•IFCC position paper about CDT outlining caveats, key points, and recommendations.•Alcohol intake versus CDT is discussed as well as the cut-off and expected range.•Comparison studies using ...inadequate study populations will lead to wrong outcome.•Standardisation has led to test accuracy improvements in national EQAS.
Carbohydrate deficient transferrin (CDT) is a biomarker for excessive alcohol consumption utilized in clinical and forensic medicine and workplace testing. Previously, many different analytical methods for CDT were used and the measurand varied considerably, making direct comparison of test results difficult. To end this confusion, the IFCC established a working group on CDT standardisation (WG-CDT) which completed its tasks in 2017.
This IFCC position paper by the WG-CDT summarizes state of the art information about the measurand and the analytical methods and gives concise recommendations for its utilization.
The results achieved by the CDT standardisation process led to accuracy improvements in national external quality assessment schemes over the years. A brief review of ROC based comparison studies with the traditional biomarkers (GGT, MCV, ALT and AST) discusses the bias resulting from inadequate study populations. In large groups of the general population the superior diagnostic performance of CDT is confirmed.
The relationship between alcohol intake versus resulting CDT is discussed as well as the cutoff and measurement uncertainty. Concerning the application in practice, potential pitfalls are considered and recommendations handling both analytical and preanalytical caveats are given. Finally, some examples of serious misunderstandings in publications about CDT are addressed.
It is well known that traffic injuries still represent one of the main causes of death and that high blood alcohol concentrations while driving significantly increase the occurrence of accidents. ...However, only limited literature on the correlation between chronic alcohol abuse and accident risk is available. The aim of the present study was to investigate the hypothesis of an association between elevated concentrations of carbohydrate deficient transferrin (CDT) and the occurrence of alcohol-related traffic accidents.
The analytical determinations of BAC and CDT were performed following certified methods in HS-GC-FID and HPLC, respectively. For BAC, 0.50 g/L was used as cut-off, whereas 2.0% was used for CDT, according to the standardisation proposed by IFCC. A total of 929 drivers, tested for BAC at the time of hospital admission after a traffic accident, were classified into two groups: InjDr 1 (BAC ≤ 0.50 g/L) and InjDr 2 (BAC>0.50 g/L); all drivers were also tested for CDT.
InjDr 1 included 674 individuals, only 2.5% showing a CDT above the cutoff, whereas InjDr 2 group consisted of 255 subjects, 28.6% testing positive for CDT (Odds Ratio 15.5). When subdividing the InjDr group into increasing classes of CDT, a steady increase in the percentage of BAC-positive drivers was appreciated. Moreover, average BAC was found to parallel each class of CDT.
The reported data strongly support the use of CDT as a biomarker of increased risk of alcohol-related traffic accidents in the procedures of re-granting of the driving license upon confiscation for “drink driving”.
•Alcohol-related road traffic accidents are still one of the major causes of death.•Chronic alcohol abuse is scarcely investigated in this context.•The association between elevated CDT concentrations and such accidents was studied.•This work provides information that may significantly help improve traffic safety.•The data may suggest the opportunity of a re-evaluation of current CDT cut-offs.
Tamoxifen, for many years the ‘gold standard’ in the adjuvant setting for the management of endocrine sensitive early breast cancer, is associated with an increased risk of endometrial cancer and ...other life-threatening events. Moreover, many women relapse during or after tamoxifen therapy due to the development of resistance. This provided the rationale for a switching trial with anastrozole, the updated results of which are reported here.
This trial investigated the efficacy of switching to anastrozole for women already receiving tamoxifen. After 2–3 years of tamoxifen treatment, postmenopausal, node-positive, ER-positive patients were randomized to receive either anastrozole 1 mg/day or to continue tamoxifen, 20 mg/day, giving a total duration of 5-years treatment. The primary end point was disease-free survival and secondary endpoints were event-free survival, overall survival and safety.
A total of 448 patients were enrolled. At a median follow-up time of 64 months (range 12–93), 63 events had been reported in the tamoxifen group compared with 39 in the anastrozole group HR 0.57 (95% CI 0.38–0.85) P = 0.005. Relapse-free and overall survival were also longer in the anastrozole group HR 0.56 (95% CI 0.35–0.89) P = 0.01 and 0.56 (95% CI 0.28–1.15) P = 0.1. However, the latter difference was not statistically significant. Overall more patients in the anastrozole group experienced at least one adverse event (209 versus 151: P = 0.000). However, numbers of patients experiencing serious adverse events were comparable (37 versus 40, respectively: P = 0.7).
