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Purpose: The objective was to develop and evaluate the portability of a text mining algorithm for prospectively capturing disease progression in electronic health record (EHR) data of patients with metastatic non-small cell lung cancer (mNSCLC) treated with immunochemotherapy., Methods: This study used EHR data from patients with mNSCLC receiving immunochemotherapy (between October 1, 2018, and December 31, 2022) in four Dutch hospitals. A text mining algorithm for capturing disease progression was developed in hospitals 1 and 2 and then transferred to hospitals 3 and 4 to evaluate portability. Performance metrics were calculated by comparing its outcomes with manual chart review. In addition, data were simulated to come available over time to assess performance in real-time applications. Median progression-free survival (PFS) was calculated using the Kaplan-Meier method to compare text mining with manual chart review., Results: During development and portability, the text mining algorithm performed well in capturing disease progression, with all performance scores >90%. When real-time performance was simulated, the performance scores in all four hospitals exceeded 90% from week 15 after the start of follow-up. Although the exact progression dates varied in 46 patients of 157 patients with progressive disease, the number of patients labeled with progression too early (n = 24) and too late (n = 22) was well balanced with discrepancies ranging from -116 to 384 days. Nevertheless, the PFS curves constructed with text mining and manual chart review were highly similar for each hospital., Conclusion: In this study, an accurate text mining algorithm for capturing disease progression in the EHR data of patients with mNSCLC was developed. The algorithm was portable across different hospitals, and the performance over time was good, making this an interesting approach for prospective follow-up of multicenter cohorts.

Aims: Computerized decision support systems (CDSSs) aim to prevent adverse drug events. However, these systems generate an overload of alerts that are not always clinically relevant. Anticoagulants are frequently involved in these alerts. The aim of this study was to investigate the efficiency of CDSS alerts on anticoagulants in Dutch hospital pharmacies., Methods: A multicentre, single-day, cross-sectional study was conducted using a flashmob design in Dutch hospital pharmacies, which have CDSSs that operate on both a national medication surveillance database and on self-developed clinical rules. Hospital pharmacists and pharmacy technicians collected data on the number and type of alerts and time needed for assessing these alerts. The primary outcome was the CDSS efficiency on anticoagulants, defined as the percentage of alerts on anticoagulants that led to an intervention. Secondary outcomes where among other CDSSs efficiency related to any medications and the time expenditure. Descriptive data-analysis was used., Results: Of the 69 hospital pharmacies invited, 42 (61%) participated. The efficiency of CDSS alerts on anticoagulants was 4.0% (interquartile range [IQR] 14.0%) for the national medication surveillance database alerts and 14.3% (IQR 40.0%) for alerts from clinical rules. For any medication, the efficiency was lower: 1.8% (IQR 7.5%) and 13.4% (IQR 21.5%) respectively. The median time for assessing the relevance of all alerts was 2 (IQR 1:21) h/day for pharmacists and 6 (IQR 5:01) h/day for pharmacy technicians., Conclusion: CDSS efficiency is generally low, both for anticoagulants and any medication, while the time investment is high. Optimization of CDSSs is needed., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Antithrombotics require careful monitoring to prevent adverse events. Safe use can be promoted through so-called antithrombotic stewardship. Clinical decision support systems (CDSSs) can be used to monitor safe use of antithrombotics, supporting antithrombotic stewardship efforts. Yet, previous research shows that despite these interventions, antithrombotics continue to cause harm. Insufficient adoption of antithrombotic stewardship and suboptimal use of CDSSs may provide and explanation. However, it is currently unknown to what extent hospitals adopted antithrombotic stewardship and utilize CDSSs to support safe use of antithrombotics. A semi-structured questionnaire-based survey was disseminated to 12 hospital pharmacists from different hospital types and regions in the Netherlands. The primary outcome was the degree of antithrombotic stewardship adoption, expressed as the number of tasks adopted per hospital and the degree of adoption per task. Secondary outcomes included characteristics of CDSS alerts used to monitor safe use of antithrombotics. All 12 hospital pharmacists completed the survey and report to have adopted antithrombotic stewardship in their hospital to a certain degree. The median adoption of tasks was two of five tasks (range 1-3). The tasks with the highest uptake were: drafting and maintenance of protocols (100%) and professional's education (58%), while care transition optimization (25%), medication reviews (8%) and patient counseling (8%) had the lowest uptake. All hospitals used a CDSS to monitor safe use of antithrombotics, mainly via basic alerts and less frequently via advanced alerts. The most frequently employed alerts were: identification of patients using a direct oral anticoagulant (DOAC) or a vitamin K antagonist (VKA) with one or more other antithrombotics (n = 6) and patients using a VKA to evaluate correct use (n = 6), both reflecting basic CDSS. All participating hospitals adopted antithrombotic stewardship, but the adopted tasks vary. CDSS alerts used are mainly basic in their logic., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: RH is a CMO at Gaston Medical which is a software company that develops medical decision support systems. The other authors report no conflicts., (Copyright: © 2024 Graafsma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The advent of Large Language Models (LLMs) such as ChatGPT introduces opportunities within the medical field. Nonetheless, use of LLM poses a risk when healthcare practitioners and patients present clinical questions to these programs without a comprehensive understanding of its suitability for clinical contexts., Objective: The objective of this study was to assess ChatGPT's ability to generate appropriate responses to clinical questions that hospital pharmacists could encounter during routine patient care., Methods: Thirty questions from 10 different domains within clinical pharmacy were collected during routine care. Questions were presented to ChatGPT in a standardized format, including patients' age, sex, drug name, dose, and indication. Subsequently, relevant information regarding specific cases were provided, and the prompt was concluded with the query "what would a hospital pharmacist do?". The impact on accuracy was assessed for each domain by modifying personification to "what would you do?", presenting the question in Dutch, and regenerating the primary question. All responses were independently evaluated by two senior hospital pharmacists, focusing on the availability of an advice, accuracy and concordance., Results: In 77% of questions, ChatGPT provided an advice in response to the question. For these responses, accuracy and concordance were determined. Accuracy was correct and complete for 26% of responses, correct but incomplete for 22% of responses, partially correct and partially incorrect for 30% of responses and completely incorrect for 22% of responses. The reproducibility was poor, with merely 10% of responses remaining consistent upon regeneration of the primary question., Conclusions: While concordance of responses was excellent, the accuracy and reproducibility were poor. With the described method, ChatGPT should not be used to address questions encountered by hospital pharmacists during their shifts. However, it is important to acknowledge the limitations of our methodology, including potential biases, which may have influenced the findings., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objective: Current Clinical Decision Support Systems (CDSSs) generate medication alerts that are of limited clinical value, causing alert fatigue. Artificial Intelligence (AI)-based methods may help in optimizing medication alerts. Therefore, we conducted a scoping review on the current state of the use of AI to optimize medication alerts in a hospital setting. Specifically, we aimed to identify the applied AI methods used together with their performance measures and main outcome measures., Materials and Methods: We searched Medline, Embase, and Cochrane Library database on May 25, 2023 for studies of any quantitative design, in which the use of AI-based methods was investigated to optimize medication alerts generated by CDSSs in a hospital setting. The screening process was supported by ASReview software., Results: Out of 5625 citations screened for eligibility, 10 studies were included. Three studies (30%) reported on both statistical performance and clinical outcomes. The most often reported performance measure was positive predictive value ranging from 9% to 100%. Regarding main outcome measures, alerts optimized using AI-based methods resulted in a decreased alert burden, increased identification of inappropriate or atypical prescriptions, and enabled prediction of user responses. In only 2 studies the AI-based alerts were implemented in hospital practice, and none of the studies conducted external validation., Discussion and Conclusion: AI-based methods can be used to optimize medication alerts in a hospital setting. However, reporting on models' development and validation should be improved, and external validation and implementation in hospital practice should be encouraged., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Introduction: Longitudinal biomarkers in patients with community-acquired pneumonia (CAP) may help in monitoring of disease progression and treatment response. The metabolic host response could be a potential source of such biomarkers since it closely associates with the current health status of the patient., Objectives: In this study we performed longitudinal metabolite profiling in patients with CAP for a comprehensive range of metabolites to identify potential host response biomarkers., Methods: Previously collected serum samples from CAP patients with confirmed Streptococcus pneumoniae infection (n = 25) were used. Samples were collected at multiple time points, up to 30 days after admission. A wide range of metabolites was measured, including amines, acylcarnitines, organic acids, and lipids. The associations between metabolites and C-reactive protein (CRP), procalcitonin, CURB disease severity score at admission, and total length of stay were evaluated., Results: Distinct longitudinal profiles of metabolite profiles were identified, including cholesteryl esters, diacyl-phosphatidylethanolamine, diacylglycerols, lysophosphatidylcholines, sphingomyelin, and triglycerides. Positive correlations were found between CRP and phosphatidylcholine (34:1) (cor = 0.63) and negative correlations were found for CRP and nine lysophosphocholines (cor = - 0.57 to - 0.74). The CURB disease severity score was negatively associated with six metabolites, including acylcarnitines (tau = - 0.64 to - 0.58). Negative correlations were found between the length of stay and six triglycerides (TGs), especially TGs (60:3) and (58:2) (cor = - 0.63 and - 0.61)., Conclusion: The identified metabolites may provide insight into biological mechanisms underlying disease severity and may be of interest for exploration as potential treatment response monitoring biomarker., (© 2024. The Author(s).)

