IntroductionThis study aimed at evaluating the overall survival (OS) gain associated with human epidermal growth factor receptor 2 (HER2)-directed therapies in patients with metastatic breast cancer (mBC).MethodsA bibliographic search was conducted in PubMed and Cochrane databases. Only phase III randomized controlled trials (RCTs) including HER2-positive (HER2+) mBC patients were included in this review. OS was defined as time from randomization until the occurrence of death from any cause. Studies have been grouped according to the line of treatment, i.e., first-line or second-line or beyond.ResultsNineteen RCTs were eligible for inclusion, of which 12 assessed therapies targeting HER2+ mBC in the first-line setting. OS improved from 20.3 months in the first RCT (standard chemotherapy; Slamon et al. (N Engl J Med 344:783–92, 2001)) evaluating HER2-targeting therapies to 48 months in the study of Swain et al. (Lancet Oncol 14:461–71, 2013), with triple combination of pertuzumab, trastuzumab and docetaxel. Seven RCTs evaluated the OS of HER2-targeting therapies in the second-line setting and beyond. The OS in second-line setting improved from 15.3 months (capecitabine; Cameron et al. (Breast Cancer Res Treat 112:533–43, 2008)) to 30.7 months (trastuzumab emtansine; Verma et al. (N Engl J Med 367:1783–91, 2012)). In the third-line setting, the association of lapatinib and trastuzumab has demonstrated to improve OS to 4.5 months compared with lapatinib alone (14 months vs. 9.5 months; Blackwell et al. (J Clin Oncol 30:2585–92, 2012)).ConclusionsHER2-directed therapies had an undeniable beneficial impact on the OS of patients with HER2+ mBC. The triple combination of docetaxel, pertuzumab and trastuzumab is associated with a survival extent of more than 4.5 years, compared with a life expectancy of 1.5 years achieved 14 years ago.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0648-2) contains supplementary material, which is available to authorized users.

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SUMMARYPurpose To compare the results of causality assessments of reported adverse drug reactions (ADR's) obtained from decisional algorithms with those obtained from an expert panel using the WHO global introspection method (GI) and to further evaluate the influence of confounding variables on algorithms ability in assessing causality. Method Two hundred sequentially reported ADR's were included in this study. An independent researcher used algorithms, while an expert panel assessed the same reports using the GI, both aimed at evaluating causality. Reports were divided into three groups according to the presence, absence or lack of information on confounding variables. Results For the total sample, observed agreements between decisional algorithms compared with GI varied from 21% to 56%, average of 47%. When confounding variables were taken into account, agreements varied between 41% and 69%, average of 58%; 8% and 65%, average of 46% and 15% and 53%, average of 42% accordingly to the absence, lack of information or presence of confounding variables, respectively. The extend of reproducibility beyond chance was low for the total sample (average Kappa ¼ 0.26) and within the groups considered. Conclusion The overall observed agreement between algorithm and GI was moderate although poorly different from chance, confounding variables being a shortcoming of algorithms ability in assessing causality.

BackgroundThe number needed to treat (NNT) is an absolute effect measure that has been used to assess beneficial and harmful effects of medical interventions. Several methods can be used to calculate NNTs, and they should be applied depending on the different study characteristics, such as the design and type of variable used to measure outcomes. Whether or not the most recommended methods have been applied to calculate NNTs in studies published in the medical literature is yet to be determined. The aim of this study is to assess whether the methods used to calculate NNTs in studies published in medical journals are in line with basic methodological recommendations.MethodsThe top 25 high-impact factor journals in the “General and/or Internal Medicine” category were screened to identify studies assessing pharmacological interventions and reporting NNTs. Studies were categorized according to their design and the type of variables. NNTs were assessed for completeness (baseline risk, time horizon, and confidence intervals [CIs]). The methods used for calculating NNTs in selected studies were compared to basic methodological recommendations published in the literature. Data were analyzed using descriptive statistics.ResultsThe search returned 138 citations, of which 51 were selected. Most were meta-analyses (n = 23, 45.1%), followed by clinical trials (n = 17, 33.3%), cohort (n = 9, 17.6%), and case–control studies (n = 2, 3.9%). Binary variables were more common (n = 41, 80.4%) than time-to-event (n = 10, 19.6%) outcomes. Twenty-six studies (51.0%) reported only NNT to benefit (NNTB), 14 (27.5%) reported both NNTB and NNT to harm (NNTH), and 11 (21.6%) reported only NNTH. Baseline risk (n = 37, 72.5%), time horizon (n = 38, 74.5%), and CI (n = 32, 62.7%) for NNTs were not always reported. Basic methodological recommendations to calculate NNTs were not followed in 15 studies (29.4%). The proportion of studies applying non-recommended methods was particularly high for meta-analyses (n = 13, 56.5%).ConclusionsA considerable proportion of studies, particularly meta-analyses, applied methods that are not in line with basic methodological recommendations. Despite their usefulness in assisting clinical decisions, NNTs are uninterpretable if incompletely reported, and they may be misleading if calculating methods are inadequate to study designs and variables under evaluation. Further research is needed to confirm the present findings.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0875-8) contains supplementary material, which is available to authorized users.

