European value-based healthcare benchmarking: moving from theory to practice.

BACKGROUND: Value-based healthcare (VBHC) is a conceptual framework to improve the value of healthcare by health, care-process and economic outcomes. Benchmarking should provide useful information to identify best practices and therefore a good instrument to improve quality across healthcare organizations. This paper aims to provide a proof-of-concept of the feasibility of an international VBHC benchmarking in breast cancer, with the ultimate aim of being used to share best practices with a data-driven approach among healthcare organizations from different health systems. METHODS: In the VOICE community-a European healthcare centre cluster intending to address VBHC from theory to practice-information on patient-reported, clinical-related, care-process-related and economic-related outcomes were collected. Patient archetypes were identified using clustering techniques and an indicator set following a modified Delphi was defined. Benchmarking was performed using regression models controlling for patient archetypes and socio-demographic characteristics. RESULTS: Six hundred and ninety patients from six healthcare centres were included. A set of 50 health, care-process and economic indicators was distilled for benchmarking. Statistically significant differences across sites have been found in most health outcomes, half of the care-process indicators, and all economic indicators, allowing for identifying the best and worst performers. CONCLUSIONS: To the best of our knowledge, this is the first international experience providing evidence to be used with VBHC benchmarking intention. Differences in indicators across healthcare centres should be used to identify best practices and improve healthcare quality following further research. Applied methods might help to move forward with VBHC benchmarking in other medical conditions.

Health Outcomes with Curative and Palliative Therapies in Real World: Role of the Quality of Life Summary Score in Thoracic Oncology Patients.

BACKGROUND: For patients receiving therapy with curative or palliative intent for a thoracic malignancy, prediction of quality of life (QOL), once therapy starts, remains challenging. The role of health assessments by the patient instead of the doctor herein remains ill-defined. AIMS: To assess the evolution of QOL in patients with thoracic malignancies treated with curative and palliative intent, respectively. To identify factors that determine QOL one year after the start of cancer therapy. To identify factors that affect survival. METHODS: We prospectively included consecutive patients with a thoracic malignancy who were starting anti-cancer therapy and measured QOL with QLQ-C30 before the start of therapy, and thereafter at regular intervals for up to 12 months. A multivariate regression analysis of the global health score (GHS) and QOL summary scores (QSS) one year after the start of therapy was conducted. A proportional hazards Cox regression was conducted to investigate the effects of case-mix variables on survival. RESULTS: Of 587 new patients, 375 started different forms of therapy. Most had non-small cell lung cancer (n = 298), 35 had small cell lung cancer, and 42 had other thoracic malignancies or were diagnosed on imaging alone. There were 203 who went for a curative intent and 172 for a palliative intent strategy. The WHO score of 0-1 was more prevalent in the former group (p = 0.02), and comorbidities were equally distributed. At baseline, all QOL indices were better in the curative group (p < 0.05). The curative group was characterized by a significant worsening of GHS and QSS (p < 0.05). The palliative group was characterized by an improvement in GHS and emotional health (p < 0.05), while other dimensions of functioning remained stable. GHS at 12 months was estimated in a multivariate linear regression model (R2 = 0.23-p < 0.001) based on baseline GHS, QSS, and comorbidity burden. QSS at 12 months was estimated (R2 = 0.31-p < 0.001) by baseline QSS and therapeutic intent strategy (curative vs. palliative). The prognostic factors for overall survival were the type of therapy (curative vs. palliative intent, p < 0.001) and occurrence of early toxicity-related hospitalization (grade ≥ 3, p = 0.001). CONCLUSION: Patients with thoracic malignancies treated with curative intent experience a worsening of their QOL in the first year, whereas those receiving palliative anti-cancer therapy do not. QOL one year after the start of therapy depends on the baseline health scores as determined by the patient, comorbidity burden, and therapeutic strategy. Survival depends on therapeutic strategy and early hospitalization due to toxicity.

NMR-Metabolomics Reveals a Metabolic Shift after Surgical Resection of Non-Small Cell Lung Cancer.