Osimertinib is prescribed to patients with metastatic non-small cell lung cancer (NSCLC) and a sensitizing EGFR mutation. Limited data exists on the impact of patient characteristics or osimertinib exposure on effectiveness outcomes. This was a Dutch, multicenter cohort study. Eligible patients were ≥18 years, with metastatic EGFRm+ NSCLC, receiving osimertinib. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Kaplan-Meier analyses and multivariate Cox proportional hazard models were performed. In total, 294 patients were included. Primary EGFR-mutations were mainly exon 19 deletions (54%) and p.L858R point mutations (30%). Osimertinib was given in first-line (40%), second-line (46%) or beyond (14%), with median PFS 14.4 (95% CI: 9.4-19.3), 13.9 (95% CI: 11.3-16.1) and 8.7 months (95% CI: 4.6-12.7), respectively. Patients with low BMI (<20.0 kg/m 2 ) had significantly shorter PFS/OS compared to all other subgroups. Patients with a high plasma trough concentration in steady state (C min,SS ; >271 ng/mL) had shorter PFS compared to a low C min,SS (<163 ng/mL; aHR 2.29; 95% CI: 1.13-4.63). A significant longer PFS was seen in females (aHR = 0.61, 95% CI: 0.45-0.82) and patients with the exon 19 deletion (aHR = 0.58, 95% CI: 0.36-0.92). A trend towards longer PFS was seen for TP53 wild-type patients, while age did not impact PFS. Patients with a primary EGFR exon 19 deletion had longer PFS, while a low BMI, male sex and a high C min,SS were indicative for shorter PFS and/or OS. Age was not associated with effectiveness outcomes of osimertinib., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Purpose: A high SUV max tumor-to-liver ratio (TLR) of 68 Ga-DOTATATE can be used to select patients with neuroendocrine tumors (NETs) for peptide receptor radionuclide therapy (PRRT). In addition, an SUV max TLR ≥ 8.1 is associated with increased progression-free survival in NET patients treated with somatostatin analogs (SSAs). To avoid a theoretical interaction, several guidelines recommend performing PET/CT just before the monthly administration of long-acting SSAs. We aimed to investigate the effect of SSA on the SUV max of 68 Ga-DOTATATE in patients with NET and to identify independent predictors for high SUV max TLR., Patients and Methods: For this retrospective study, 192 68 Ga-DOTATATE PET/CT scans of 165 patients without (n = 115) and with (n = 77) SSA (octreotide or lanreotide) in the 3 months before PET/CT were collected and reviewed. The effect of SSA on SUV max values was analyzed by a maximum likelihood mixed model., Results: Patients with SSA had a significantly higher median SUV max TLR than patients without SSA (4.7 [IQR], 3.1-7.7) versus 3.2 [IQR, 2.0-5.4]; P < 0.001). Multivariable logistic regression analysis showed that SSA use was an independent predictor for SUV max TLR ≥ 8.1 (odds ratio, 2.91; 95% confidence interval, 1.26-6.72; P = 0.012)., Conclusions: Our data suggest that higher SSA concentrations do not have a negative effect on 68 Ga-DOTATATE uptake in tumor lesions. In addition, we found that only SSA use was associated with SUV max TLR ≥ 8.1. Our results are consistent with previously conducted studies and in line with the recently published guideline that suggests that the relatively recent use of SSA does not necessitate any delay in 68 Ga-DOTATATE PET/CT imaging., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Side effects limit the long-term use of glucocorticoids in cardiac sarcoidosis (CS), and methotrexate has gained attention as steroid sparing agent although the supporting evidence is poor. This study compared prednisone monotherapy, methotrexate monotherapy or a combination of both, in the reduction of myocardial Fluorine-18 fluorodeoxyglucose (FDG) uptake and clinical stabilization of CS patients., Methods and Results: In this retrospective cohort study, 61 newly diagnosed and treatment naïve CS patients commenced treatment with prednisone (N = 21), methotrexate (N = 30) or prednisone and methotrexate (N = 10) between January 2010 and December 2017. Primary outcome was metabolic response on FDG PET/CT and secondary outcomes were treatment patterns, major adverse cardiovascular events, left ventricular ejection fraction, biomarkers and side effects. At a median treatment duration of 6.2 [5.7-7.2] months, 71.4% of patients were FDG PET/CT responders, and the overall myocardial maximum standardized uptake value decreased from 6.9 [5.0-10.1] to 3.4 [2.1-4.7] (P < 0.001), with no significant differences between treatment groups. During 24 months of follow-up, 7 patients (33.3%; prednisone), 6 patients (20.0%; methotrexate) and 1 patient (10.0%; combination group) experienced at least one major adverse cardiovascular event (P = 0.292). Left ventricular ejection fraction was preserved in all treatment groups., Conclusions: Significant suppression of cardiac FDG uptake occurred in CS patients after 6 months of prednisone, methotrexate or combination therapy. There were no significant differences in clinical outcomes during follow-up. These results warrant further investigation of methotrexate treatment in CS patients., (© 2023. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

Introduction: Immune-mediated interstitial pneumonitis may be treated with anti-CD20 therapy after failure of conventional therapies. However, clinical response is variable. It was hypothesized that autoreactive CD20-positive cells may play an important role in this variability. This prospective study aims to elucidate if imaging of CD20-positive cells in the lungs allows prediction of the response to anti-CD20 treatment., Methods: Twenty-one patients with immune-mediated interstitial lung disease (ILD) with deteriorated pulmonary function received a dose of 1000 mg rituximab on day 1 and day 14 spiked with a tracer dose of radiolabeled [89Zr]-rituximab. PET/CT was performed on days 3 and 6. Standardized uptake values (SUV) were calculated as a measure for pulmonary CD20 expression. Based on pulmonary function tests (PFT), forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO), prior to and 6 months after treatment, patients were classified as responder (stable disease or improvement) or non-responder., Results: Fifteen patients (71%) were classified as responder. Pulmonary [89Zr]-rituximab PET SUVmean was significantly correlated with the change in FVC and DLCO (K = 0.49 and 0.56, respectively) when using target-to-background ratios, but not when using SUVmean alone. [89Zr]-rituximab SUVmean was significantly higher in responders than in non-responders (0.35 SD 0.09 vs. 0.23 SD 0.06; P = 0.02)., Conclusion: Rituximab treatment was effective in the majority of patients. As a higher pulmonary uptake of [89Zr]-rituximab correlated with improvement of PFT and treatment outcome, [89Zr]-rituximab PET imaging may serve as a potential predictive biomarker for anti-CD20 therapy., Trial Registration: Clinicaltrials.gov identifier NCT02251964., (© 2023. The Author(s).)