Background: Patients with undiagnosed hypothyroidism are not treated for the disease and are at high risk of developing serious complications, with major impact on public health. There is a need to systematically review the available evidence on this topic. Objective: To identify the prevalence of undiagnosed hypothyroidism in Europe. Methods: A systematic review of the literature (Medline, EMBASE, and Cochrane Central) was performed to identify epidemiological studies on the prevalence of undiagnosed hypothyroidism among European populations published between January 2008 and April 2018. The Newcastle-Ottawa Scale was used to assess the methodological quality of the included studies. Random-effects meta-analyses were performed to pool estimates of proportions (with 95% confidence intervals [CIs]) of undiagnosed (1) subclinical, (2) overt, and (3) total hypothyroidism. Results: The search returned 15,565 citations (4,526 duplicates). Twenty papers were included in the study. Fourteen and 6 studies were of good and moderate methodological quality, respectively. The results of the meta-analyses were as follows for the prevalence of undiagnosed hypothyroidism: subclinical, 4.11% (95% CI 3.05–5.31%, I² = 99.32%); overt, 0.65% (95% CI 0.38–0.99%, I² = 96.67%); and total, 4.70% (95% CI 2.98–6.79%, I² = 99.53%). According to the sensitivity analysis, the prevalence of hypothyroidism tends to be higher in female patients, in those aged ≥65 years, among studies with lower sample sizes, in those with thyroid-stimulating hormone levels <4.5 mIU/L, and in Eastern and Southern Europe. Conclusions: The current evidence suggests that a considerable proportion of the European population has hypothyroidism, particularly subclinical hypothyroidism, which is undiagnosed. This issue deserves further investigation because of possible deleterious consequences for public health.

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IntroductionThe growing evidence of the increased frequency and severity of adverse drug events (ADEs), besides the negative impact on patient’s health status, indicates that costs due to ADEs may be steadily rising. Observational studies are an important tool in pharmacovigilance. Despite these studies being more susceptible to bias than experimental designs, they are more competent in assessing ADEs and their associated costs.ObjectiveTo identify and characterize the best available evidence on ADE-associated costs.MethodsMEDLINE, Cochrane Library, and Embase were searched from 1995 to 2015. Observational studies were included. The methodological quality of selected studies was assessed by Cochrane Collaboration tool for experimental and observational studies. Studies were classified according to the setting analyzed in “ambulatory”, “hospital”, or both. Costs were classified as “direct” and “indirect”. Data were analyzed using descriptive statistics. The total incremental cost per patient with ADE was estimated.ResultsTwenty-nine (94%) longitudinal observational studies and two (7%) cross-sectional studies were included. Twenty-three (74%) studies were assessed with the highest methodological quality score. The studies were mainly conducted in the US (61%). Twenty (65%) studies evaluated any therapeutic group. Twenty (65%) studies estimated costs of ADEs leading to or prolonging hospitalization. The “direct costs” were evaluated in all studies, whereas only two (7%) also estimated the “indirect costs”. The “direct costs” in ambulatory ranged from €702.21 to €40,273.08, and the in hospital from €943.40 to €7,192.36.DiscussionMethodological heterogeneities were identified among the included studies, such as design, type of ADEs, suspected drugs, and type and structure of costs. Despite such discrepancies, the financial burden associated with ADE costs was found to be high. In the light of the present findings, validated methods to measure ADE-associated costs need future research efforts.

BackgroundOral cancer is one of the most common malignant lesions of the head and neck. This cancer is an aggressive and lethal disease with no significant improvements in the overall survival in the last decades. Moreover, the incidence of oral HPV-positive tumors is rising, especially in young people. This oral neoplasm develops through numerous molecular imbalances that affect key genes and signaling pathways; however, the molecular mechanisms involved in the pathogenesis and progression of oral tumors are still to be fully determined. In order to improve the quality of life and long-term survival rate of these patients, it is vital to establish accurate biomarkers that help in the early diagnosis, prognosis and development of target treatments. Such biomarkers may possibly allow for selection of patients that will benefit from each therapy modality, helping in the optimization of intensity and sequence of the treatments in order to decrease side effects and improve survival.ConclusionIn this review we discuss the current knowledge of oral cancer and the potential role of omics approaches to identify molecular biomarkers in the improvement of early diagnosis, treatment and prognosis. The pursuit to improve the quality of life and decrease mortality rates of the oral patients needs to be centralized on the identification of critical genes in oral carcinogenesis. Understanding the molecular biology of oral cancer is vital for search new therapies, being the molecular-targeted therapies the most promising treatment for these patients.