BACKGROUND: Lung cancer can be detected by measuring the patient's plasma metabolomic profile using nuclear magnetic resonance (NMR) spectroscopy. This NMR-based plasma metabolomic profile is patient-specific and represents a snapshot of the patient's metabolite concentrations. The onset of non-small cell lung cancer (NSCLC) causes a change in the metabolite profile. However, the level of metabolic changes after complete NSCLC removal is currently unknown. PATIENTS AND METHODS: Fasted pre- and postoperative plasma samples of 74 patients diagnosed with resectable stage I-IIIA NSCLC were analyzed using 1H-NMR spectroscopy. NMR spectra (s = 222) representing two preoperative and one postoperative plasma metabolite profile at three months after surgical resection were obtained for all patients. In total, 228 predictors, i.e., 228 variables representing plasma metabolite concentrations, were extracted from each NMR spectrum. Two types of supervised multivariate discriminant analyses were used to train classifiers presenting a strong differentiation between the pre- and postoperative plasma metabolite profiles. The validation of these trained classification models was obtained by using an independent dataset. RESULTS: A trained multivariate discriminant classification model shows a strong differentiation between the pre- and postoperative NSCLC profiles with a specificity of 96% (95% CI [86-100]) and a sensitivity of 92% (95% CI [81-98]). Validation of this model results in an excellent predictive accuracy of 90% (95% CI [77-97]) and an AUC value of 0.97 (95% CI [0.93-1]). The validation of a second trained model using an additional preoperative control sample dataset confirms the separation of the pre- and postoperative profiles with a predictive accuracy of 93% (95% CI [82-99]) and an AUC value of 0.97 (95% CI [0.93-1]). Metabolite analysis reveals significantly increased lactate, cysteine, asparagine and decreased acetate levels in the postoperative plasma metabolite profile. CONCLUSIONS: The results of this paper demonstrate that surgical removal of NSCLC generates a detectable metabolic shift in blood plasma. The observed metabolic shift indicates that the NSCLC metabolite profile is determined by the tumor's presence rather than donor-specific features. Furthermore, the ability to detect the metabolic difference before and after surgical tumor resection strongly supports the prospect that NMR-generated metabolite profiles via blood samples advance towards early detection of NSCLC recurrence.

EBUS versus EUS-B for diagnosing sarcoidosis: The International Sarcoidosis Assessment (ISA) randomized clinical trial.

BACKGROUND AND OBJECTIVE: Endosonography with intrathoracic nodal sampling is proposed as the single test with the highest granuloma detection rate in suspected sarcoidosis stage I/II. However, most studies have been performed in limited geographical regions. Studies suggest that oesophageal endosonographic nodal sampling has higher diagnostic yield than endobronchial endosonographic nodal sampling, but a head-to-head comparison of both routes has never been performed. METHODS: Global (14 hospitals, nine countries, four continents) randomized clinical trial was conducted in consecutive patients with suspected sarcoidosis stage I/II presenting between May 2015 and August 2017. Using an endobronchial ultrasound (EBUS) scope, patients were randomized to EBUS or endoscopic ultrasound (EUS)-B-guided nodal sampling, and to 22- or 25-G ProCore needle aspiration (2 × 2 factorial design). Granuloma detection rate was the primary study endpoint. Final diagnosis was based on cytology/pathology outcomes and clinical/radiological follow-up at 6 months. RESULTS: A total of 358 patients were randomized: 185 patients to EBUS-transbronchial needle aspiration (EBUS-TBNA) and 173 to EUS-B-fine-needle aspiration (FNA). Final diagnosis was sarcoidosis in 306 patients (86%). Granuloma detection rate was 70% (130/185; 95% CI, 63-76) for EBUS-TBNA and 68% (118/173; 95% CI, 61-75) for EUS-B-FNA (p = 0.67). Sensitivity for diagnosing sarcoidosis was 78% (129/165; 95% CI, 71-84) for EBUS-TBNA and 82% (115/141; 95% CI, 74-87) for EUS-B-FNA (p = 0.46). There was no significant difference between the two needle types in granuloma detection rate or sensitivity. CONCLUSION: Granuloma detection rate of mediastinal/hilar nodes by endosonography in patients with suspected sarcoidosis stage I/II is high and similar for EBUS and EUS-B. These findings imply that both diagnostic tests can be safely and universally used in suspected sarcoidosis patients.

A Steep Increase in the HeartLogic Index Predicts COVID-19 Disease in an Advanced Heart Failure Patient.

