ABSTRACT
Multipartite virus genomes are composed of two or more segments, each packaged into an independent viral particle. A potential advantage of multipartitism is the regulation of gene expression through changes in the segment copy number. Soil-borne beet necrotic yellow vein virus (BNYVV) is a typical example of multipartism, given its high number of genomic positive-sense RNAs (up to five). Here we analyse the relative frequencies of the four genomic RNAs of BNYVV type B during infection of different host plants (Chenopodium quinoa, Beta macrocarpa and Spinacia oleracea) and organs (leaves and roots). By successfully validating a two-step reverse-transcriptase digital droplet PCR protocol, we show that RNA1 and -2 genomic segments always replicate at low and comparable relative frequencies. In contrast, RNA3 and -4 accumulate with variable relative frequencies, resulting in distinct RNA1â¯:â¯RNA2â¯:â¯RNA3â¯:â¯RNA4 ratios, depending on the infected host species and organ.
Subject(s)
Beta vulgaris , Plant Viruses , Genomics , Plant Viruses/genetics , Genome, Viral , RNAABSTRACT
The prognosis of patients affected by malignant pleural mesothelioma (MPM) is presently poor and no therapeutic strategies have improved their survival yet. Introduction of miRNA mimics to restore their reduced or absent functionality in cancer cells is considered an important opportunity and a combination of miR's might be even more effective. In the present study, miR-16 and miR-34a were transfected, singularly and in combination, in MPM cell lines H2052 and H28, and their effects on cell proliferation and sensitivity to cisplatin are reported. Interestingly, the overexpression of both miRs, alone or combined, slows down the cell cycle progression, modulates the p53 and HMGB1 expression and increases the sensitivity of cells to cisplatin, producing a marked impairment of cell proliferation and strengthening the apoptotic effect of the drug. However, the co-overexpression of the two miRs results more effective only in the regulation of the cell cycle, but does not enhance the sensitivity of MPM cells to cisplatin. Consequently, although the potential of miR-16 and miR-34a is confirmed, we must conclude that their combination does not improve the response of MPM to chemotherapy.
Subject(s)
Cisplatin/pharmacology , Mesothelioma, Malignant/genetics , MicroRNAs/metabolism , Pleural Neoplasms/genetics , Apoptosis/genetics , Cell Cycle/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Cisplatin/therapeutic use , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , HMGB1 Protein/genetics , Humans , Mesothelioma, Malignant/drug therapy , Mesothelioma, Malignant/pathology , MicroRNAs/genetics , Pleural Neoplasms/drug therapy , Pleural Neoplasms/pathology , Transfection , Tumor Suppressor Protein p53/geneticsABSTRACT
PURPOSE: Because the role of the primary tumour location in the adjuvant setting has not been clearly established in colon cancer, we analysed the clinical outcome according to the primary tumour location from three Italian trials assessing adjuvant therapy in colon cancer. PATIENTS AND METHODS: Overall survival (OS) and disease-free survival (DFS) were assessed globally and in each trial, according to right-sided, transverse and left-sided primary colon cancer. Analysis was planned to provide overall and stage-specific results. RESULTS: Individual data of 5239 patients were included in this analysis. The right-sided tumours were 1540 (29%), tumours originating in the transverse were 815 (16%) and left-sided tumours were 2884 (55%). At the multivariate analysis, DFS findings from the comparison of the right-sided versus left-sided tumours (hazard ratio [HR] = 1.00; 95% confidence interval [CI] = 0.89-1.14) were not statistically associated with clinical outcomes in the overall population. On the contrary, OS findings, from the comparison of the right-sided versus left-sided tumours, were significantly associated with outcomes (HR = 1.20; 95% CI = 1.04-1.39). In stage II patients, there was no difference in terms of DFS and OS among the three different tumour locations, whereas in stage III patients, the left-sided tumours showed an improved prognosis in terms of OS (HR: 1.36 95% CI = 1.14-1.62, p < 0.001). CONCLUSION: This is the largest analysis demonstrating a prognostic effect of the tumour location on patients with colon cancer receiving adjuvant chemotherapy. Nevertheless, the effect is limited to OS in stage III colon cancer. In stage II tumours, the primary location has a lesser impact. The transverse tumours should be prognostically considered in between the right-sided and left-sided tumours.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemotherapy, Adjuvant/mortality , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Adult , Aged , Chemotherapy, Adjuvant/methods , Colonic Neoplasms/mortality , Disease-Free Survival , Female , Humans , Male , Middle Aged , Neoplasm Staging , Prognosis , Randomized Controlled Trials as Topic , Treatment OutcomeSubject(s)