Purpose: For many malignancies, considerable divergence between the efficacy found in clinical trials and effectiveness in routine practice have been reported (efficacy-effectiveness gap). The purpose of this study was to evaluate the efficacy-effectiveness gap in palliative first-line (1L) chemotherapy treatment (CTx) for urothelial carcinoma of the bladder., Methods: From seven Dutch teaching hospitals, all patients diagnosed with unresectable stage III (cT2-4aN1-3M0) and IV (cT4b and/or cM1) disease, who received 1L-CTx (for both primary as recurrent disease after radical cystectomy) between 2008 and 2016, were captured. Results were compared with data from seven randomised trials that investigated 1L gemcitabine + cisplatin (GemCis) and/or gemcitabine + carboplatin (GemCarbo)., Results: Of the 835 included patients, 191 received 1L-CTx. Median overall survival (mOS) of GemCis patients (N = 88) was 10.4 months [95% CI 7.9-13.0], which was shorter compared to clinical trial findings (range mOS: 12.7-14.3 months) despite comparable clinical characteristics. The mOS of GemCarbo patients (N = 92) was 9.3 months [95% CI 7.5-11.1]. Patients who received GemCarbo had worse prognostic characteristics (higher age, impaired renal function and worse performance status (all P-values < 0.001)) compared to GemCis patients, but were equal in occurrence of dose reductions (24.4% vs. 29.5%, P-value = 0.453), early termination (55.7% vs. 54.1%, P-value = 0.839), clinical best response (P-value = 0.733), and toxicity (68.1% vs. 63.3%, P-value = 0.743). In multivariable regression, GemCis was not superior to GemCarbo (HR 0.90 [95% CI 0.55-1.47], P-value = 0.674)., Conclusion: There seems to be an efficacy-effectiveness gap in 1L GemCis treatment, despite patients having similar baseline characteristics. Early termination of treatment occurred more often and dose reduction less often compared to clinical trials, hinting towards abandonment of treatment in case of adverse events. Patients treated with 1L GemCis did not have superior survival compared to GemCarbo patients, even though GemCarbo patients had worse baseline characteristics., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Metabolic changes induced by the host immune response to pathogens found in patients with community-acquired pneumonia (CAP) may provide insight into its pathogenesis. In this study, we characterized differences in the host metabolic response to common CAP-associated pathogens., Method: Targeted metabolomic profiling was performed on serum samples obtained from hospitalized CAP patients (n = 119) at admission. We quantified 347 unique metabolites across multiple biochemical classes, including amines, acylcarnitines, and signaling lipids. We evaluated if unique associations between metabolite levels and specific CAP-associated pathogens could be identified., Results: Several acylcarnitines were found to be elevated in C. burnetii and herpes simplex virus and lowered in M. pneumoniae as compared to other pathogens. Phenylalanine and kynurenine were found elevated in L. pneumophila as compared to other pathogens. S-methylcysteine was elevated in patients with M. pneumoniae , and these patients also showed lowered cortisol levels in comparison to almost all other pathogens. For the herpes simplex virus, we observed a unique elevation of eicosanoids and several amines. Many lysophosphatidylcholines showed an altered profile in C. burnetii versus S . pneumoniae, L. pneumophila, and respiratory syncytial virus. Finally, phosphatidylcholines were negatively affected by the influenza virus in comparison to S. pneumoniae ., Conclusions: In this exploratory analysis, metabolites from different biochemical classes were found to be altered in serum samples from patients with different CAP-associated pathogens, which may be used for hypothesis generation in studies on differences in pathogen host response and pathogenesis of CAP., Competing Interests: None to declare., (© 2023 The Authors.)

In patients with community-acquired pneumonia, LCA can identify robust prognostic subgroups based on clinical and inflammatory parameters. Yet, these subgroups have not proven robust in predicting response to adjunctive dexamethasone treatment. https://bit.ly/3O5eaxz., Competing Interests: Conflict of interest: E. Wittermans has nothing to disclose. Conflict of interest: P.A. van der Zee has nothing to disclose. Conflict of interest: H. Qi has nothing to disclose. Conflict of interest: J.C. Grutters has nothing to disclose. Conflict of interest: G.P. Voorn has nothing to disclose. Conflict of interest: W.J.W. Bos reports grants from Zilveren Kruis Insurance outside the submitted work. Conflict of interest: E.M.W. van de Garde has nothing to disclose. Conflict of interest: H. Endeman has nothing to disclose., (Copyright ©The authors 2023.)

Recent discoveries in molecular diagnostics and drug treatments have improved the treatment of patients with advanced (inoperable) non-squamous non-small cell lung cancer (NSCLC) from solely platinum-based chemotherapy to more personalized treatment, including targeted therapies and immunotherapies. However, these improvements come at considerable costs, highlighting the need to assess their cost-effectiveness in order to optimize lung cancer care. Traditionally, cost-effectiveness models for the evaluation of new lung cancer treatments were based on the findings of the randomized control trials (RCTs). However, the strict RCT inclusion criteria make RCT patients not representative of patients in the real-world. Patients in RCTs have a better prognosis than patients in a real-world setting. Therefore, in this study, we developed and validated a diagnosis-treatment decision model for patients with advanced (inoperable) non-squamous NSCLC based on real-world data in the Netherlands. The model is a patient-level microsimulation model implemented as discrete event simulation with five health events. Patients are simulated from diagnosis to death, including at most three treatment lines. The base-model (non-personalized strategy) was populated using real-world data of patients treated with platinum-based chemotherapy between 2008 and 2014 in one of six Dutch teaching hospitals. To simulate personalized care, molecular tumor characteristics were incorporated in the model based on the literature. The impact of novel targeted treatments and immunotherapies was included based on published RCTs. To validate the model, we compared survival under a personalized treatment strategy with observed real-world survival. This model can be used for health-care evaluation of personalized treatment for patients with advanced (inoperable) NSCLC in the Netherlands., (© 2023. The Author(s).)

Background: Many studies have compared real-world clinical outcomes of immunotherapy in patients with metastatic non-small cell lung cancer (NSCLC) with reported outcomes data from pivotal trials. However, any differences observed could be only limitedly explored further for causation because of the unavailability of individual patient data (IPD) from trial participants. The present study aims to explore the additional benefit of comparison with IPD., Methods: This study compares progression free survival (PFS) and overall survival (OS) of metastatic NSCLC patients treated with second line nivolumab in real-world clinical practice (n = 141) with IPD from participants in the Checkmate-057 clinical trial (n = 292). Univariate and multivariate Cox proportional hazards models were used to construct HRs for real-world practice versus clinical trial., Results: Real-world patients were older (64 vs. 61 years), had more often ECOG PS ≥ 2 (5 vs. 0%) and were less often treated with subsequent anti-cancer treatment (28.4 vs. 42.5%) compared to trial patients. The median PFS in real-world patients was longer (3.84 (95%CI: 3.19-5.49) vs 2.30 (2.20-3.50) months) and the OS shorter than in trial participants (8.25 (6.93-13.2) vs. 12.2 (9.90-15.1) months). Adjustment with available patient characteristics, led to a shift in the hazard ratio (HR) for OS, but not for PFS (HRs from 1.13 (0.88-1.44) to 1.07 (0.83-1.38), and from 0.82 (0.66-1.03) to 0.79 (0.63-1.00), respectively)., Conclusions: This study is an example how IPD from both real-world and trial patients can be applied to search for factors that could explain an efficacy-effectiveness gap. Making IPD from clinical trials available to the international research community allows this., (© 2022. The Author(s).)