We present a patient with severe nonischemic cardiomyopathy in whom the HeartLogic algorithm was activated on her Boston Scientific cardioverter defibrillator. She had an out-of-alert state for several months and had clinically "stable" heart failure with no hospitalizations in the last 6 months. A sudden and fast increase of the HeartLogic index preceded her presentation in the emergency ward by several days. The detailed readout of HeartLogic however had some atypical features for heart failure decompensation. The patient presented at the emergency department with an increased dyspnea and a dry cough. Clinical exam showed desaturation and was suggestive for an acute respiratory infection. Subsequent imaging with CT thorax and nasopharyngeal real-time polymerase chain reaction (RT-PCR) confirmed SARS-CoV-2 viral pneumonia (COVID-19). This case illustrates that a timely and detailed analysis of HeartLogic alerts could help in the early differentiation of disease in patients with severe heart failure.

A Randomized Open-Label Phase III Trial Evaluating the Addition of Denosumab to Standard First-Line Treatment in Advanced NSCLC: The European Thoracic Oncology Platform (ETOP) and European Organisation for Research and Treatment of Cancer (EORTC) SPLENDOUR Trial.

INTRODUCTION: Receptor activator of NF-kB ligand stimulates NF-kB-dependent cell signaling and acts as the primary signal for bone resorption. Retrospective analysis of a large trial comparing denosumab versus zoledronic acid in bone metastatic solid tumors suggested significant overall survival (OS) advantage for patients with lung cancer with denosumab (p = 0.01). The randomized open-label phase III SPLENDOUR trial was designed to evaluate whether the addition of denosumab to standard first-line platinum-based doublet chemotherapy improved OS in advanced NSCLC. METHODS: Patients with stage IV NSCLC were randomized in a 1:1 ratio to either chemotherapy with or without denosumab (120 mg every 3-4 wks), stratified by the presence of bone metastases (at diagnosis), Eastern Cooperative Oncology Group performance status, histology, and region. To detect an OS increase from 9 to 11.25 months (hazard ratio [HR] = 0.80), 847 OS events were required. The trial closed prematurely owing to decreasing accrual rate. RESULTS: A total of 514 patients were randomized, with 509 receiving one or more doses of the assigned treatment (chemotherapy: 252, chemotherapy-denosumab: 257). The median age was 66.1 years, 71% were men, and 59% were former smokers. Bone metastases were identified in 275 patients (53%). Median OS (95% confidence interval [CI]) was 8.7 (7.6-11.0) months in the control arm versus 8.2 (7.5-10.4) months in the chemotherapy-denosumab arm (HR = 0.96; 95% CI: 0.78-1.19; one-sided p = 0.36). For patients with bone metastasis, HR was 1.02 (95% CI: 0.77-1.35), whereas for those without, HR was 0.90 (95% CI: 0.66-1.23). Adverse events grade 3 or greater were observed in 40.9%, 5.2%, 8.7% versus 45.5%, 10.9%, 10.5% of patients. Conditional power for OS benefit was less than or equal to 10%. CONCLUSIONS: Denosumab was well-tolerated without unexpected safety concerns. There was no OS improvement for denosumab when added to chemotherapy in the intention-to-treat population and the subgroups with and without bone metastases. Our data do not provide evidence of a clinical benefit for denosumab in patients with NSCLC without bone metastases.

Health Outcomes for Definite Concurrent Chemoradiation in Locally Advanced Non-Small Cell Lung Cancer: A Prospective Study.

BACKGROUND: In patients with locally advanced lung cancer treated with concurrent chemoradiation, outcome measurements have been mostly limited to survival. OBJECTIVES: We aimed to measure outcomes that matter to these patients beyond survival in a general clinical practice. METHODS: In a prospective single-centre study, consecutive patients with locally advanced non-small cell lung cancer reported their own outcomes using the EORTC Quality of Life Questionnaire Core 30 at baseline, during therapy, at therapy stop and till 1 year after therapy end every 3 months. Survival, complications, quality of death and case-mix variables were measured. RESULTS: There were 32 consecutive patients included prospectively from June 2013 until September 2016. Median overall survival was 24.3 months (95% CI 12.7-35.9). Severe toxicity (grade III-IV) was frequent (haematologic toxicity III-IV in 59%). Patient-reported outcomes (PROs) documented the burden on global health status and on functional domains (physical, role, social, emotional and cognitive functioning). Deterioration was pronounced during and after treatment with drops over 20 up to 40% points from baseline for physical, role and social functioning. Clinically meaningful negative effects did persist up to 6 and 9 months for physical and role functioning. Fifty-six percent of the deceased patients died in hospital. CONCLUSIONS: The assault on health-related quality of life during concurrent chemoradiation for locally advanced lung cancer is considerable. Loss of physical and role functioning persists up to 6 and 9 months after therapy end, respectively. Measuring PROs can help to identify issues for improvement of the value of care delivered.