Venous Thromboembolism , Anticoagulants , Blood Coagulation , Hemorrhage , Humans , Thrombolytic Therapy , United StatesABSTRACT
Essentials The risk of bleeding influences the duration of anticoagulation (AC) after venous thromboembolism. We assessed the ACCP bleeding risk score in an inception-cohort of patients receiving AC. 53% were categorized at high-risk, but their bleeding rate was low during long-term AC. ACCP score had low predictive value for bleeding. SUMMARY: Background The American College of Chest Physicians (ACCP) guideline proposes a score to decide on extended anticoagulation after an unprovoked venous thromboembolism (VTE). Methods We investigated the ACCP score to predict bleeding risk in an inception cohort of 2263 patients on long-term anticoagulation (1522 treated with vitamin K antagonists [VKAs] and the remaining with direct oral anticoagulants [DOACs]) belonging to the Italian START2 Register. Results More than half the patients were categorized as high risk; nevertheless, a higher proportion received anticoagulation for > 1 year compared with those in the low-risk category. For 3130 years (median 12 [interquartile range 6, 24] months), 48 bleeding outcomes occurred (1.53%/year) in the cohort (1.7%/year and 0.95%/year in high- and low-risk categories, respectively). The c-statistic of the ACCP score was 0.55 (0.48-0.63), 0.50 (0.42-0.58) and 0.56 (0.48-0.64) in low-, moderate- and high-risk categories, respectively. The bleeding incidence was higher during the first 90 days of treatment (3.0%/year) than afterwards (1.2%/year; relative risk (RR), 2.5 [1.3-4.7]), and similar among the three categories. The bleeding rate was not different during the initial 3 months of treatment in patients receiving VKAs or DOACs; it was, however, lower in the latter patients in the subsequent period (0.5%/year vs. 1.4%/year, respectively). Conclusion The bleeding rate during extended treatment was rather low in our patients. ACCP score had insufficiently predictive value for bleeding and cannot be used to guide decisions on extended treatment. New prediction tools for bleeding risk during anticoagulant treatments (including DOACs) are required.
Subject(s)
Anticoagulants/adverse effects , Blood Coagulation/drug effects , Decision Support Techniques , Hemorrhage/chemically induced , Venous Thromboembolism/drug therapy , Administration, Oral , Aged , Anticoagulants/administration & dosage , Drug Administration Schedule , Female , Humans , Male , Predictive Value of Tests , Prospective Studies , Registries , Risk Assessment , Risk Factors , Time Factors , Treatment Outcome , Venous Thromboembolism/blood , Venous Thromboembolism/diagnosis , Vitamin K/antagonists & inhibitorsABSTRACT
Essentials Direct oral anticoagulants (DOACs) do not require laboratory monitoring currently. DOAC specific measurements were performed at trough in patients with atrial fibrillation. Patients who developed thromboembolic events showed lower DOAC plasma levels. This study supports the concept of measuring DOAC levels at steady state. SUMMARY: Background Direct oral anticoagulants (DOACs) are administered at fixed doses without the need for dose adjustment according to laboratory testing. High interindividual variability in drug blood levels has been shown with all DOACs. To evaluate a possible relationship between DOAC C-trough anticoagulant levels and thromboembolic events, 565 consecutive naive patients with atrial fibrillation (AF) were enrolled in this study performed within the START Laboratory Registry. Methods DOAC-specific measurements (diluted thrombin time or anti-activated factor II calibrated for dabigatran; anti-activated FX calibrated for rivaroxaban or apixaban) at C-trough were performed locally at steady state within 15-25 days after the start of treatment. For each DOAC, the interval of C-trough levels, from the limit of quantification to the highest value, was subdivided into four equal classes, and results were attributed to these classes; the median values of results were also calculated. Thromboembolic complications occurring during 1 year of follow-up were recorded. Results Thromboembolic events (1.8%) occurred in 10 patients who had baseline C-trough levels in the lowest class of drug levels. The incidence of thromboembolic events among patients with DOAC C-trough levels in the lowest level class was 2.4%, and that in the remaining groups was 0%. The patients with thrombotic complications also had a higher mean CHA2 DS2 -VASc score than that of the total patient population: 5.3 (95% confidence interval [CI] 4.3-6.3 versus 3.0 (95% CI 2.9-3.1). Conclusion In this study cohort, thrombotic complications occurred only in DOAC-treated AF patients who had very low C-trough levels, with a relatively high CHA2 DS2 -VASc score. Larger studies are warranted to confirm these preliminary observations.