Background: Currently, outcomes of Multiple Sclerosis (MS) are not standardized and it is unclear which outcomes matter most to people living with MS. A consensus between patients and healthcare professionals on which outcomes to measure and how, would facilitate a move towards value-based MS care., Objective: to develop an internationally accepted, patient-relevant Standard Outcome Set for MS (S.O.S.MS)., Methods: A mixed-method design was used, including a systematic literature review, four patient focus groups (n=30) and a RAND-modified Delphi process with seventeen MS experts of five disciplines from seven countries (the Netherlands, United States of America, Portugal, Ireland, India, New Zealand, Switzerland and Turkey)., Results: A standard outcome set for MS was defined, consisting of fourteen outcomes divided in four domains: disease activity (n=3), symptoms (n=4), functional status (n=6), and quality of life (n=1). For each outcome, an outcome measure was selected and the measurement protocol was defined. In addition, seven case-mix variables were selected., Conclusion: This standard outcome set provides a guideline for measuring outcomes of MS in clinical practice and research. Using this set to monitor and (inter)nationally benchmark real-world outcomes of MS can support improvement of patient value and ultimately guide the transition towards value-based MS care., Competing Interests: Declaration of Competing Interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: In addition to clinical trials, real-world data is needed to verify the effectiveness of the CDK 4/6 inhibitor palbociclib. The primary aim was to examine real-world variation in treatment modification strategies for neutropenia and its relation to progression-free survival (PFS). The secondary aim was to assess if there is a gap between real-world and clinical trial outcomes., Materials and Methods: In this multicenter, retrospective observational cohort study 229 patients were analyzed who started palbociclib and fulvestrant as second- or later-line therapy for HR-positive, HER2-negative metastatic breast cancer in the Santeon hospital group in the Netherlands between September 2016 and December 2019. Data were manually retrieved from patients' electronic medical records. PFS was examined using the Kaplan-Meier method to compare neutropenia-related treatment modification strategies within the first three months after neutropenia grade 3 - 4 occurred, as well as patients' eligibility to have participated in the PALOMA-3 clinical trial or not., Results: Even though treatment modification strategies differed from those in PALOMA-3 (dose interruptions: 26 vs 54%, cycle delays: 54 vs 36%, and dose reductions: 39 vs 34%), these did not influence PFS. Patients who were PALOMA-3 ineligible experienced a shorter median PFS than those who were eligible (10.2 vs. 14.1 months; HR 1.52; 95% CI 1.12 - 2.07). An overall longer median PFS was found compared to PALOMA-3 (11.6 vs. 9.5 months; HR 0.70; 95% CI 0.54 - 0.90)., Conclusion: This study suggests no impact of neutropenia-related treatment modifications on PFS and confirms inferior outcomes outside clinical trial eligibility., (Copyright © 2023. Published by Elsevier Ltd.)

Introduction: Carboplatin is an anticancer drug used for treatment of various types of cancer including non-small cell lung cancer (NSCLC). Dosing is based on estimated glomerular filtration rate (GFR) using the Cockcroft-Gault formula. In overweight patients, the GFR is more likely overestimated, resulting in a potentially overdose of carboplatin affecting treatment response. This study investigated the association of body mass index (BMI) on overall survival (OS) and progression-free survival (PFS) in stage-IV NSCLC patients treated with first-line carboplatin-based chemotherapy. Secondary safety endpoints were thrombocytopenia and toxicity-related hospitalizations., Materials and Methods: This was a retrospective multicenter cohort study. Patients were categorized according to BMI<25.0 kg/m 2 (normal weight and reference), 25.0-29.9 kg/m 2 (overweight) or ≥30.0 kg/m 2 (obese). For survival analyses adjusted hazard ratios [aHR] were calculated using multivariate Cox regression analysis. Secondary outcomes were analyzed using multivariate logistic regression providing adjusted odd ratios [aOR]., Results: Overweight patients (n=174) had a significantly better OS (aHR=0.72, 95%-CI:0.59-0.89) and PFS (aHR=0.74, 95%-CI:0.61-0.90) compared to normal weight patients (n=268). OS nor PFS were different in obese (n=51) compared to normal weight patients. However, obesity was associated with significantly higher incidences of thrombocytopenia grade ≥3 (aOR=3.47, 95%-CI:1.75-6.90)., Conclusion: This study shows a significantly longer survival for overweight compared to normal weight patients. Obese patients have an increased risk for grade ≥3 thrombocytopenia without a difference in survival following carboplatin-based chemotherapy. The implications for clinical practice are to use the Cockcroft-Gault formula with caution in patients with BMI≥30.0 kg/m 2 , and to verify calculated dosing of carboplatin for appropriateness., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: A fixed 6 mg dexamethasone dose for 10 days is the standard treatment for all hospitalised COVID-19 patients who require supplemental oxygen. Yet, the pharmacokinetic properties of dexamethasone can lead to diminishing systemic dexamethasone exposure with increasing body mass index (BMI). The present study examines whether this translates to overweight and obesity being associated with worse clinical outcomes, defined as ICU admission or in hospital death, in COVID-19 patients treated with fixed-dose dexamethasone., Methods: We conducted a single centre retrospective cohort study in COVID-19 patients who were admitted to a non-ICU ward and were treated with dexamethasone (6 mg once daily for a maximum of ten days) between June 2020 and January 2021. Univariable and multivariable logistic regression analyses were conducted to assess the association between BMI-categories and an unfavourable clinical course (ICU admission and/or in hospital death). Analyses were adjusted for age, comorbidities, inflammatory status, and oxygen requirement at admission. For reference, similar analyses were repeated in a cohort of patients hospitalised before dexamethasone was introduced (March 2020 through May 2020)., Results: In patients treated with dexamethasone (n = 385) an unfavourable clinical course was most prevalent in patients with normal weight (BMI < 25) compared to patients with overweight (BMI 25-30) and patients with obesity (BMI ≥ 30) with percentages of 33, 26 and 21% respectively. In multivariable analyses, there was no association between BMI-category and an unfavourable clinical course (respectively with aORs of 0.81 (0.43-1.53) and 0.61 (0.30-1.27) with normal weight as reference). In the reference cohort (n = 249) the opposite was observed with an unfavourable clinical course being most prevalent in patients with overweight (39% vs 28%; aOR 2.17 (0.99-4.76)). In both cohorts, CRP level at admission was higher and lymphocyte count was lower in patients with normal weight compared to patients with obesity., Conclusions: Overweight and obesity are not associated with an unfavourable clinical course in COVID-19 patients admitted to a non-ICU ward and treated with 6 mg dexamethasone once daily., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: We aimed to assess the cost-effectiveness of screening smokers and ex-smokers for lung cancer in the Netherlands., Methods: A Markov model was used to evaluate the health effects and costs of lung cancer screening from the healthcare perspective. The effects and costs of ten screening scenarios with different start and stop ages of screening were examined across a lifetime horizon in a cohort of 100,000 smokers and ex- smokers 50 years and older., Results: The incremental cost-effectiveness ratios (ICERs) of screening smokers and ex-smokers aged 50-60 years, 50-70 years, and 50 years and older are below the cost-effectiveness threshold of € 20,000 per quality adjusted life year (QALY) gained. Screening 50-60-year-old smokers and ex-smokers was the most cost-effective scenario with an ICER of € 14,094 per QALY gained. However, screening smokers and ex-smokers 50 years and older yielded the highest QALYs and resulted in an ICER of € 16,594 per QALY, which is below the threshold of € 20,000 per QALY. All screening scenarios compared to no screening resulted in CERs between the € 14,000 and € 16,000 per QALY gained. The efficiency frontier showed that screening smokers and ex-smokers in the age groups 70 years and older, 60-70 years, 60 years and older are excluded by extended dominance by no screening, screening smokers and ex-smokers aged 50-60 years and 50-70 years., Conclusion: This study showed that lung cancer screening is cost-effective in the Netherlands., (© 2022. The Author(s).)