Systematic and combined endosonographic staging of lung cancer (SCORE study).

Guidelines recommend endosonography for mediastinal nodal staging in patients with resectable nonsmall cell lung cancer (NSCLC). We hypothesise that a systematic endobronchial ultrasound (EBUS) evaluation combined with an oesophageal investigation using the same EBUS bronchoscope (EUS-B) improves mediastinal nodal staging versus the current practice of targeted positron emission tomography (PET)-computed tomography (CT)-guided EBUS staging alone.A prospective, multicentre, international study (NCT02014324) was conducted in consecutive patients with (suspected) resectable NSCLC. After PET-CT, patients underwent systematic EBUS and EUS-B. Node(s) suspicious on CT, PET, EBUS and/or EUS-B imaging and station 4R, 4L and 7 (short axis ≥8 mm) were sampled. For patients without N2/N3 disease determined on endosonography, surgical-pathological staging was the reference standard.229 patients were included in this study. The prevalence of N2/N3 disease was 103 out of 229 patients (45%). A PET-CT-guided targeted approach by EBUS identified 75 patients with N2/N3 disease (sensitivity 73%, 95% CI 63-81%; negative predictive value (NPV) 81%, 95% CI 74-87%). Four additional patients with N2/N3 disease were found by systematic EBUS (sensitivity 77%, 95% CI 67-84%; NPV 84%, 95% CI 76-89%) and five more by EUS-B (84 patients total; sensitivity 82%, 95% CI 72-88%; NPV 87%, 95% CI 80-91%). Additional clinical relevant staging information was obtained in 23 out of 229 patients (10%).Systematic EBUS followed by EUS-B increased sensitivity for the detection of N2/N3 disease by 9% compared to PET-CT-targeted EBUS alone.

Does nivolumab for progressed metastatic lung cancer fulfill its promises? An efficacy and safety analysis in 20 general hospitals.

OBJECTIVES: In patients with refractory or recurrent non-small-cell lung cancer (NSCLC) after first line chemotherapy, phase III trials showed superiority of nivolumab, an IgG4 programmed death-1 immune-checkpoint-inhibitor antibody, over docetaxel. We evaluated case mix, effectiveness and safety of nivolumab upon implementation in general practice. MATERIALS AND METHODS: In 20 general hospitals, all consecutive NSCLC patients treated with nivolumab within the medical need program (inclusion period 12 months) in Flanders - Belgium were evaluated. RESULTS: There were 267 patients, Eastern Cooperative Oncology Group (ECOG) score was 2 in 24% and 0-1 in 76%. In 48%, two or more systemic regimens were given before nivolumab. The median overall survival was 7.8 months (95% confidence interval (CI) 6.3-9.3). At one year, the overall survival rate was 36.5±0.34%. Median progression-free survival was 3.7 months (95% CI 2.9-4.5). An objective response was obtained in 23.2%. ECOG score 2 and presence of liver metastasis strongly correlated with worse survival (p<0.00001). Treatment related adverse events grade 3 or 4 were reported in 21%, colitis (4%) and pneumonitis (7%) were most frequent. CONCLUSION: Upon implementation of nivolumab therapy in general hospitals, the case mix was characterized by a more heavily pretreated population with a substantial fraction of patients with ECOG score 2. The median overall survival is slightly inferior to what was published in the randomized phase III trials. An ECOG score 2 and the presence of liver metastasis correlated strongly with a worse survival. We report a high prevalence of serious adverse events.

Mediastinal staging by videomediastinoscopy in clinical N1 non-small cell lung cancer: a prospective multicentre study.

