Ellen Deschepper

Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial.

CONTEXT Mediastinal nodal staging is recommended for patients with resectable non-small cell lung cancer (NSCLC). Surgical staging has limitations, which results in the performance of unnecessary thoracotomies. Current guidelines acknowledge minimally invasive endosonography followed by surgical staging (if no nodal metastases are found by endosonography) as an alternative to immediate surgical staging. OBJECTIVE To compare the 2 recommended lung cancer staging strategies. DESIGN, SETTING, AND PATIENTS Randomized controlled multicenter trial (Ghent, Leiden, Leuven, Papworth) conducted between February 2007 and April 2009 in 241 patients with resectable (suspected) NSCLC in whom mediastinal staging was indicated based on computed or positron emission tomography. INTERVENTION Either surgical staging or endosonography (combined transesophageal and endobronchial ultrasound [EUS-FNA and EBUS-TBNA]) followed by surgical staging in case no nodal metastases were found at endosonography. Thoracotomy with lymph node dissection was performed when there was no evidence of mediastinal tumor spread. MAIN OUTCOME MEASURES The primary outcome was sensitivity for mediastinal nodal (N2/N3) metastases. The reference standard was surgical pathological staging. Secondary outcomes were rates of unnecessary thoracotomy and complications. RESULTS Two hundred forty-one patients were randomized, 118 to surgical staging and 123 to endosonography, of whom 65 also underwent surgical staging. Nodal metastases were found in 41 patients (35%; 95% confidence interval [CI], 27%-44%) by surgical staging vs 56 patients (46%; 95% CI, 37%-54%) by endosonography (P = .11) and in 62 patients (50%; 95% CI, 42%-59%) by endosonography followed by surgical staging (P = .02). This corresponded to sensitivities of 79% (41/52; 95% CI, 66%-88%) vs 85% (56/66; 95% CI, 74%-92%) (P = .47) and 94% (62/66; 95% CI, 85%-98%) (P = .02). Thoracotomy was unnecessary in 21 patients (18%; 95% CI, 12%-26%) in the mediastinoscopy group vs 9 (7%; 95% CI, 4%-13%) in the endosonography group (P = .02). The complication rate was similar in both groups. CONCLUSIONS Among patients with (suspected) NSCLC, a staging strategy combining endosonography and surgical staging compared with surgical staging alone resulted in greater sensitivity for mediastinal nodal metastases and fewer unnecessary thoracotomies. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00432640.

Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial

Background Patients with severe asthma are at increased risk of exacerbations and lower respiratory tract infections (LRTI). Severe asthma is heterogeneous, encompassing eosinophilic and non-eosinophilic (mainly neutrophilic) phenotypes. Patients with neutropilic airway diseases may benefit from macrolides. Methods We performed a randomised double-blind placebo-controlled trial in subjects with exacerbation-prone severe asthma. Subjects received low-dose azithromycin (n=55) or placebo (n=54) as add-on treatment to combination therapy of inhaled corticosteroids and long-acting β2 agonists for 6 months. The primary outcome was the rate of severe exacerbations and LRTI requiring treatment with antibiotics during the 26-week treatment phase. Secondary efficacy outcomes included lung function and scores on the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ). Results The rate of primary endpoints (PEPs) during 6 months was not significantly different between the two treatment groups: 0.75 PEPs (95% CI 0.55 to 1.01) per subject in the azithromycin group versus 0.81 PEPs (95% CI 0.61 to 1.09) in the placebo group (p=0.682). In a predefined subgroup analysis according to the inflammatory phenotype, azithromycin was associated with a significantly lower PEP rate than placebo in subjects with non-eosinophilic severe asthma (blood eosinophilia ≤200/µl): 0.44 PEPs (95% CI 0.25 to 0.78) versus 1.03 PEPs (95% CI 0.72 to 1.48) (p=0.013). Azithromycin significantly improved the AQLQ score but there were no significant between-group differences in the ACQ score or lung function. Azithromycin was well tolerated, but was associated with increased oropharyngeal carriage of macrolide-resistant streptococci. Conclusions Azithromycin did not reduce the rate of severe exacerbations and LRTI in patients with severe asthma. However, the significant reduction in the PEP rate in azithromycin-treated patients with non-eosinophilic severe asthma warrants further study. ClinicalTrials.gov number NCT00760838.