Purpose: Population-based studies on treatment patterns in oncology and corresponding clinical outcomes can help identify strategies towards optimal value for patients. This study was performed to describe the variation in treatment patterns and major oncological outcomes for muscle-invasive or metastatic bladder cancer (MIBC/mBC) patients in the Netherlands., Methods: Patients diagnosed with cT2-4aN0-3M0-1 disease between 2008 and 2016 in seven large teaching hospitals in the Netherlands were included. Baseline characteristics, disease stage, intended and definitive treatment, and oncological outcomes were collected. Patients were categorized based on cTNM-stage: (1) cT2-4aN0M0, (2) cT2-4aN1-3M0 and (3) cT4b and/or M1., Results: The total study population comprised 1853 patients, of which 1303 patients were diagnosed with cT2-4aN0M0 disease. Overall, curative treatment was intended in 81% (range 74-85%, P value = 0.132). Radical cystectomy (RC) and curative radiotherapy (RTx) ranged between hospitals from 42 to 66% and 13 to 27%, respectively (P value < 0.001). For 334 patients staged cT4b and/or M1, frequencies for palliative therapy and best supportive care (no anti-cancer therapy) ranged between hospitals from 20 to 54% and 44 to 71%, respectively (P value < 0.001). There was no association between hospital site and overall survival (OS) in a univariable and multivariable Cox regression for survival analysis (after adjusting for age and cT-stage), for all three cTNM-groups. Neoadjuvant or induction chemotherapy (NAIC) utilization rates before RC ranged from 8 to 38% (P value < 0.001)., Conclusions: There is large inter-hospital variation in treatment intent in MIBC/mBC patients. This variation does not seem to translate to differences in overall survival rates. There is an ongoing trend of increased use of RC. Utilisation of NAIC is relatively low considering European guideline recommendations., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Standardized risk assessment tools can be used to identify patients at higher risk for postoperative complications and death. In this study, we validate the PreOperative Score to predict Post-Operative Mortality (POSPOM) for in-hospital mortality in a large cohort of non-cardiac surgery patients. In addition, the performance of POSPOM to predict postoperative complications was studied., Methods: Data from the control cohort of the TRACE (routine posTsuRgical Anesthesia visit to improve patient outComE) study was analysed. POSPOM scores for each patient were calculated post-hoc. Observed in-hospital mortality was compared with predicted mortality according to POSPOM. Discrimination was assessed by receiver operating characteristic curves with C-statistics for in-hospital mortality and postoperative complications. To describe the performance of POSPOM sensitivity, specificity, negative predictive values, and positive predictive values were calculated. For in-hospital mortality, calibration was assessed by a calibration plot., Results: In 2490 patients, the observed in-hospital mortality was 0.5%, compared to 1.3% as predicted by POSPOM. 27.1% of patients had at least one postoperative complication of which 22.4% had a major complication. For in-hospital mortality, POSPOM showed strong discrimination with a C-statistic of 0.86 (95% CI, 0.78-0.93). For the prediction of complications, the discrimination was poor to fair depending on the severity of the complication. The calibration plot showed poor calibration of POSPOM with an overestimation of in-hospital mortality., Conclusion: Despite the strong discriminatory performance, POSPOM showed poor calibration with an overestimation of in-hospital mortality. Performance of POSPOM for the prediction of any postoperative complication was poor but improved according to severity., (© 2022. The Author(s).)

Objective: At the beginning of the COVID-19 pandemic in the Netherlands, the Dutch Working Party on Antibiotic Policy constructed an advisory document about off-label drug treatment options that was regularly updated with new scientific findings. The aim of this study is to describe the dynamics in applied COVID-19 pharmacotherapy during the first 100 days of the pandemic and to assess how the national advisory document influenced local hospital policies., Methods: A multicentre observational cohort study was conducted in six hospitals in the Netherlands. Patients with confirmed COVID-19 admitted between 27 February and 7 June 2020 were studied. Drug prescription data were collected and percentages of patients receiving a specific treatment were calculated. These percentages were plotted together with release dates of the national advisory document. Semi-structured in-depth interviews with hospital pharmacists and infectious diseases specialists were conducted to gain insight into the development and implementation of pharmacotherapy treatment protocols in hospitals., Results: Data from 1511 patients (60% men, mean age 66 years) were analysed. From mid-March (hydroxy)chloroquine was being prescribed in all six hospitals to approximately 70% of patients at admission. Frequencies of other off-label treatments were below 2%. In the week of 6 April 2020, the first hospital discontinued prescribing (hydroxy)chloroquine and the last hospital discontinued in the week of 4 May 2020 (total range -19 to +10 days after the national advisory document advised against its use (1 May 2020)). All interviewees (n=6) stated that the hospitals based their policies mainly on the national advisory document but also assessed scientific literature themselves. Order panels were constructed to support prescribing., Conclusion: Dutch hospitals opted en masse for (hydroxy)chloroquine as COVID-19 therapy at the start of the pandemic, although the time until the therapy was no longer prescribed differed by several weeks. The fact that hospitals defined pharmacotherapy regimens based on their own assessment of the scientific literature besides the national advisory document can explain this variation., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2022. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Background: Latent class analysis (LCA) has identified subgroups with meaningful treatment implications in acute respiratory distress syndrome. We performed a secondary analysis of three studies to assess whether LCA can identify clinically distinct subgroups in community-acquired pneumonia (CAP) and whether the treatment effect of adjunctive corticosteroids differs between subgroups., Methods: LCA was performed on baseline clinical and biomarker data from the Ovidius trial (n=304) and the Steroids in Pneumonia (STEP) trial (n=727), both randomised controlled trials investigating adjunctive corticosteroid treatment in CAP, and the observational TripleP cohort (n=201). Analyses were conducted independently in two cohorts (Ovidius-TripleP combined and the STEP trial). In both cohorts, differences in clinical outcomes and response to adjunctive corticosteroid treatment were examined between subgroups identified through LCA., Results: A two-class model fitted both cohorts best. Class 2 patients had more signs of systemic inflammation compared to class 1. In both cohorts, length of stay was longer and in-hospital mortality rate was higher in class 2. In the Ovidius trial, corticosteroids reduced the median length of stay in class 2 (6.5 versus 9.5 days) but not in class 1 (p-value for interaction=0.02). In the STEP trial, there was no significant interaction for length of stay. We found no significant interaction between class assignment and adjunctive corticosteroid treatment for secondary outcomes., Conclusions: In two independent cohorts, LCA identified two classes of CAP patients with different clinical characteristics and outcomes. Given the different response to adjunctive corticosteroids in the Ovidius trial, LCA might provide a useful basis to improve patient selection for future trials., Competing Interests: Conflict of interest: E. Wittermans has nothing to disclose. Conflict of interest: P.A. van der Zee has nothing to disclose. Conflict of interest: H. Qi has nothing to disclose. Conflict of interest: E.M.W. van de Garde has nothing to disclose. Conflict of interest: C.A. Blum reports grants from the Helmut Horten Foundation, Switzerland, and Novo Nordisk, outside the submitted work. Conflict of interest: M. Christ-Crain has nothing to disclose. Conflict of interest: D. Gommers reports speaker fees and travel expenses from Drager and Maquet, personal fees and other support for a medical advisory board from 2009 to 2012 from GE Healthcare, and personal fees and other support for a medical advisory board from 2015 to 2018 from Novalung, outside the submitted work. Conflict of interest: J.C. Grutters has nothing to disclose. Conflict of interest: G.P. Voorn has nothing to disclose. Conflict of interest: W.J.W. Bos has nothing to disclose. Conflict of interest: H. Endeman has nothing to disclose., (Copyright ©The authors 2022.)

Several observational studies suggested that gut microbiome-affecting-medication impairs the effectiveness of immunotherapy in patients with metastatic non-small-cell lung cancer (NSCLC). We postulated that if the effectiveness of immunotherapy is affected by drug-related changes of the microbiome, a stronger association between the use of co-medication and overall survival (OS) will be observed in patients treated with immunotherapy as compared to patients treated with chemotherapy. In a retrospective matched cohort study, immunotherapy patients were matched (1:1) to patients treated with chemotherapy in the pre immunotherapy era. The association between the use of antibiotics, opioids, proton pump inhibitors, metformin and other antidiabetics on OS was assessed with multivariable cox-regression analyses. Interaction tests were applied to investigate whether the association differs between patients treated with immuno- or chemotherapy. A total of 442 patients were studied. The use of antibiotics was associated with worse OS (adjusted Hazard Ratio (aHR) 1.39, p = 0.02) independent of the type of therapy (chemotherapy or immunotherapy). The use of opioids was also associated with worse OS (aHR 1.33, p = 0.01). The other drugs studied showed no association with OS. Interaction term testing showed no effect modification by immuno- or chemotherapy for the association of antibiotics and opioids with OS. The use of antibiotics and opioids is similarly associated with worse outcomes in both chemotherapy and immunotherapy treated NSCLC patients. This suggests that the association is likely to be a consequence of confounding rather than disturbing the composition of the microbiome., (© 2021. The Author(s).)

