Diagnostic accuracy and cost-effectiveness of different strategies to triage women with adnexal masses: a prospective study.

OBJECTIVE: Transvaginal sonography (TVS) and serum biomarkers are used widely in clinical practice to triage women with adnexal masses, but the effectiveness of current biomarkers is weak. The aim of this study was to determine the best method of diagnosing patients with adnexal masses, in terms of diagnostic accuracy and economic costs, among four triage strategies: (1) the International Ovarian Tumor Analysis group's simple rules (SR) for interpretation of TVS with subjective assessment (SA) by an experienced ultrasound operator when TVS results are inconclusive (referred to hereafter as SR ± SA), (2) SR ± SA and cancer antigen 125 (CA 125), (3) SR ± SA and human epididymis protein 4 (HE4) and (4) SR ± SA and the risk of malignancy algorithm (ROMA). Our main hypothesis was that the addition of the biomarkers to SR ± SA could improve triaging of these patients in terms of diagnostic accuracy (i.e. malignant vs benign). As secondary analyses, we estimated the cost effectiveness of the four strategies and the diagnostic accuracy of SR ± SA at the study hospitals. METHODS: Between February 2013 and January 2015, 447 consecutive patients who were scheduled for surgery for an adnexal mass at the S. Anna and Mauriziano Hospitals in Turin were enrolled in this multicenter prospective cohort study. Preoperative TVS was performed and preoperative CA 125 and HE4 levels were measured. Pathology reports were used to assess the diagnostic accuracy of the four triage strategies and the cost of each strategy was calculated. RESULTS: A total of 391 patients were included in the analysis: 57% (n = 221) were premenopausal and 43% (n = 170) were postmenopausal. The overall prevalence of malignancy was 21%. SR were conclusive in 89% of patients and thus did not require SA; the overall performance of SR ± SA showed a sensitivity of 82%, specificity of 92% and positive and negative predictive values and positive and negative likelihood ratios of 74%, 95%, 10.5 and 0.19, respectively. In premenopausal women, mean cost among the four triage strategies varied from €36.41 for SR ± SA to €70.12 for SR ± SA + ROMA. The addition of biomarkers to SR ± SA showed no diagnostic advantage compared with SR ± SA alone and was more costly. Among postmenopausal women, mean cost among the four triage strategies varied from €39.52 for SR ± SA to €73.23 for SR ± SA + ROMA. Among these women, SR ± SA + CA 125 and SR ± SA + ROMA had a higher sensitivity (both 92% (95% CI, 85-99%)) than SR ± SA (81% (95% CI, 71-91%)), but SR ± SA had a higher specificity (84% (95% CI, 77-91%)). SR ± SA + CA 125 and SR ± SA + ROMA improved diagnostic accuracy, each diagnosing a third more malignant adnexal masses. In postmenopausal women, compared with SR ± SA alone, SR ± SA + CA 125 showed a net reclassification improvement (NRI) of 28.8% at an extra cost of €13.00, while the extra cost for SR ± SA + ROMA was €33.71, with a comparable gain, in terms of NRI, as that of SR ± SA + CA 125. CONCLUSIONS: In our study sample, SR ± SA seems to be the best strategy to triage women with adnexal masses for surgical management. Among postmenopausal women, SR ± SA + CA 125 increased the NRI at a reasonable extra cost. Our data do not justify the use of HE4 and ROMA in the initial triage of women with adnexal masses. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Long-acting beta-agonists and their association with inhaled corticosteroids in COPD.

Inhaled bronchodilators, including beta(2)-agonists and antimuscaric receptor antagonists, are the mainstay of pharmacotherapy in chronic obstructive pulmonary disease (COPD). The short-acting beta(2)-agonists, including salbutamol, and fenoterol, have a rapid onset of action, a bronchodilating effect for 3-6 h and are used on demand. The long-acting beta(2)-agonists (LABAs), including salmeterol and formoterol, have 12-hour duration of action and are used with a twice-daily dosing regimen for long-term COPD treatment. Unlike salmeterol, formoterol has a rapid onset of action. Pharmacological characteristics required by novel inhaled LABAs include 24 h bronchodilator effect in vivo which would make them suitable for once daily administration (ultra-LABA), high potency and selectivity for beta(2)-adrenoceptors, rapid onset of action, low oral bioavailability (< 5%) after inhalation, and high systemic clearance. Indacaterol, which has been approved for long-term treatment of COPD in Europe and in the USA, has a 24-h duration of action and a once-daily dosing regimen. Newer ultra-LABAs, including olodaterol, vilanterol, milveterol, carmoterol, and abediterol, are in development. Combination with ICS (fluticasone/salmeterol, budesonide/formoterol, beclomethasone/formoterol) appears to provide an additional benefit over the monocomponent therapy, although the extent of this benefit is variable and often not clinically significant in all the endpoints assessed. In patients with COPD, treatment with ICS is associated with increased risk of pneumonia which should be carefully considered when assessing the risk/benefit ratio of ICS/LABA combinations. Subphenotyping of patients with COPD (e.g., frequent exacerbations, sputum eosinophilia, mixed asthma/COPD phenotype) might help identify those patients who are most likely to benefit from addition of ICS to bronchodilating treatment. Ultra-LABA/ long-acting muscarinic receptor antagonist (LAMA) combination treatment is under development and is likely to become a standard pharmacological strategy for COPD. Dual-pharmacology inhaled muscarinic antagonist-beta(2) agonist (MABA) molecules provide a new approach to the treatment of COPD.

Inhaled muscarinic acetylcholine receptor antagonists for treatment of COPD.

Bronchodilators, generally administered via metered dose or dry powder inhalers, are the mainstays of pharmacological treatment of stable COPD. Inhaled long-acting beta-agonists (LABA) and anticholinergics are the bronchodilators primarily used in the chronic treatment of COPD. Anticholinergics act as muscarinic acetylcholine receptor antagonists and are frequently preferred over beta-agonists for their minimal cardiac stimulatory effects and greater efficacy in most studies. Their therapeutic efficacy is based on the fact that vagally mediated bronchoconstriction is the major reversible component of airflow obstruction in patients with COPD. However, bronchodilators are effective only on the reversible component of airflow obstruction, which by definition is limited, as COPD is characterized by a fixed or poorly reversible airflow obstruction. Inhaled anticholinergic antimuscarinic drugs approved for the treatment of COPD include ipratropium bromide, oxitropium bromide and tiotropium bromide. Ipratropium bromide, the prototype of anticholinergic bronchodilators, is a short-acting agent. Oxitropium bromide is administered twice a day. Tiotropium bromide, the only long-acting antimuscarinic agent (LAMA) currently approved, is administered once a day. Newer LAMAs including aclidinium bromide and glycopyrrolate bromide are currently in phase III development for treatment of COPD. Some new LAMAs, including glycocpyrrolate, are suitable for once daily administration and, unlike tiotropium, have a rapid onset of action. New LAMAs and their combination with ultra-LABA and, possibly, inhaled corticosteroids, seem to open new perspectives in the management of COPD. Dual-pharmacology muscarinic antagonist-beta2 agonist (MABA) molecules present a novel approach to the treatment of COPD by combining muscarinic antagonism and beta2 agonism in a single molecule.