Switching to anastrozole after the first 2–3 years of treatment was confirmed to improve event-free and relapse-free survival of postmenopausal, node-positive, ER-positive early breast cancer patients already receiving adjuvant tamoxifen.
In the context of fitness certification to hold the driving license, GGT and CDT have been used, sometimes in combination (γ-CDT), to exclude chronic alcohol abuse. The present study was carried out ...with the aim of comparing the power of these biomarkers as tools for the objective screening of subjects at high risk of alcohol-associated traffic injuries.
288 male drivers admitted to hospital after traffic accidents were examined by determination of GGT, CDT and BAC. The degree of association of GGT, CDT and γ-CDT with BAC was analysed using non-parametric statistics.
Partitioning the cases using the cut-off concentrations of 0.5 g/L for BAC (the legal limit adopted in most European countries), 55 U/L for GGT and 1.9% for CDT, a highly significant difference was found between the frequency of elevated GGT or CDT in cases where BAC was within the legal limits and those with elevated BAC values (Fisher’s exact test: p < 0.001). However, the calculation of the odds ratio showed a much higher increase for CDT (28 times) than for GGT (6 times) in those drivers with a BAC above the Italian legal limit in comparison with those showing a BAC within the cut-off; conversely, γ-CDT does not provide any significant advantage vs. CDT alone.
Both GGT and CDT provide objective evidence of an association with the occurrence of alcohol-related severe traffic accidents, but CDT shows superior association with these events. Therefore, CDT, notwithstanding higher costs, should be preferred in a forensic/certification context.
•GGT, CDT and γ-CDT were compared as diagnostic tools in a certification context.•Samples from traffic accidents were examined by determination of GGT, CDT and BAC.•The degree of association of these biomarkers with BAC was studied.•CDT provided a stronger association with the risk of traffic accidents vs. GGT.•CDT, notwithstanding higher costs, should be preferred in forensic contexts.
The BOLERO-2 trial reported efficacy and safety of Everolimus (EVE) and Exemestane (EXE) combination in HR+ advanced breast cancer (ABC) patients. The BALLET trial further evaluated the safety of ...EVE-EXE in HR+ ABC patients, without reporting efficacy data. Aim of the EVA real-life study was to collect data of efficacy and safety of EVE-EXE combination in the clinical setting, as well as exploring efficacy according to EVE Dose-Intensity (DI) and to previous treatment with Fulvestrant.
This study aimed to describe the outcome of ABC pts treated with EVE-EXE combination in terms of median duration of EVE treatment and ORR in a real-life setting.
From July 2013 to December 2015, the EVA study enrolled 404 pts. Median age was 61 years (33–83). Main metastatic sites were: bone (69.1%), soft tissue (34.7%) and viscera (33.2%). Median number of previous treatments was 2 (1–7). 43.3% of the pts had received Fulvestrant. Median exposure to EVE was 31.0 weeks (15.4–58.3) in the whole population. No difference was observed in terms of EVE exposure duration according to DI (p for trend = 0.27) or type of previous treatments (p = 0.33). ORR and Disease Control Rate (DCR) were observed in 31.6% and 60.7% of the patients, respectively, with the lowest ORRs confined in CHT pre-treated patients or in those who received the lowest DI of EVE. Grade 3-4 adverse events (AEs) were reported in 37.9% of the patients. Main AEs were: stomatitis (11.2%), non-infectious pneumonitis - NIP (3.8%), anaemia (3.8%) and fatigue (3.2%).
The EVA study provided new insights in the use of EVE-EVE combination in HR+ ABC pts many years after the publication of the pivotal trial. The combination is safe and the best response could be obtained in patients receiving the full dose of EVE and/or after hormone-therapy as Fulvestrant in ABC.
•In this real-life study, median duration of EVE-EXE combination was higher than that reported in the pivotal trial (31.0 vs. 14.6 weeks), with similar incidence of severe adverse events, namely stomatitis (11.2% vs. 8%) and non-infectious pneumonitis (3% vs. 3.8%).•Better selection of patients (visceral sites: 33.2% vs. 54%) and an appropriate management of adverse events can lead to a longer disease control.•Previous treatment with Fulvestrant doesn’t affect the efficacy of EVE-EXE combination; no difference was observed in terms of EVE exposure duration according to Dose Intensity (p for trend = 0.27), even if the lowest ORR was observed in those patients who received a median DI below or equal 5 mg per day.•The EVA study provides useful information for the selection of advanced breast cancer patients for whom EVE-EXE can represent a valid treatment option.