Do worsening scleroderma capillaroscopic patterns predict future severe organ involvement? a pilot study

Objective Assessment of associations of nailfold videocapillaroscopy (NVC) scleroderma patterns (‘early’, ‘active’ and ‘late’) with future severe clinical involvement in a systemic sclerosis (SSc) population. Methods Sixty-six consecutive patients with SSc according to the LeRoy and Medsger criteria underwent NVC assessment at baseline. Videocapillaroscopic images were classified into ‘normal’, ‘early’, ‘active’ or ‘late’ NVC pattern. Clinical evaluation was performed for nine organ systems (general, peripheral vascular, skin, joint, muscle, gastrointestinal tract, lung, heart and kidney) according to the disease severity scale of Medsger (DSS) at 18–24 months of follow-up. Severe clinical involvement was defined as category 2–4 per organ of the DSS. Results NVC patterns were significantly associated with future severe, peripheral vascular/lung involvement at 18–24 months. The OR rose steadily throughout the patterns. The OR for future severe peripheral disease based on simple/multiple (correcting for disease duration, subset and medication) logistic regression was 2.49/2.52 (95% CI 1.33 to 5.43, p=0.003/1.11 to 7.07, p=0.026) for early, 6.18/6.37 for active and 15.35/16.07 for late NVC scleroderma patterns versus the normal NVC pattern. The OR for future severe lung involvement based on simple/multiple regression was 2.54/2.33 (95% CI 1.40 to 5.22, p=0.001/1.13 to 5.52, p=0.021) for early, 6.43/5.44 for active and 16.30/12.68 for late NVC patterns. Conclusions This pilot study is the first demonstrating an association between baseline NVC patterns and future severe, peripheral vascular and lung involvement with stronger odds according to worsening scleroderma patterns. This may indicate a putative role of capillaroscopy as a biomarker.

Nailfold capillaroscopy for day-to-day clinical use: construction of a simple scoring modality as a clinical prognostic index for digital trophic lesions

Objective Construction of a simple nailfold videocapillaroscopic (NVC) scoring modality as a prognostic index for digital trophic lesions for day-to-day clinical use. Methods An association with a single simple (semi)-quantitatively scored NVC parameter, mean score of capillary loss, was explored in 71 consecutive patients with systemic sclerosis (SSc), and reliable reduction in the number of investigated fields (F32–F16–F8–F4). The cut-off value of the prognostic index (mean score of capillary loss calculated over a reduced number of fields) for present/future digital trophic lesions was selected by receiver operating curve (ROC) analysis. Results Reduction in the number of fields for mean score of capillary loss was reliable from F32 to F8 (intraclass correlation coefficient of F16/F32: 0.97; F8/F32: 0.90). Based on ROC analysis, a prognostic index (mean score of capillary loss as calculated over F8) with a cut-off value of 1.67 is proposed. This value has a sensitivity of 72.22/70.00, specificity of 70.59/69.77, positive likelihood ratio of 2.46/2.32 and a negative likelihood ratio of 0.39/0.43 for present/future digital trophic lesions. Conclusions A simple prognostic index for digital trophic lesions for daily use in SSc clinics is proposed, limited to the mean score of capillary loss as calculated over eight fields (8 fingers, 1 field per finger).