Background: With the increased use of acid suppressants, significant potential complications such as community-acquired pneumonia (CAP) are becoming more apparent. Paradoxically, in spite of an increased focus on potential complications, there is an increased use of acid suppressants in children and a lack of data specifically targeting the association between acid suppressants and CAP. Our main objective was to evaluate the risk of CAP in children using acid suppressants (proton pump inhibitors (PPIs) and/or histamine-2 receptor antagonists (H2RAs))., Methods: We performed a cohort study using data from the UK Clinical Practice Research Datalink. All patients aged 1 month to 18 years with a prescription of acid suppressants were included and matched to up to four unexposed children. Time-varying Cox proportional hazards models were used to estimate the risk of CAP. The cohort consisted of 84 868 exposed and 325 329 unexposed children., Results: Current use of PPIs and H2RAs was associated with an increased risk of CAP (adjusted hazard ratio 2.05 (95% CI 1.90-2.22) and 1.80 (95% CI 1.67-1.94), respectively). The risk was even greater in patients with respiratory disease. Long-term use (≥211 days) of PPIs and H2RAs led to a significantly greater risk of CAP compared with short-term use (<31 days). After cessation of therapy, the risk remained increased for the following 7 months., Conclusion: The use of acid suppressants in children was associated with a doubled risk of CAP. This risk increased with chronic use and respiratory disease, and remained increased after discontinuation of therapy., Competing Interests: Conflict of interest: L.J.T.M. van der Sande has nothing to disclose. Conflict of interest: Q. Jöbsis has nothing to disclose. Conflict of interest: M.A.G.E. Bannier has nothing to disclose. Conflict of interest: E.M.W. van de Garde has nothing to disclose. Conflict of interest: J.J.M. Coremans has nothing to disclose. Conflict of interest: F. de Vries is supervisor to two PhD students who are employed by F. Hoffmann La Roche Ltd (Basel, Switzerland and Welwyn Garden City, UK); the topics of the studies are not related to the current manuscript and no fees or reimbursements have been received for this. Conflict of interest: E. Dompeling has nothing to disclose. Conflict of interest: J.H.M. Driessen has nothing to disclose., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Adjunctive intravenous corticosteroid treatment has been shown to reduce length of stay (LOS) in adults hospitalised with community-acquired pneumonia (CAP). We aimed to assess the effect of oral dexamethasone on LOS and whether this effect is disease severity dependent., Methods: In this multicentre, stratified randomised, double-blind, placebo-controlled trial, immunocompetent adults with CAP were randomly assigned (1:1 ratio) to receive oral dexamethasone (6 mg once daily) or placebo for 4 days in four teaching hospitals in the Netherlands. Randomisation (blocks of four) was stratified by CAP severity (pneumonia severity index class I-III and IV-V). The primary outcome was LOS., Results: Between December 2012 and November 2018, 401 patients were randomised to receive dexamethasone (n=203) or placebo (n=198). Median LOS was shorter in the dexamethasone group (4.5 days, 95% CI 4.0-5.0 days) than in the placebo group (5.0 days, 95% CI 4.6-5.4 days; p=0.033). Within both CAP severity subgroups, differences in LOS between treatment groups were not statistically significant. The secondary ICU admission rate was lower in the dexamethasone arm (5 (3%) versus 14 (7%); p=0.030); 30-day mortality did not differ between groups. In the dexamethasone group the rate of hospital readmission tended to be higher (20 (10%) versus 9 (5%); p=0.051) and hyperglycaemia (14 (7%) versus 1 (1%); p=0.001) was more prevalent., Conclusion: Oral dexamethasone reduced LOS and ICU admission rate in adults hospitalised with CAP. It remains unclear for which patients the risk-benefit ratio is optimal., Competing Interests: Conflict of interest: E. Wittermans has nothing to disclose. Conflict of interest: S.M.T. Vestjens has nothing to disclose. Conflict of interest: S.M.C. Spoorenberg has nothing to disclose. Conflict of interest: W.L. Blok has nothing to disclose. Conflict of interest: J.C. Grutters has nothing to disclose. Conflict of interest: R. Janssen has nothing to disclose. Conflict of interest: G.T. Rijkers has nothing to disclose. Conflict of interest: F.W.J.M. Smeenk has nothing to disclose. Conflict of interest: G.P. Voorn has nothing to disclose. Conflict of interest: E.M.W. van de Garde has nothing to disclose. Conflict of interest: W.J.W. Bos reports grants from Zilveren Kruis Insurance, outside the submitted work., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Accurate sentinel lymph node (SLN) staging is essential for both prognosis and treatment in patients with breast cancer. However, the preoperative lymphoscintigraphy may fail to visualize the SLN in some patients. The purpose of this retrospective study was to identify risk factors associated with SLN nonvisualization on lymphoscintigraphy. For this single-center retrospective study, all data of lymphoscintigraphy of SLN procedures from March 2011 to April 2021 were collected and reviewed from the Amsterdam UMC database., Results: A total of 1886 SLN procedures were included in this study. The SLN nonvisualization rate was 25.1% on lymphoscintigraphy at 4 h post-injection. The SLN nonvisualization rate decreased to 9.4% after reinjection. Multivariable analysis showed that age ≥ 70 years (P < 0.001; OR: 2.27; 95% CI: 1.46-3.53), BMI ≥ 30 kg/m 2 (P = 0.031; OR: 1.48; 95% CI: 1.04-2.12) and nonpalpable tumors (P = 0.004; OR: 1.54; 95% CI: 1.15-2.07) were independent predictors of SLN nonvisualization. Tumor location, brand of radiopharmaceutical, injected dose and volume, experience of preparer and administrator were not associated with SLN nonvisualization. None of the patient, tumor or tracer characteristics were associated with SLN nonvisualization after radiotracer reinjection., Conclusions: This study shows that risk factors for SLN nonvisualization in breast cancer patients during preoperative lymphoscintigraphy are age ≥ 70 years, BMI ≥ 30 kg/m 2 and nonpalpable tumors. Our results support the notion that SLN lymphoscintigraphy is a very robust technique that does not depend on the experience of the preparer or administrator of the radiotracer.

Diagnosis of microbial disease etiology in community-acquired pneumonia (CAP) remains challenging. We undertook a large-scale metabolomics study of serum samples in hospitalized CAP patients to determine if host-response associated metabolites can enable diagnosis of microbial etiology, with a specific focus on discrimination between the major CAP pathogen groups S. pneumoniae, atypical bacteria, and respiratory viruses. Targeted metabolomic profiling of serum samples was performed for three groups of hospitalized CAP patients with confirmed microbial etiologies: S. pneumoniae (n = 48), atypical bacteria (n = 47), or viral infections (n = 30). A wide range of 347 metabolites was targeted, including amines, acylcarnitines, organic acids, and lipids. Single discriminating metabolites were selected using Student's T-test and their predictive performance was analyzed using logistic regression. Elastic net regression models were employed to discover metabolite signatures with predictive value for discrimination between pathogen groups. Metabolites to discriminate S. pneumoniae or viral pathogens from the other groups showed poor predictive capability, whereas discrimination of atypical pathogens from the other groups was found to be possible. Classification of atypical pathogens using elastic net regression models was associated with a predictive performance of 61% sensitivity, 86% specificity, and an AUC of 0.81. Targeted profiling of the host metabolic response revealed metabolites that can support diagnosis of microbial etiology in CAP patients with atypical bacterial pathogens compared to patients with S. pneumoniae or viral infections., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To develop and evaluate a tool for patients with stage IV non-small-cell lung cancer and their thoracic oncologists (TOs) that provides insight into real-world effectiveness of systemic treatments to support informed clinical decision making in the palliative setting., Methods: A participatory design approach was used to acquire insights from patients and TOs into preferences regarding the content and design of the web-based tool. Implementation was investigated by means of an adoption and usage rate. The appreciation of the tool was evaluated through a telephone survey with patients and a questionnaire for TOs., Results: From clinical data of 2,989 patients with stage IV non-small-cell lung cancer diagnosed in one of the Santeon hospitals, an interface was developed to show treatments plus both real-world outcomes and clinical trial results after selecting patient characteristics (patients like me). This prototype of the tool was finalized after discussion in a focus group with four TOs and semi-structured interviews with six patients. The tool was implemented and used by TOs in three of six Santeon hospitals (50% adoption rate). The tool was used in 48 patients (29% usage rate), of which 17 participated in the telephone survey. Ten TOs responded to the questionnaire. The responses varied from positive reactions on the clear overview of treatment outcomes to statements that the tool rarely changed treatment decisions. Overall, the majority of patients and TOs scored the tool as of added value (71% and 83%, respectively)., Conclusion: Our real-world data tool in metastatic lung cancer was appreciated in clinical practice by both patients and TOs. However, the efficacy of the implementation can be improved., Competing Interests: Harry J. M. GroenConsulting or Advisory Role: Novartis, Bristol Myers Squibb, Lilly, Roche/Genentech, AstraZenecaResearch Funding: Roche, Boehringer Ingelheim Ewoudt M. W. Van de GardeResearch Funding: AbbVieNo other potential conflicts of interest were reported.