Abstract The Italian Tamoxifen Anastrozole (ITA) trial investigated the efficacy of switching to anastrozole for women who were already on adjuvant tamoxifen since 2–3 years. Relapse-free survival ...(RFS) was the primary end-point; event-free survival (EFS), overall survival (OS) and safety were secondary end-points. Herein, we report an update on the long term results of this trial. At a median follow-up time of 128 months (range14–168 months), 94 events have been recorded in the tamoxifen group compared with 71 events in the anastrozole group (hazard ratio (HR) = 0.71; 95% confidence interval (CI), 0.52–0.97; p = 0.03). RFS was also significantly longer in the anastrozole group (HR = 0.64; 95% CI, 0.44–0.94; p = 0.023); no statistically significant difference between study arms concerning OS was shown, but the trial was not powered enough in respect to this end-point. The incidence of serious adverse events (SAE) like bone fractures was comparable (four in each arm), while gynaecological problems were still significantly more numerous among the women continued on tamoxifen (21 patients developed a SAE in this group, including eight endometrial cancers, compared to three patients who suffered from a SAE, including one endometrial cancer, in the anastrozole group: p < 0.000). Present data confirm that switch is safe and can provide long-term gain in terms both of RFS and of EFS, which persists even several years since treatment discontinuation.
Background
Erythrocyte mean corpuscular volume (MCV) has been used for decades as a biomarker of chronic alcohol abuse and in the treatment of alcohol dependence. More recently, it has also been ...adopted to investigate the fitness of subjects to hold the driving license to prevent traffic accidents. So far, however, the studies on the association of MCV with an increased risk of alcohol‐associated car accidents are extremely scarce, if not totally absent. To the best of our knowledge, the present work is the first specifically aimed at studying a plausible association between elevated MCV and crash accidents correlated with alcohol abuse.
Methods
A total of 6,244 drivers involved in traffic accidents underwent mandatory laboratory analyses including blood alcohol concentration (BAC) determination and MCV analysis. BAC and MCV determinations were performed by headspace gas chromatography and complete blood count, respectively.
Results
The chi‐square test evaluating the proportions of subjects with elevated MCVs (>95 fl) yielded a highly significant result (χ2 = 68.0; p < 0.001) in the blood samples where the BAC was above the legal limit (i.e., >0.5 g/l). However, when considering only drivers showing BACs in the range of 0.51 to 1.5 g/l, the frequencies of elevated MCV values are fairly comparable (χ2 = 0.062, p = 0.80). In contrast, limiting the evaluation to BACs > 1.5 g/l, the frequency of elevated MCVs raised to 19.1% (χ2 = 58.9, p value < 0.001 vs. the group with BAC within the legal limits).
Conclusions
The present observations show that MCV increases are typically associated with drivers involved in accidents only if driving under severe alcohol intoxication, leading to a preliminary conclusion that, in the context of the certification of the fitness to the driving license, MCV fails to reveal individuals at risk who tend to drive in a condition of low‐to‐moderate alcohol intoxication.
Obesity is an independent adverse prognostic factor in early breast cancer patients, but it is still controversial whether obesity may affect adjuvant endocrine therapy efficacy. The aim of our study ...(ancillary to the two clinical trials Gruppo Italiano Mammella (GIM)4 and GIM5) was to investigate whether the circulating oestrogen levels during treatment with the aromatase inhibitor letrozole are related to body mass index (BMI) in postmenopausal women with breast cancer.
Plasma concentration of oestrone sulphate (ES) was evaluated by radioimmunoassay in 370 patients. Plasma samples were obtained after at least 6 weeks of letrozole therapy (steady-state time). Patients were divided into four groups according to BMI. Differences among the geometric means (by ANOVA and ANCOVA) and correlation (by Spearman's rho) between the ES levels and BMI were assessed.
Picomolar geometric mean values (95% confidence interval, n=patients) of circulating ES during letrozole were 58.6 (51.0-67.2, n=150) when BMI was <25.0 kg m(-2); 65.6 (57.8-74.6, n=154) when 25.0-29.9 kg m(-2); 59.3 (47.1-74.6, n=50) when 30.0-34.9 kg m(-2); and 43.3 (23.0-81.7, n=16) when ≥35.0 kg m(-2). No statistically significant difference in terms of ES levels among groups and no correlation with BMI were observed.
Body mass index does not seem to affect circulating oestrogen levels in letrozole-treated patients.
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