapy compared with patients without AEs during therapy. To correct for time dependency of occurrence of AEs, a pseudolandmark analysis at 6 months of therapy was performed. Although significance was lost (Wald test P>0.05), prolonged survival in 3 patients who stopped therapy within 6 months due to the occurrence of AEs was observed, suggesting the potential treatment benefit despite the premature ending of therapy. The occurrence of high-grade toxicity at any time during treatment was associated with higher objective response rates, progression-free survival, and overall survival. There remains a need to assess the predictive value of early occurring AEs on patient survival. Show less