Reliability of the qualitative and semiquantitative nailfold videocapillaroscopy assessment in a systemic sclerosis cohort: a two-centre study

Objective Investigation of the reliability of the qualitative and semiquantitative scoring of nailfold videocapillaroscopy (NVC) assessment between two raters in a systemic sclerosis (SSc) cohort. Methods Two raters from different centres blindly assessed the NVC images of 71 consecutive patients with SSc qualitatively as belonging to the scleroderma spectrum (SDS) category (‘early’, ‘active’, ‘late’ scleroderma pattern or ‘scleroderma-like’ pattern) or to the ‘normal’ category and semiquantitatively by calculating the mean score for capillary loss, giant capillaries, microhaemorrhages and capillary ramifications. Inter-rater/intrarater agreement was assessed by calculation of the proportion of agreement and by κ coefficients. Rater agreement of mean score values of hallmark parameters was assessed by intraclass correlation coefficients. Results The inter-rater/intrarater proportion of agreement to qualitatively assess an image as belonging to the SDS category or not was 90% and 96%, whereas the agreement to distinguish between only ‘early’, ‘active’ and ‘late’ scleroderma NVC patterns was 62% and 81%. The agreement of the semiquantitative scoring, as assessed by intraclass correlation coefficient, was 0.96 and 0.95 for capillary loss, 0.84 and 0.95 for giant capillaries, 0.90 and 0.95 for microhaemorrhages and 0.64 and 0.95 for capillary ramifications. Conclusions This is the first study to demonstrate reliability of the qualitative and semiquantitative NVC assessment in an SSc cohort between raters at different centres. Reliability of NVC assessment is essential for use of this tool in multicentre SSc trials.

Clinical effectiveness and cost-effectiveness of endobronchial and endoscopic ultrasound relative to surgical staging in potentially resectable lung cancer: results from the ASTER randomised controlled trial

OBJECTIVE To assess the clinical effectiveness and cost-effectiveness of endosonography (followed by surgical staging if endosonography was negative), compared with standard surgical staging alone, in patients with non-small cell lung cancer (NSCLC) who are otherwise candidates for surgery with curative intent. DESIGN A prospective, international, open-label, randomised controlled study, with a trial-based economic analysis. SETTING Four centres: Ghent University Hospital, Belgium; Leuven University Hospitals, Belgium; Leiden University Medical Centre, the Netherlands; and Papworth Hospital, UK. PARTICIPANTS INCLUSION CRITERIA known/suspected NSCLC, with suspected mediastinal lymph node involvement; otherwise eligible for surgery with curative intent; clinically fit for endosonography and surgery; and no evidence of metastatic disease. EXCLUSION CRITERIA previous lung cancer treatment; concurrent malignancy; uncorrected coagulopathy; and not suitable for surgical staging. INTERVENTIONS Study patients were randomised to either surgical staging alone (n = 118) or endosonography followed by surgical staging if endosonography was negative (n = 123). Endosonography diagnostic strategy used endoscopic ultrasound-guided fine-needle aspiration combined with endobronchial ultrasound-guided transbronchial needle aspiration, followed by surgical staging if these tests were negative. Patients with no evidence of mediastinal metastases or tumour invasion were referred for surgery with curative intent. If evidence of malignancy was found, patients were referred for chemoradiotherapy. MAIN OUTCOME MEASURES The main clinical outcomes were sensitivity (positive diagnostic test/nodal involvement during any diagnostic test or thoracotomy) and negative predictive value (NPV) of each diagnostic strategy for the detection of N2/N3 metastases, unnecessary thoracotomy and complication rates. The primary economic outcome was cost-utility of the endosonography strategy compared with surgical staging alone, up to 6 months after randomisation, from a UK NHS perspective. RESULTS Clinical and resource-use data were available for all 241 patients, and complete utilities were available for 144. Sensitivity for detecting N2/N3 metastases was 79% [41/52; 95% confidence interval (CI) 66% to 88%] for the surgical arm compared with 94% (62/66; 95% CI 85% to 98%) for the endosonography strategy (p = 0.02). Corresponding NPVs were 86% (66/77; 95% CI 76% to 92%) and 93% (57/61; 95% CI 84% to 97%; p = 0.26). There were 21/118 (18%) unnecessary thoracotomies in the surgical arm compared with 9/123 (7%) in the endosonography arm (p = 0.02). Complications occurred in 7/118 (6%) in the surgical arm and 6/123 (5%) in the endosonography arm (p = 0.78): one pneumothorax related to endosonography and 12 complications related to surgical staging. Patients in the endosonography arm had greater EQ-5D (European Quality of Life-5 Dimensions) utility at the end of staging (0.117; 95% CI 0.042 to 0.192; p = 0.003). There were no other significant differences in utility. The main difference in resource use was the number of thoracotomies: 66% patients in the surgical arm compared with 53% in the endosonography arm. Resource use was similar between the groups in all other items. The 6-month cost of the endosonography strategy was £9713 (95% CI £7209 to £13,307) per patient versus £10,459 (£7732 to £13,890) for the surgical arm, mean difference £746 (95% CI -£756 to £2494). The mean difference in quality-adjusted life-year was 0.015 (95% CI -0.023 to 0.052) in favour of endosonography, so this strategy was cheaper and more effective. CONCLUSIONS Endosonography (followed by surgical staging if negative) had higher sensitivity and NPVs, resulted in fewer unnecessary thoracotomies and better quality of life during staging, and was slightly more effective and less expensive than surgical staging alone. Future work could investigate the need for confirmatory mediastinoscopy following negative endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), the diagnostic accuracy of EUS-FNA or EBUS-TBNA separately and the delivery of both EUS-FNA or EBUS-TBNA by suitably trained chest physicians. TRIAL REGISTRATION Current Controlled Trials ISRCTN 97311620. FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 18. See the HTA programme website for further project information.

