Exploring the impact of patient-specific clinical features on osimertinib effectiveness in a real-world cohort of patients with EGFR mutated non-small cell lung cancer.

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/m2 ) had significantly shorter PFS/OS compared to all other subgroups. Patients with a high plasma trough concentration in steady state (Cmin,SS ; >271 ng/mL) had shorter PFS compared to a low Cmin,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 Cmin,SS were indicative for shorter PFS and/or OS. Age was not associated with effectiveness outcomes of osimertinib.

Longitudinal metabolite profiling of Streptococcus pneumoniae-associated community-acquired pneumonia.

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.

Real-world outcomes of first-line chemotherapy for unresectable stage III and IV bladder cancer.

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.

Prednisone vs methotrexate in treatment naïve cardiac sarcoidosis.

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.

Overweight and obesity are not associated with worse clinical outcomes in COVID-19 patients treated with fixed-dose 6 mg dexamethasone.

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.

Hospital variation in treatment patterns and oncological outcomes for patients with muscle-invasive and metastatic bladder cancer in the Netherlands.

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.

Validation of the PreOperative Score to predict Post-Operative Mortality (POSPOM) in Dutch non-cardiac surgery patients.

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.

The risk of community-acquired pneumonia in children using gastric acid suppressants.

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.

Adjunctive treatment with oral dexamethasone in non-ICU patients hospitalised with community-acquired pneumonia: a randomised clinical trial.

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.

Systematic evaluation of the efficacy-effectiveness gap of systemic treatments in extensive disease small cell lung cancer.

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.

Quality of clinical direct oral anticoagulant prescribing and identification of risk factors for inappropriate prescriptions.

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.

Real-world treatment patterns and outcomes of patients with extensive disease small cell lung cancer.

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.

Needs with Regard to Decision Support Systems for Treating Patients with Incurable Non-small Cell Lung Cancer.

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.

The extent of microbiological testing is associated with alteration of antibiotic therapy in adults with community-acquired pneumonia.

The aim of this study was to explore the relationship between the extent of microbiological testing and the frequency of antibiotic alteration in adults hospitalised with community-acquired pneumonia (CAP). We retrospectively studied 283 immunocompetent patients hospitalised with CAP. Information on microbiological testing and prescribed antibiotics was obtained. Patients were grouped according to the number of different microbiological tests performed within the first 2 days of admission (0-5 tests). Alteration rates were compared between these groups. Antimicrobial alteration was defined as a switch at day 3 of hospital stay to (1) a narrower spectrum antibiotics, or (2) a different class of antibiotics, or (3) a switch from dual therapy to monotherapy (4) or discontinuation of antibiotic treatment because the indication for antibiotic treatment did no longer exist. For each additional test performed, a stepwise increase in percentage of patients with altered antibiotic regimen ranging from 0 to 59% (p = 0.001) was found. Multivariate logistic regression analyses showed that performing PCR assay for atypical pathogens was most strongly associated with any alteration of antibiotic treatment (OR 2.6 (95% CI 1.4-4.9)) and with changes in atypical coverage specifically (OR 3.1 (95% CI 1.6-6.0). The extent of microbiological testing was positively associated with antibiotic alteration in adults hospitalised with CAP. Antibiotic treatment was most likely to be altered in patients in whom PCR assay for atypical pathogens was performed.

Consecutive antibiotic use in the outpatient setting: an extensive, longitudinal descriptive analysis of antibiotic dispensing data in the Netherlands.