Subject(s)
Antithrombins/administration & dosage , Antithrombins/blood , Atrial Fibrillation/drug therapy , Drug Monitoring/methods , Factor Xa Inhibitors/administration & dosage , Factor Xa Inhibitors/blood , Thromboembolism/prevention & control , Administration, Oral , Adult , Aged , Aged, 80 and over , Antithrombins/adverse effects , Atrial Fibrillation/blood , Atrial Fibrillation/complications , Atrial Fibrillation/diagnosis , Blood Coagulation Tests , Dabigatran/administration & dosage , Dabigatran/adverse effects , Dabigatran/blood , Factor Xa Inhibitors/adverse effects , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Preliminary Data , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyrazoles/blood , Pyridones/administration & dosage , Pyridones/adverse effects , Pyridones/blood , Registries , Risk Assessment , Risk Factors , Rivaroxaban/administration & dosage , Rivaroxaban/adverse effects , Rivaroxaban/blood , Thromboembolism/blood , Thromboembolism/diagnosis , Thromboembolism/etiology , Time Factors , Treatment OutcomeABSTRACT
INTRODUCTION: Several specific assays are commercially available to determine dabigatran anticoagulant activity. Aims of this multicenter and multiplatform study were to compare five methods for dabigatran measurement and investigate their performances in the low concentration range. METHODS: Dabigatran levels were analyzed in 295 plasma samples from patients enrolled in the START-Laboratory Register by the following methods using dedicated calibrators and controls: STA-ECA II (Diagnostica Stago), standard and low range Hemoclot Thrombin Inhibitors (Hyphen BioMed), Direct Thrombin Inhibitor Assay (Instrumentation Laboratory), Direct Thrombin Inhibitor Assay (Siemens), Technoclot DTI (Technoclone). RESULTS: Methods showed variable agreement with the Hemoclot Thrombin Inhibitors assay used as reference test, with modest under- or overestimations (Bland-Altman bias from -17.3 to 4.0 ng/mL). Limits of detection and quantification varied depending on the assay (4-52 and 7-82 ng/mL, respectively). Between-run precision and accuracy were good for all methods for both quality control levels. Assay's repeatability assessed at very low dabigatran concentrations (from 10 to 60 ng/mL) was also acceptable, variability generally increased at lower drug levels. CONCLUSION: The five dabigatran-specific assays evaluated in this study provided reliable assessment of dabigatran plasma levels, although showing different performances.