Second generation antipsychotics in the treatment of bipolar depression: a systematic review and meta-analysis

Depressive symptoms and episodes dominate the course of bipolar disorder. However, the therapeutic armamentarium for bipolar depression is limited. Recent evidence points to the efficacy of second generation antipsychotics (SGAs) for the treatment of bipolar depression. We conducted a systematic review and meta-analysis of the efficacy and safety of SGAs (randomized, double-blind, placebo-controlled trials; used in monotherapy) in the treatment of adult patients with bipolar depression. Publication bias was corrected for by performing similar searches using the clinical trials register of the respective pharmaceutical companies, the Cochrane Database and ClinicalTrials.gov. Seven published papers were identified on the use of aripiprazole, olanzapine and quetiapine. Internal validity of the trials was fairly good, external validity only moderate. Different outcome measures of efficacy and safety were assessed. When the individual trials were looked at, quetiapine and to a lesser extent olanzapine demonstrated significant improvement in MADRS (Montgomery–Åsberg Depression Rating Scale) total scores. This was not demonstrated for aripiprazole. Efficacy was hampered by adverse events, such as weight gain, akathisia and somnolence/sedation. Both clinical heterogeneity of the included trials and statistical heterogeneity of the meta-analytic data were considerable. The number of quetiapine trials was disproportionate to the number of trials of aripiprazole and olanzapine. Further research is needed to assess differential efficacy of the different SGAs and their use in clinical practice.

Nailfold Capillaroscopy for Prediction of Novel Future Severe Organ Involvement in Systemic Sclerosis

Objective. Assessment of associations of nailfold videocapillaroscopy (NVC) scleroderma (systemic sclerosis; SSc) (“early,” “active,” and “late”) with novel future severe clinical involvement in 2 independent cohorts. Methods. Sixty-six consecutive Belgian and 82 Italian patients with SSc underwent NVC at baseline. Images were blindly assessed and classified into normal, early, active, or late NVC pattern. Clinical evaluation was performed for 9 organ systems (general, peripheral vascular, skin, joint, muscle, gastrointestinal tract, lung, heart, and kidney) according to the Medsger disease severity scale (DSS) at baseline and in the future (18–24 months of followup). Severe clinical involvement was defined as category 2 to 4 per organ of the DSS. Logistic regression analysis (continuous NVC predictor variable) was performed. Results. The OR to develop novel future severe organ involvement was stronger according to more severe NVC patterns and similar in both cohorts. In simple logistic regression analysis the OR in the Belgian/Italian cohort was 2.16 (95% CI 1.19–4.47, p = 0.010)/2.33 (95% CI 1.36–4.22, p = 0.002) for the early NVC SSc pattern, 4.68/5.42 for the active pattern, and 10.14/12.63 for the late pattern versus the normal pattern. In multiple logistic regression analysis, adjusting for disease duration, subset, and vasoactive medication, the OR was 2.99 (95% CI 1.31–8.82, p = 0.007)/1.88 (95% CI 1.00–3.71, p = 0.050) for the early NVC SSc pattern, 8.93/3.54 for the active pattern, and 26.69/6.66 for the late pattern versus the normal pattern. Conclusion. Capillaroscopy may be predictive of novel future severe organ involvement in SSc, as attested by 2 independent cohorts.

