Influence of esomeprazole on the bioavailability of afatinib: A pharmacokinetic cross-over study in patients with non-small cell lung cancer.

Afatinib is an oral small-molecule kinase inhibitor (SMKI) approved for treatment of metastatic non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) driver mutation. Although oral administration is convenient, most SMKIs experience pH-dependent solubility. A drug-drug interaction between afatinib and proton-pump inhibitors (PPIs) has, however, never been studied in humans. Hence, we performed a randomized, three-period cross-over study. Afatinib (30 mg or 40 mg) was administered without PPI (period A), concomitantly with esomeprazole (period B) and three hours after esomeprazole intake (period C). Primary objective was the area under the curve (AUC0-24 h) comparing period A to period B and period A to period C. Secondary objectives were other pharmacokinetic parameters and toxicity. Linear mixed effect modelling was performed for differences in AUC0-24 h and Cmax between periods A and B and periods A and C. In 18 evaluable NSCLC patients, concomitant use of 40 mg esomeprazole decreased the steady-state afatinib AUC0-24 h with 10.2% (95% CI -29.2 to +14.0%; p = 0.564) compared to afatinib administration without PPI. Esomeprazole intake three hours prior to afatinib did not significantly influence afatinib AUC0-24 h (-0.6%; 95% CI -14.9 to +16.1%; p = 1.0). No differences in toxicity were observed. To conclude, esomeprazole did not change the exposure to afatinib in patients with NSCLC. Since there is no clinically relevant drug-drug interaction, esomeprazole can safely be co-administered with afatinib. This is important for clinical practice, because other EGFR-SMKIs (e.g. erlotinib and gefitinib) do experience clinically relevant drug-drug interactions with acid-suppressive agents.

Ruling out Pulmonary Embolism in Patients with (Suspected) COVID-19-A Prospective Cohort Study.

Background Diagnostic strategies for suspected pulmonary embolism (PE) have not been prospectively evaluated in COVID-19 patients. Methods Prospective, multicenter, outcome study in 707 patients with both (suspected) COVID-19 and suspected PE in 14 hospitals. Patients on chronic anticoagulant therapy were excluded. Informed consent was obtained by opt-out approach. Patients were managed by validated diagnostic strategies for suspected PE. We evaluated the safety (3-month failure rate) and efficiency (number of computed tomography pulmonary angiographies [CTPAs] avoided) of the applied strategies. Results Overall PE prevalence was 28%. YEARS was applied in 36%, Wells rule in 4.2%, and "CTPA only" in 52%; 7.4% was not tested because of hemodynamic or respiratory instability. Within YEARS, PE was considered excluded without CTPA in 29%, of which one patient developed nonfatal PE during follow-up (failure rate 1.4%, 95% CI 0.04-7.8). One-hundred seventeen patients (46%) managed according to YEARS had a negative CTPA, of whom 10 were diagnosed with nonfatal venous thromboembolism (VTE) during follow-up (failure rate 8.8%, 95% CI 4.3-16). In patients managed by CTPA only, 66% had an initial negative CTPA, of whom eight patients were diagnosed with a nonfatal VTE during follow-up (failure rate 3.6%, 95% CI 1.6-7.0). Conclusion Our results underline the applicability of YEARS in (suspected) COVID-19 patients with suspected PE. CTPA could be avoided in 29% of patients managed by YEARS, with a low failure rate. The failure rate after a negative CTPA, used as a sole test or within YEARS, was non-negligible and reflects the high thrombotic risk in these patients, warranting ongoing vigilance.

Wide Variation in Perioperative Care in Anatomical Lung Resections in the Netherlands: A National Survey.

This study aimed to describe perioperative care after anatomical lung resection in the Netherlands, before publication of Enhanced Recovery After Surgery/European Society of Thoracic Surgeons (ERAS/ESTS) guidelines in 2019. An online survey was sent to all 43 Dutch lung surgical centers in December 2017, addressing topics in the 4 phases of perioperative care (preoperative, admission, perioperative, postoperative). Respondents were requested to report care that would be delivered to a standardized patient without perioperative complications. To compare current care with ERAS/ESTS guidelines, we assigned an ERAS/ESTS score per hospital, weighted for evidence level per recommendation. Higher scores indicate higher application of recommendations. Response rate of centers was 100%, median response rate per question was 98% (interquartile range 94-100). Some perioperative recommendations are commonly applied (>85%), such as minimally invasive surgery and regional anesthesia; others, such as admission carbohydrate drinks, are not (<35%). Wide variation was observed regarding patient counselling, pre- and postoperative admission logistics, anemia correction, fluid management, pain management, and chest drain management. Median 62% (interquartile range 53%-72%) of the maximum ERAS/ESTS score was achieved. Large variation in ERAS/ESTS score between hospitals were found in all phases (preoperative: 6.0 [6.5-10.5] points, admission: 5.0 [1.0-6.0] points, perioperative: 21.5.0 [16.0-22.5] points, postoperative: 8.0 [5.0-8.5] points). Large variation exists in perioperative care after anatomical lung resection in the Netherlands. Given previously published data linking variation in perioperative care to variation in outcomes, standardization of perioperative care in lung surgery, preferably based on the ERAS/ESTS guidelines, may be warranted but requires further study.