Subject(s)
Blood Coagulation Tests/methods , Dabigatran/blood , Antithrombins , Humans , Limit of Detection , Quality Control , Reproducibility of ResultsABSTRACT
Essentials The role of cerebral venous thrombosis (CVT) recanalization on neurologic outcome is still debated. We studied a large cohort of 508 CVT patients with 419 patient years of radiological follow-up. Recanalization rate is high during the first months after CVT and neurologic outcome is favorable. High recanalization grade of CVT independently predicts good neurological outcome. SUMMARY: Background Studies with limited sample size and with discordant results described the recanalization time-course of cerebral venous thrombosis (CVT). The neurological outcome after a first episode of CVT is good, but the role of recanalization on neurological dependence is still debated. Objectives The aim of the study is to assess the recanalization rate after cerebral venous thrombosis (CVT) and its prognostic role in long-term neurological outcome. Patients/Methods In a retrospective observational multicenter cohort study, patients with an acute first episode of CVT with at least one available imaging test during follow-up were enrolled. Patency status of the vessels was categorized as complete, partial or not recanalized. Neurological outcome was defined using the modified Rankin scale (mRS) as good (mRS = 0-1) or poor (mRS = 2-6). Results Five-hundred and eight patients (median [IQR] age, 39 [28.5-49] years; 26% male) were included. Complete or partial recanalization was not differently represented in patients undergoing scans at different periods of time (from 28-day to 3 month-period up to a 1-3 year-period). mRS at the time of follow-up imaging was available in 483 patients; 92.8% of them had a mRS of 0-1. CVT recanalization (odds ratio [OR], 2.56; 95% confidence interval [CI], 1.59-4.13) was positively associated, whereas cancer (OR, 0.29; 95% CI, 0.09-0.88), and personal history of venous thromboembolism (VTE) (OR, 0.36; 95% CI, 0.14-0.92) were negatively associated as independent predictors of favorable (mRS = 0-1) outcome at follow-up. Conclusions Most patients with a first CVT had complete or partial recanalization at follow-up. Recanalization was independently associated with a favorable neurological outcome.
Subject(s)
Intracranial Thrombosis/surgery , Neurosurgical Procedures , Venous Thrombosis/surgery , Adult , Cerebral Angiography/methods , Cerebrovascular Circulation , Computed Tomography Angiography/methods , Disability Evaluation , Female , Humans , Intracranial Thrombosis/diagnostic imaging , Intracranial Thrombosis/physiopathology , Magnetic Resonance Angiography/methods , Male , Middle Aged , Neurosurgical Procedures/adverse effects , Phlebography/methods , Recovery of Function , Retrospective Studies , Time Factors , Treatment Outcome , Vascular Patency , Venous Thrombosis/diagnostic imaging , Venous Thrombosis/physiopathologyABSTRACT
Essentials Predicting recurrences may guide therapy after unprovoked venous thromboembolism (VTE). We evaluated the DASH score in 827 patients with unprovoked VTE to verify prediction accuracy. A DASH score ≤ 1 had a cumulative recurrence risk at 1 year of 3.6%, as predicted by the model. The DASH score performed better in younger (< 65 years old) subjects. SUMMARY: Background The DASH prediction model has been proposed as a guide to identify patients at low risk of recurrence of venous thromboembolism (VTE), but has never been validated in an independent cohort. Aims To validate the calibration and discrimination of the DASH prediction model, and to evaluate the DASH score in a predefined patient subgroup aged > 65 years. Methods Patients with a proximal unprovoked deep vein thrombosis (DVT) or pulmonary embolism (PE) who received a full course of vitamin K antagonist or direct oral anticoagulant (> 3 months) and had D-dimer measured after treatment withdrawal were eligible. The DASH score was computed on the basis of the D-dimer level after therapy withdrawal and personal characteristics at the time of the event. Recurrent VTE events were symptomatic proximal or distal DVT/PE, and were analyzed with a time-dependent analysis. Observed 12-month and 24-month recurrence rates were compared with recurrence rates predicted by the DASH model. Results We analyzed a total of 827 patients, of whom 100 (12.1%) had an objectively documented recurrence. As compared with the original DASH cohort, there was a greater proportion of subjects with a 'low-risk' (≤ 1) DASH score (66.3% versus 51.6%, P < 0.001). The slope of the observed versus expected cumulative incidence at 2 years was 0.71 (95% confidence interval 0.51-1.45). The c-statistic was lower for subjects aged > 65 years (0.54) than for younger subjects (0.72). Conclusions These results confirm the validity of DASH prediction model, particularly in young subjects. The recurrence risk in elderly patients (> 65 years) was, however, > 5% even in those with the lowest DASH scores.