Patient‐centered outcome of immediately loaded implants in the rehabilitation of fully edentulous jaws

INTRODUCTION Edentulism often involves functional, esthetic, phonetic and psychological problems. OBJECTIVES To evaluate patient-centered outcomes of full-arch screw-retained rehabilitation on immediately loaded implants. MATERIAL AND METHODS Fifty patients treated with Astra Tech(TM) implants answered self-administered questionnaires on a visual analogue scale (VAS) 100 mm scale or with multiple-choice or open questions: at baseline, 1 week, 3 or 6 months and 1 year. Changes of VAS in time were analyzed using mixed models for repeated measures, adjusting for gender, age and jaw; comparison of cross-sectional parameters between jaws was performed with the Mann-Whitney U- or chi(2)-test, all at the 0.05 significance level. RESULTS The median calculated general satisfaction score increased from 40.25 (mean=40.9; SD=23.82; range=0-95) at baseline to 98.25 (mean=95.3; SD=6.68; range=74-100) after 1 year. Overall comfort, eating comfort, speaking comfort and perceived esthetics improved significantly within 1 week after surgery and immediate provisionalization. This did not change significantly until the final bridge was installed after 3 months (mandible) or 6 months (maxilla), when a further significant improvement was demonstrated. The most common postoperative complication was swelling, especially in the maxilla. The importance of one-stage surgery and immediate loading was rated very high by patients before treatment, especially in the mandible. The main reason for choosing fixed prosthetics was eating comfort. Phonetics and esthetics were more important in the maxilla than in the mandible. CONCLUSION Immediate full-arch rehabilitation yeilds an instant significant improvement in general patient satisfaction and self-perceived factors related to comfort, function and esthetics. Eating comfort is the main concern for the patient and shows the highest improvement. Postoperative complications are limited and patients considered immediate loading important.

Two-year Results of an Open Pilot Study of a 2-treatment Course with Rituximab in Patients with Early Systemic Sclerosis with Diffuse Skin Involvement

Objective. To study safety and potential efficacy of a 2-treatment course (month 0/6) with rituximab (RTX) in early diffuse systemic sclerosis (dcSSc). Methods. Two years’ followup (open-label study) was done of 8 patients with early dcSSc. Patients received an infusion of 1000 mg RTX 2 times at months 0 and 6, with 100 mg methylprednisolone. Clinical measurements, Disease Activity Score, functional status, and CD19+ peripheral blood count were performed at months 0, 3, 6, 12, 15, 18, and 24 and histopathological evaluation of the skin at months 0, 3, 12, and 24. Results. There was a clinically significant change in skin score, with a mean Modified Rodnan skin score of 24.8 at baseline (SD 3.4) and 13.6 at Month 24 [SD 5.6; mixed models analyses (MMA) p < 0.0001] and a significant decrease in Disease Activity Score (DAS), with a median of 4.5 at baseline (range 1.5–7.5) and 0.5 at Month 24 (range 0.0–5.5; MMA p < 0.0001). Indices of internal organ involvement remained stable throughout the study. RTX induced effective B cell depletion at baseline and Month 6 (< 5 CD19+ cells/μl blood). The blindly assessed hyalinized collagen score changed significantly over time (MMA p = 0.009), with a mean of 69.3 at baseline (SD 22.8) and 33.1 at 24 months (SD 27.0). Five serious adverse events were considered unrelated to the RTX treatment. Conclusion. A 2-treatment course (months 0/6) with RTX appears to be well tolerated and may have potential efficacy for skin disease and stabilization of internal organ status in early dcSSc. Clinical Trials Registration NCT00379431.