INTRODUCTION: Taking consecutive antibiotic use into account is of importance to obtain insight in treatment within disease episodes, use of 2nd- and 3rd-choice antibiotics, therapy failure and/or side effects. Nevertheless, studies dealing with consecutive antibiotic use are scarce. We aimed at evaluating switch patterns in antibiotic use in the outpatient setting in the Netherlands. METHODS: Outpatient antibiotic dispensing data was processed to antibiotic treatment episodes consisting of single prescriptions or consecutive prescriptions (2006 to 2014). Consecutive prescriptions were categorised into prolongations and switches. Switches were further analysed to obtain antibiotic switch percentages and trends over time. Outcomes were compared with recommendations of Dutch guidelines. RESULTS: A total of 43,179,867 antibiotic prescriptions were included in the analysis, consisting of single prescriptions (95%), prolongations (2%) and switches (3%). The highest switch percentages were found for trimethoprim (7.6%) and nitrofurantoin (5.4%). For fosfomycin, ciprofloxacin, flucloxacillin and trimethoprim we found the highest yearly increase in switching. Amoxicillin/clavulanic acid was most often used as second antibiotic in a switch. A surprisingly high number of 2nd- and 3rd-choice antibiotics are prescribed as first antibiotic in a treatment. CONCLUSIONS: Although the actual reason for a switch is unknown, switch patterns can reveal problems concerning treatment failure and guideline adherence. In general, switch percentages of antibiotics in the Netherlands are low. The data contributes to the knowledge regarding antibiotic switch patterns in the outpatient setting.

Host-response biomarkers for the diagnosis of bacterial respiratory tract infections.

Appropriate antibiotic treatment for respiratory tract infections (RTIs) necessitates rapid and accurate diagnosis of microbial etiology, which remains challenging despite recent innovations. Several host response-based biomarkers due to infection have been suggested to allow discrimination of bacterial and non-bacterial microbial RTI etiology. This review provides an overview of clinical studies that investigated the diagnostic performance of host-response proteomic biomarkers to identify RTI microbial etiology. Procalcitonin and C-reactive protein have been studied most extensively; whereof procalcitonin has demonstrated the strongest diagnostic performance compared to other biomarkers. Proadrenomedullin, soluble triggering receptor expressed on myeloid cells-1, neopterin and pentraxin-3 need more studies to confirm their diagnostic value. For syndecan-4 and lipocalin-2 currently insufficient evidence exists. Common limitations in several of the studies were the relatively small scale setting, heterogeneous patient population and the absence of statistical power calculation.

The effect of neutropenia on the clinical pharmacokinetics of vancomycin in adults.

AIM: There is accumulating evidence that neutropenic patients require higher dosages of vancomycin. To prevent sub-therapeutic drug exposure, it is of utmost importance to obtain adequate exposure from the first dose onwards. We aimed to quantify the effect of neutropenia on the pharmacokinetics of vancomycin. METHODS: Data were extracted from a matched patient cohort of patients known with (1) hematological disease, (2) solid malignancy, and (3) patients not known with cancer. Pharmacokinetic analysis was performed using non-linear mixed effects modeling with neutropenia investigated as a binary covariate on clearance and volume of distribution of vancomycin. RESULTS: A total of 116 patients were included (39 hematologic patients, 39 solid tumor patients, and 38 patients not known with cancer). In total, 742 paired time-concentration observations were available for the pharmacokinetic analysis. Presence of neutropenia showed to significantly (p = 0.00157) increase the clearance of vancomycin by 27.7% (95% CI 10.2-46.2%), whereas it did not impact the volume of distribution (p = 0.704). CONCLUSIONS: This study shows that vancomycin clearance is increased in patients with neutropenia by 27.7%. Therefore, the vancomycin maintenance dose should be pragmatically increased by 25% in neutropenic patients at the start of treatment. Since the volume of distribution appeared unaffected, no adjustment in loading dose is required. These dose adjustments do not rule out the necessity of further dose individualization by means of therapeutic drug monitoring.

Intra-operative red blood cell transfusion and mortality after cardiac surgery.