A quarter of patients with clinical N1 (cN1) non-small cell lung cancer (NSCLC) based on positron emission tomography-computed tomography (PET-CT) imaging have occult mediastinal nodal involvement (N2 disease). In a prospective study, endosonography alone had an unsatisfactory sensitivity (38%) in detecting N2 disease. The current prospective multicentre trial investigated the sensitivity of preoperative mediastinal staging by video-assisted mediastinoscopy (VAM) or VAM-lymphadenectomy (VAMLA).Consecutive patients with operable and resectable (suspected) NSCLC and cN1 after PET-CT imaging underwent VAM(LA). The primary study outcome was sensitivity to detect N2 disease. Secondary endpoints were the prevalence of N2 disease, negative predictive value (NPV) and accuracy of VAM(LA).Out of 105 patients with cN1 on imaging, 26% eventually developed N2 disease. Invasive mediastinal staging with VAM(LA) had a sensitivity of 73% to detect N2 disease. The NPV was 92% and accuracy 93%. Median number of assessed lymph node stations during VAM(LA) was 4 (IQR 3-5), and in 96%, at least three stations were assessed.VAM(LA) has a satisfactory sensitivity of 73% to detect mediastinal nodal disease in cN1 lung cancer, and could be the technique of choice for pre-resection mediastinal lymph node assessment in this patient group with a one in four chance of occult-positive mediastinal nodes after negative PET-CT.

Role of tumor necrosis factor-α and its receptors in diesel exhaust particle-induced pulmonary inflammation.

Inhalation of diesel exhaust particles (DEP) induces an inflammatory reaction in the lung. However, the underlying mechanisms remain to be elucidated. Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine that operates by binding to tumor necrosis factor receptor 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2). The role of TNF-α signaling and the importance of either TNFR1 or TNFR2 in the DEP-induced inflammatory response has not yet been elucidated. TNF-α knockout (KO), TNFR1 KO, TNFR2 KO, TNFR1/TNFR2 double KO (TNFR-DKO) and wild type (WT) mice were intratracheally exposed to saline or DEP. Pro-inflammatory cells and cytokines were assessed in the bronchoalveolar lavage fluid (BALF). Exposure to DEP induced a dose-dependent inflammation in the BALF in WT mice. In addition, levels of TNF-α and its soluble receptors were increased upon exposure to DEP. The DEP-induced inflammation in the BALF was decreased in TNF-α KO, TNFR-DKO and TNFR2 KO mice. In contrast, the inflammatory response in the BALF of DEP-exposed TNFR1 KO mice was largely comparable with WT controls. In conclusion, these data provide evidence for a regulatory role of TNF-α in DEP-induced pulmonary inflammation and identify TNFR2 as the most important receptor in mediating these inflammatory effects.

Pro- and Anti-Inflammatory Role of ChemR23 Signaling in Pollutant-Induced Inflammatory Lung Responses.

Inhalation of traffic-related particulate matter (e.g., diesel exhaust particles [DEPs]) is associated with acute inflammatory responses in the lung, and it promotes the development and aggravation of allergic airway diseases. We previously demonstrated that exposure to DEP was associated with increased recruitment and maturation of monocytes and conventional dendritic cells (DCs), resulting in TH2 polarization. Monocytes and immature DCs express the G-protein coupled receptor chemR23, which binds the chemoattractant chemerin. Using chemR23 knockout (KO) and corresponding wild-type (WT) mice, we determined the role of chemR23 signaling in response to acute exposure to DEPs and in response to DEP-enhanced house dust mite (HDM)-induced allergic airway inflammation. Exposure to DEP alone, as well as combined exposure to DEP plus HDM, elevated the levels of chemerin in the bronchoalveolar lavage fluid of WT mice. In response to acute exposure to DEPs, monocytes and monocyte-derived DCs accumulated in the lungs of WT mice, but this response was significantly attenuated in chemR23 KO mice. Concomitant exposure to DEP plus HDM resulted in allergic airway inflammation with increased eosinophilia, goblet cell metaplasia, and TH2 cytokine production in WT mice, which was further enhanced in chemR23 KO mice. In conclusion, we demonstrated an opposing role for chemR23 signaling depending on the context of DEP-induced inflammation. The chemR23 axis showed proinflammatory properties in a model of DEP-induced acute lung inflammation, in contrast to anti-inflammatory effects in a model of DEP-enhanced allergic airway inflammation.