Purpose: The aim of this study is to assess how clinical outcomes in real-world (effectiveness) correspond to the outcomes in clinical trials (efficacy) of systemic treatments for extensive disease small cell lung cancer (ED SCLC)., Methods: All patients diagnosed with ED SCLC between 2008 and 2014 in six Dutch large teaching hospitals (Santeon network) were identified and followed-up from date of diagnosis until death or end of data collection. For every patient, an efficacy-effectiveness factor (EE factor) was calculated by dividing individual patients' overall survival (OS) by the pooled median OS assessed from clinical trials with the respective treatment., Results: From 792 diagnosed patients, 568 (72%) started with first-line treatment. Overall, the median EE factor was 0.79 (P < .001 from 1.00). Poor performance status (ECOG≥2) and a higher age at diagnosis (age ≥ 65 years) were independent predictors for a lower EE factor. The EE gap was 43% in patients with both age ≥ 65 years and ECOG ≥2 (EE factor 0.57). The mean age and the proportion of patients with ECOG≥2 in real-world were different from those in clinical trials (mean age of 66 versus 62 years, and ECOG≥2 25% versus 17%; both P < .001)., Conclusion: OS of patients with ED SCLC treated with systemic therapy in real-world practice is 21% shorter than for patients included in trials. Age at diagnosis and performance status partly explain this gap., (© 2020 John Wiley & Sons Ltd.)

This study aims to assess how clinical outcomes of immunotherapy in real-world (effectiveness) correspond to outcomes in clinical trials (efficacy) and to look into factors that might explain an efficacy-effectiveness (EE) gap. All patients diagnosed with stage IV non-small cell lung cancer (NSCLC) in 2015-2018 in six Dutch large teaching hospitals (Santeon network) were identified and followed-up from date of diagnosis until death or end of data collection. Progression-free survival (PFS) and overall survival (OS) from first-line (1L) pembrolizumab and second-line (2L) nivolumab were compared with clinical trial data by calculating hazard ratios (HRs). From 1950 diagnosed patients, 1005 (52%) started with any 1L treatment, of which 83 received pembrolizumab. Nivolumab was started as 2L treatment in 141 patients. For both settings, PFS times were comparable between real-world and trials (HR 1.08 (95% CI 0.75-1.55), and HR 0.91 (95% CI 0.74-1.14), respectively). OS was significantly shorter in real-world for 1L pembrolizumab (HR 1.55; 95% CI 1.07-2.25). Receiving subsequent lines of treatment was less frequent in real-world compared to trials. There is no EE gap for PFS from immunotherapy in patients with stage IV NSCLC. However, there is a gap in OS for 1L pembrolizumab. Fewer patients proceeding to a subsequent line of treatment in real-world could partly explain this.

Background: The Value-Based Health Care concept defines patient value as patient-relevant outcomes divided by costs. The aim of the present study was to assess the development of systemic treatment costs over the years compared with changes in overall survival (OS) at the level of a diagnosis of stage IV non-small cell lung cancer (NSCLC)., Methods: All patients diagnosed (in 2008-2014) with stage IV NSCLC and treated with systemic treatment in six Dutch large teaching hospitals (Santeon network) were included. We collected data on OS and amounts of drug units (milligrams) for every drug in the applied systemic cancer treatments, until death. These amounts were multiplied by Dutch unit costs (Euros/mg) expressed in 2018 Euros to construct total drug costs per line of treatment per patient. Costs for day care visits were added for drugs requiring parenteral administration., Results: Data were collected from 1214 patients. Median OS and mean total drug costs showed no significant variation over the years (p = 0.437 and p = 0.693, respectively). Mean total drug costs per 1 year of survival ranged from €20,665 to €26,438 during the period under study. Costs for first-line systemic treatment were significantly higher in 2011-2014 compared with 2008-2010., Conclusion: This study shows that overall drug costs were stable over the years, despite a relative increase in first-line treatment costs. Median OS remained at around 8 months from year to year. These trend data are very relevant as background for the assessment of costs and achieved outcomes in the more recent years.

Background: To improve and compare outcomes in healthcare, it is necessary to standardise outcome measurements. There are no widely accepted standardised outcome measures reflecting quality of care for bladder cancer (BCa) patients., Objective: The aim of this study was to create a standardised set of outcomes for patients with muscle-invasive or metastatic BCa, using the value-based healthcare principles., Design Setting and Participants: A multidisciplinary working group of 25 healthcare professionals and patient representatives was assembled, to develop the set., Outcome Measurements and Statistical Analysis: We used an online RAND-modified Delphi process to prioritise, discuss, and reach consensus regarding the outcomes, case-mix variables, and treatment factors., Results and Limitations: Recognising the heterogeneity of patients with BCa, the working group defined the scope as patients with muscle-invasive and metastatic BCa. A total of 24 outcomes, including ten patient-reported outcomes, were included in the standard set of outcomes, covering survival, complication rates, recurrence of disease, readmissions after treatment, and quality of life (QoL). Fourteen case-mix variables were included. The EQ-5D and European Organisation for Research and Treatment of Cancer quality of life (EORTC-QLQ) questionnaires were recommended to measure QoL., Conclusions: We developed the first standardised set of patient-centred outcomes for muscle-invasive and metastatic BCa. The sue of this set enables institutions to monitor, compare, and improve the quality of BCa care, on an international level., Patient Summary: Our group of healthcare professionals and patient representatives recommended a standardised set of patient-centred outcomes to be followed during the treatment of patients with muscle-invasive or metastatic bladder cancer, in order to monitor, compare, and improve the quality of care., (© 2021 The Author(s).)

Scope: The Dutch Working Party on Antibiotic Policy constituted a multidisciplinary expert committee to provide evidence-based recommendation for the use of antibacterial therapy in hospitalized adults with a respiratory infection and suspected or proven 2019 Coronavirus disease (COVID-19)., Methods: We performed a literature search to answer four key questions. The committee graded the evidence and developed recommendations by using Grading of Recommendations Assessment, Development, and Evaluation methodology., Questions Addressed by the Guideline and Recommendations: We assessed evidence on the risk of bacterial infections in hospitalized COVID-19 patients, the associated bacterial pathogens, how to diagnose bacterial infections and how to treat bacterial infections. Bacterial co-infection upon admission was reported in 3.5% of COVID-19 patients, while bacterial secondary infections during hospitalization occurred up to 15%. No or very low quality evidence was found to answer the other key clinical questions. Although the evidence base on bacterial infections in COVID-19 is currently limited, available evidence supports restrictive antibiotic use from an antibiotic stewardship perspective, especially upon admission. To support restrictive antibiotic use, maximum efforts should be undertaken to obtain sputum and blood culture samples as well as pneumococcal urinary antigen testing. We suggest to stop antibiotics in patients who started antibiotic treatment upon admission when representative cultures as well as urinary antigen tests show no signs of involvement of bacterial pathogens after 48 hours. For patients with secondary bacterial respiratory infection we recommend to follow other guideline recommendations on antibacterial treatment for patients with hospital-acquired and ventilator-associated pneumonia. An antibiotic treatment duration of five days in patients with COVID-19 and suspected bacterial respiratory infection is recommended upon improvement of signs, symptoms and inflammatory markers. Larger, prospective studies about the epidemiology of bacterial infections in COVID-19 are urgently needed to confirm our conclusions and ultimately prevent unnecessary antibiotic use during the COVID-19 pandemic., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This retrospective study was performed to evaluate real-world oncological outcomes of patients treated with chemo-based therapy for muscle-invasive or metastatic bladder cancer (MIBC/mBC) and compare results to data from RCTs and other cohorts. Among 1578 patients diagnosed, 470 (30%) had MIBC/mBC. Median overall survival (mOS) for RC alone (47 months), first-line (13 months) and second-line (7 months) chemotherapy, and chemotherapy for recurrent disease (8 months) were similar to literature. Treatment with neoadjuvant and induction chemotherapy (NAIC) was only utilized in 9% of patients, and often in patients with poor disease status, resulting in a lower mOS compared to literature (35 and 20 months, respectively). Patients treated with chemotherapy had many adversities to treatment, with only 50%, 13%, 18% and 7% of patients in NAIC, first-line, salvage after RC, and second-line setting completing the full pre-planned chemotherapy treatment. Real-world data shows NAIC before RC is underutilized. Adversities during chemotherapy treatment are frequent, with many patients requiring dose reduction or early treatment termination, resulting in poor treatment response. Although treatment efficacy between RCTs and real-world patients is quite similar, there are large differences in baseline characteristics and treatment patterns. Possibly, results from retrospective studies on real-world data can deliver missing evidence on efficacy of chemotherapy treatment on older and 'unfit' patients.