Variation in length of stay after minimally invasive lung resection: a reflection of perioperative care routines?

OBJECTIVES: Good perioperative care is aimed at rapid recovery, without complications or readmissions. Length of stay (LOS) is influenced not only by perioperative care routines but also by patient factors, tumour factors, treatment characteristics and complications. The present study examines variation in LOS between hospitals after minimally invasive lung resections for both complicated and uncomplicated patients to assess whether LOS is a hospital characteristic influenced by local perioperative routines or other factors. METHODS: Dutch Lung Cancer Audit (surgery) data were used. Median LOS was calculated on hospital level, stratified by the severity of complications. Lowest quartile (short) LOS per hospital, corrected for case-mix factors by multivariable logistic regression, was presented in funnel plots. We correlated short LOS in complicated versus uncomplicated patients to assess whether short LOS clustered in the same hospitals regardless of complications. RESULTS: Data from 6055 patients in 42 hospitals were included. Median LOS in uncomplicated patients varied from 3 to 8 days between hospitals and increased most markedly for patients with major complications. Considerable between-hospital variation persisted after case-mix correction, but more in uncomplicated than complicated patients. Short LOS in uncomplicated and complicated patients were significantly correlated (r = 0.53, P < 0.001). CONCLUSIONS: LOS after minimally invasive anatomical lung resections varied between hospitals particularly in uncomplicated patients. The significant correlation between short LOS in uncomplicated and complicated patients suggests that LOS is a hospital characteristic potentially influenced by local processes. Standardizing and optimizing perioperative care could help limit practice variation with improved LOS and complication rates.

Malignant pleural mesothelioma: when is radiation therapy indicated?

Malignant pleural mesothelioma is an aggressive tumor of serosal surfaces resistant to many current treatment options. This article will provide a comprehensive discussion of the latest developments in the treatment of malignant pleural mesothelioma, with a focus on radiation therapy. We will discuss the role of radiotherapy as a prophylactic, palliative and potentially curative treatment of malignant pleural mesothelioma. An update will be provided of the latest clinical trials including new treatment.

Investigational approaches for mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare, aggressive tumor with a poor prognosis. In view of the poor survival benefit from first-line chemotherapy and the lack of subsequent effective treatment options, there is a strong need for the development of more effective treatment approaches for patients with MPM. This review will provide a comprehensive state of the art of new investigational approaches for mesothelioma. In an introductory section, the etiology, epidemiology, natural history, and standard of care treatment for MPM will be discussed. This review provide an update of the major clinical trials that impact mesothelioma treatment, discuss the impact of novel therapeutics, and provide perspective on where the clinical research in mesothelioma is moving. The evidence was collected by a systematic analysis of the literature (2000-2011) using the databases Medline (National Library of Medicine, USA), Embase (Elsevier, Netherlands), Cochrane Library (Great Britain), National Guideline Clearinghouse (USA), HTA Database (International Network of Agencies for Health Technology Assessment - INAHTA), NIH database (USA), International Pleural Mesothelioma Program - WHOLIS (WHO Database), with the following keywords and filters: mesothelioma, guidelines, treatment, surgery, chemotherapy, radiotherapy, review, investigational, drugs. Currently different targeted therapies and biologicals are under investigation for MPM. It is important that the molecular biologic research should first focus on mesothelioma-specific pathways and biomarkers in order to have more effective treatment options for this disease. The use of array technology will be certainly an implicit gain in the identification of new potential prognostic or biomarkers or important pathways in the MPM pathogenesis. Probably a central mesothelioma virtual tissue bank may contribute to the ultimate goal to identify druggable targets and to develop personalized treatment for the MPM patients.