Endosonography for lung cancer staging: predictors for false-negative outcomes.

OBJECTIVES: Non-small cell lung cancer (NSCLC) guidelines recommend endosonography (endobronchial [EBUS] and/or transesophageal ultrasound [EUS]) as the initial step for mediastinal tissue staging. Identifying predictors for false negative results could help establish which patients should undergo confirmatory surgical staging. MATERIALS AND METHODS: 775 NSCLC patients staged negative by EBUS, EUS or combined EUS/EBUS were retrospectively analyzed. Predictors of false-negative outcomes were identified by logistic regression analysis. RESULTS AND CONCLUSION: Three predictors for false-negative outcomes were identified: central location of the lung tumor (OR 3.7/4.5/3.6 for EBUS, EUS and EUS/EBUS respectively, p<0.05), nodal enlargement on CT (OR 3.2/2.5/4.9 for EBUS, EUS and EUS/EBUS respectively, p<0.05) and FDG-avidity of N2/N3 lymph node stations on PET (OR 4.2/4.0/7.5 for EBUS, EUS and EUS/EBUS respectively, p<0.05). One subgroup (peripheral lung tumor, nodal enlargement on CT without FDG-avidity for N2/N3) had a low predicted probability (7.8%) for false-negative EUS. For combined EUS/EBUS, two subgroups were identified: peripheral located tumor with nodal enlargement on CT but without FDG-avidity for N2/N3 (predicted probability 4.7%) and centrally located tumor without affected lymph nodes on CT or PET (predicted probability 3.4%). In conclusion, for specific well-defined subsets of NSCLC patients the low predicted probability of metastasis after negative endosonography might justify omitting confirmatory surgical staging.

Endosonography for mediastinal nodal staging of clinical N1 non-small cell lung cancer: a prospective multicenter study.

BACKGROUND: Patients with clinical N1 (cN1) lung cancer based on imaging are at risk for malignant mediastinal nodal involvement (N2 disease). Endosonography with a needle technique is suggested over surgical staging as a best first test for preoperative invasive mediastinal staging. The addition of a confirmatory mediastinoscopy seems questionable in patients with a normal mediastinum on imaging. This prospective multicenter trial investigated the sensitivity of preoperative linear endosonography and mediastinoscopy for mediastinal nodal staging of cN1 lung cancer. METHODS: Consecutive patients with operable and resectable cN1 non-small cell lung cancer underwent a lobe-specific mediastinal nodal staging by endosonography. The primary study outcome was sensitivity to detect N2 disease. The secondary end points were the prevalence of N2 disease, the negative predictive value (NPV) of both endosonography and endosonography with confirmatory mediastinoscopy, and the number of patients needed to detect one additional N2 disease with mediastinoscopy. RESULTS: Of the 100 patients with cN1 on imaging, 24 patients were diagnosed with N2 disease. Invasive mediastinal nodal staging with endosonography alone has a sensitivity of 38%, which can be increased to 73% by adding a mediastinoscopy. NPV was 81% and 91%, respectively. Ten mediastinoscopies are needed to detect one additional N2 disease missed by endosonography. CONCLUSIONS: Endosonography alone has an unsatisfactory sensitivity to detect mediastinal nodal metastasis in cN1 lung cancer, and the addition of a confirmatory mediastinoscopy is of added value. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01456429; URL: www.clinicaltrials.gov.

Cost effectiveness of endosonography versus surgical staging in potentially resectable lung cancer: a health economics analysis of the ASTER trial from a European perspective.

In the ASTER study, mediastinal staging was more accurate for patients randomised to combined endobronchial and endoscopic ultrasound, followed by surgical staging if endoscopy was negative, versus surgical staging alone. Here, we report survival, quality of life and cost effectiveness up to 6 months, for the UK, The Netherlands and Belgium, separately. Survival in the two arms of the study was similar. In all three countries, the endosonography strategy had slightly higher quality-adjusted life years over 6 months, and was cheaper. Therefore, based on clinical accuracy and cost effectiveness, we conclude that mediastinal staging should commence with endosonography.