BACKGROUND: Anemia in cardiac surgery patients has been associated with poor outcomes. Transfusion of red blood cells during surgery is common practice for perioperative anemia, but may come with risks. Little is known about the association between intra-operative transfusion and mortality in patients undergoing cardiac surgery. METHODS: Single centre historical cohort study in 2933 adult patients undergoing coronary surgery with or without aortic valve replacement from June 2011 until September 2014. To estimate the odds ratio for mortality in patients receiving intra-operative transfusion, a propensity score based logistic regression analysis was performed. RESULTS: Intra-operative transfusion was associated with a more than three-fold increased risk of 30-day mortality. Patients in the highest quartile of probability of transfusion were older (age 75 vs 66; P <  0.001), had a higher EuroSCORE (6 vs 3; P <  0.001), had lower preoperative hemoglobin levels (7.6 vs 8.9 mmol/l; P < 0.001), had combined surgery more often (CABG + AVR in 33.4% of cases vs 6.6% (P < 0.001) and a longer duration of surgery (224 vs 188 min; P < 0.001). The association between intra-operative transfusion and mortality persisted after adjustment for these risk factors (adjusted OR 2.6; P = 0.007). CONCLUSIONS: Intra-operative transfusion of red blood cells was found to be associated with increased mortality in adults undergoing coronary surgery. Preoperative patient optimization may improve perioperative outcomes by reducing the likelihood of requiring transfusion and thus its associated risk.

Systematic evaluation of the efficacy-effectiveness gap of systemic treatments in metastatic nonsmall cell lung cancer.

The divergence between clinical trial results and real-world outcomes is largely unknown for many cancer types. The present study aims overall to assess the efficacy-effectiveness gap (difference between outcomes in clinical trials and the real world) in systemic treatment for metastatic nonsmall cell lung cancer (NSCLC).All patients diagnosed with stage IV NSCLC between 2008 and 2014 within a network of seven Dutch large teaching hospitals (Santeon) were studied. For every patient, an efficacy-effectiveness (EE) factor was calculated by dividing individual patients' overall survival (OS) by the pooled median OS assessed from clinical trials with the respective treatment.From 2989 diagnosed patients, 1214 (41%) started with first-line treatment. For all studied regimens, real-world OS was shorter than OS reported in clinical trials. Overall, the EE factor was 0.77 (95% CI 0.70-0.85; p<0.001). Real-world patients completed their treatment plan less often and proceeded less frequently to further lines of treatment. These parameters together with Eastern Cooperative Oncology Group performance status explained 35% of the variation in EE factor.Survival of patients with metastatic NSCLC treated with chemotherapy or targeted therapy in real-world practice is nearly one-quarter shorter than for patients included in trials. Patients' performance status, earlier discontinuation and fewer subsequent lines of treatment partly explained this difference.

Randomized Controlled Trial on the Influence of Intraoperative Remifentanil versus Fentanyl on Acute and Chronic Pain after Cardiac Surgery.

BACKGROUND: Remifentanil has been associated with increased acute and potentially chronic postoperative pain. The objective of this prospective randomized controlled trial was to investigate the influence of intraoperative remifentanil on acute and chronic postoperative pain after cardiac surgery. METHODS: Patients (N = 126) receiving standardized anesthesia with propofol and intermittent intravenous fentanyl at predetermined times for cardiac surgery were randomized to intraoperatively receive either a continuous remifentanil infusion or additional intermittent intraoperative fentanyl as needed. The primary endpoint was chronic thoracic pain at 12 months after surgery. Secondary endpoints were pain at 3 and 6 months after surgery and analgesic requirements and pain levels in the first 72 hours. RESULTS: There was no significant difference in incidence of chronic thoracic pain between the remifentanil and fentanyl groups, respectively (20% vs. 18%; P = 0.817). At 3 months, however, significantly more patients in the remifentanil group reported chronic thoracic pain (51% vs. 33%; P = 0.047). This effect was more pronounced in younger patients and in patients receiving a higher dose of remifentanil (both P < 0.05). The first 24 and 48 hours postoperatively, morphine consumption in the remifentanil group was significantly higher than in the fentanyl group (34.3 mg [interquartile range (IQR) 25.3 to 48.2] vs. 30.2 mg [IQR 19.2 to 38.1], P = 0.028; and 46.8 mg [IQR 33.8 to 59.2] vs. 39.0 mg [IQR 6.2 to 51.4], P = 0.047, respectively). CONCLUSIONS: Intraoperative use of remifentanil during cardiac surgery does not impact chronic postoperative pain 1 year after surgery. Nevertheless, remifentanil increases analgesic requirements and thoracic pain until 3 months after surgery, and its use is therefore less favorable during cardiac surgery.