Objective: Clinical outcome data on patients with extensive disease small cell lung cancer (ED SCLC) treated in routine practice is limited. The aim of this retrospective study is to present data on treatment patterns and survival in an unselected patient population with ED SCLC., Methods: All patients diagnosed with ED SCLC between 2008 and 2014 in six Dutch large teaching hospitals (Santeon network) were included. We collected data on patient characteristics, systemic treatments, overall survival (OS), dose reductions (<80% of initial dose) and early discontinuation (<4 cycles)., Results: From 792 diagnosed patients, 568 (72%) started with first-line treatment. Of these patients, 41% received second-line treatment. Only 68 patients received third-line treatment. For all treated patients, the mean age was 66 years. The majority (72%) had a performance status (ECOG) of 0 or 1 at diagnosis. Median OS of treated patients was 7.4 months. Of all patients with first-line treatment, 26% received <4 cycles and dose reductions were observed in 29%., Conclusion: After first-line systemic treatment in ED SCLC the fraction of patients receiving subsequent lines of treatment is rapidly decreasing. This information is necessary as background for evaluation of the added value of future drugs under study for ED SCLC., (© 2020 The Authors. European Journal of Cancer Care published by John Wiley & Sons Ltd.)

Aims: Even though the use of direct oral anticoagulants (DOACs) is safe based on clinical outcomes, drug safety also depends on appropriateness of drug prescription, which is challenging for DOACs since many patient factors need to be considered. The aim of this study was to assess the appropriateness of DOAC prescriptions and to identify risk factors of determinants for inappropriate DOAC prescriptions., Methods: A retrospective study in a nonuniversity teaching hospital was performed of hospitalized patients (≥18 years) who received an initial DOAC prescription between February and August 2018. Appropriateness of prescribing was evaluated on 8 criteria by using a modified version of the medication appropriateness index., Results: A total of 770 initial DOAC prescriptions of inpatients were evaluated: 267 patients (34.6%) had at least met 1 inappropriate criterion for a DOAC prescription. The most frequent inappropriate criterion was dosage (17.4%). Of the 4 DOACs, dabigatran (21.6%) and apixaban (21.2%) were mostly inappropriate dosed. In a multivariable analysis, reduced renal function (estimated glomerular filtration rate <50 mL/min; odds ratio [OR] = 2.35; P < .001), a diagnosis of atrial fibrillation (OR = 1.87; P = .004), and 'prescribed by surgeons' (OR = 1.9; P = .013) were independently associated with inappropriateness of prescribing., Conclusion: This study has highlighted a high degree of inappropriate prescribing of DOACs. These results underline the need for targeted interventions to improve DOAC prescribing., (© 2020 The British Pharmacological Society.)

Background: In the battle against the SARS-CoV‑2 pandemic, chloroquine has emerged as a new potential therapeutic option for the treatment of infected patients. A safety consideration for the application of chloroquine is its QTc-prolonging potential. Thus far, no data are available on the QTc-prolonging potential of chloroquine in COVID-19 patients., Objective: To assess the degree of chloroquine-induced QTc prolongation in hospitalised COVID-19 patients., Methods: A baseline electrocardiogram (ECG) and ECGs recorded during chloroquine treatment were retrospectively collected in patients suspected of having COVID-19. The QTc interval was calculated by computerised and manual interpretation. Baseline and follow-up QTc intervals were compared using the paired samples t-test., Results: A total of 95 patients had a baseline ECG recording and at least one ECG recording during chloroquine therapy. Chloroquine treatment resulted in a mean QTc prolongation of 35 ms (95% CI 28-43 ms) using computerised interpretation and 34 ms (95% CI 25-43 ms) using manual interpretation. No torsade de pointes was observed during chloroquine treatment. After manual review, 22 patients (23%) had a QTc interval exceeding 500 ms during chloroquine treatment. None of these patients had a prolonged QTc interval prior to the initiation of chloroquine treatment., Conclusions: Chloroquine significantly prolongs the QTc interval in a clinically relevant matter. This highlights the need for ECG monitoring when prescribing chloroquine to COVID-19 patients.

Background: Recently, ocrelizumab (Ocrevus®) was approved for the treatment of primary progressive multiple sclerosis (PPMS) based on data from the ORATORIO clinical trial. Real-world data about the clinical effectiveness of ocrelizumab has yet to be gathered., Objective: The aim of this study was to provide data about the clinical effectiveness of ocrelizumab for patients diagnosed with PPMS in a real-world setting., Methods: We conducted a retrospective cohort study of all patients with PPMS who started ocrelizumab treatment ( n = 21) in St. Antonius Hospital (Utrecht/Nieuwegein, the Netherlands) between April 2018 and December 31, 2018. Primary outcome was pre- versus post-ocrelizumab disability worsening rate (from 96 weeks prior to first ocrelizumab administration up to 24 weeks post first ocrelizumab administration)., Results: Disability worsening rate while on treatment significantly differed (lower) from disability worsening rate in pre-treatment period ( Z = -2.81, p ≤ .01). Three out of 17 patients showed a clinically relevant improvement in disability status after treatment start., Conclusion: Ocrelizumab can stabilize disability progression in patients with PPMS. Some patients even showed a clinically relevant improvement in disability status. Further research should help to identify which patients benefit most from ocrelizumab., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2020 K. Daniels et al.)

Treatment decision-making for patients with incurable non-small cell lung cancer (NSCLC) is complex due to the rapidly increasing number of treatments and discovery of new biomarkers. Decision support systems (DSS) could assist thoracic oncologists (TO) weighing of the pros and cons of treatments in order to arrive at an evidence-based and personalized treatment advice. Our aim is to inventory (1) TO's needs with regard to DSS in the treatment of incurable (stage IIIB/IV) NSCLC patients, and (2) preferences regarding the development of future tools in this field. We disseminated an online inventory questionnaire among all members of the Section of Oncology within the Society of Physicians in Chest Medicine and Tuberculosis. Telephone interviews were conducted to better contextualize the findings from the questionnaire. In total, 58 TO completed the questionnaire and expressed a need for new DSS. They reported that it is important for tools to include genetic and immune markers, to be sufficiently validated, regularly updated, and time-efficient. Also, future DSS should incorporate multiple treatment options, integrate estimates of toxicity, quality of life and cost-effectiveness of treatments, enhance communication between caregivers and patients, and use IT solutions for a clear interface and continuous updating of tools. With this inventory among Dutch TO, we summarized the need for new DSS to aid treatment decision-making for patients with incurable NSCLC. To meet the expressed needs, substantial additional efforts will be required by DSS developers, above already existing tools.