Subject(s)
Pulmonary Embolism/diagnosis , Venous Thromboembolism/diagnosis , Venous Thrombosis/diagnosis , Administration, Oral , Adult , Age Factors , Aged , Anticoagulants/administration & dosage , Biomarkers/blood , Decision Support Techniques , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Incidence , Italy/epidemiology , Male , Middle Aged , Predictive Value of Tests , Pulmonary Embolism/blood , Pulmonary Embolism/drug therapy , Pulmonary Embolism/epidemiology , Recurrence , Reproducibility of Results , Retrospective Studies , Risk Assessment , Risk Factors , Time Factors , Treatment Outcome , Venous Thromboembolism/blood , Venous Thromboembolism/drug therapy , Venous Thromboembolism/epidemiology , Venous Thrombosis/blood , Venous Thrombosis/drug therapy , Venous Thrombosis/epidemiologyABSTRACT
Essentials Prothrombin and partial thromboplastin time (PT/PTT) measure direct oral anticoagulants (DOACs). PT, PTT and specific tests for DOACs were performed on patients treated for atrial fibrillation. Normal PT/PTT don't exclude DOAC activity and their prolongation doesn't confirm DOAC action. The use of PT or PTT to evaluate DOAC activity could cause dangerous misinterpretations. SUMMARY: Background Prothrombin time (PT) and activated partial thromboplastin time (APTT) have been proposed to measure the effect of oral anti-activated factor X (FXa) or anti-activated FII drugs, respectively. Aims To evaluate the relationships and responsiveness of PT and APTT versus direct oral anticoagulant (DOAC) concentrations measured with specific coagulation tests performed with different platforms in four Italian anticoagulation clinics. Methods Six hundred and thirty-five patients with atrial fibrillation participated in the study: 240 were receiving dabigatran, 264 were receiving rivaroxaban, and 131 were receiving apixaban. Blood was taken at trough and peak within the first month (15-25 days) of treatment. PT, APTT, diluted thrombin time (dTT) calibrated for dabigatran and anti-FXa calibrated for rivaroxaban or apixaban were determined. Results For dabigatran, the correlation between APTT and dTT ranged from r = 0.80 to r = 0.62. For rivaroxaban, the correlation between the anti-FXa assay and PT ranged from r = 0.91 to r = 0.73. For apixaban, the correlation between the anti-FXa assay and PT was lower than for the two other drugs (r = 0.81 to r = 0.54). Despite the above significant correlations, the responsiveness of PT or APTT was relatively poor. A discrepancy between global testing and DOAC plasma concentrations was shown in a considerable proportion of patients, depending on the platform and drug, with values ranging from 6% to 62%. Conclusions Overall, poor responsiveness of the screening tests to DOAC concentrations was observed. PT and APTT normal values cannot exclude DOAC anticoagulant activity, and PT or APTT prolongation is not always associated with DOAC anticoagulant effect as determined with specific tests.
Subject(s)
Anticoagulants/therapeutic use , Atrial Fibrillation/drug therapy , Factor Xa Inhibitors/therapeutic use , Partial Thromboplastin Time , Prothrombin Time , Administration, Oral , Antithrombins/adverse effects , Blood Coagulation/drug effects , Blood Coagulation Tests/methods , Calibration , Dabigatran/administration & dosage , Dabigatran/therapeutic use , Factor Xa/chemistry , Factor Xa Inhibitors/adverse effects , Female , Humans , Italy , Male , Pyrazoles/administration & dosage , Pyrazoles/therapeutic use , Pyridones/administration & dosage , Pyridones/therapeutic use , Regression Analysis , Rivaroxaban/administration & dosage , Rivaroxaban/therapeutic use , Thrombin Time , Treatment OutcomeABSTRACT
INTRODUCTION: Idiopathic venous thromboembolism (VTE) is associated with the risk of cancer but the risk factors for cancer development in such patients are still uncertain. AIM: To assess risk factors for the development of cancer after a standard course of anticoagulation in patients with first episode of idiopathic VTE. MATERIALS AND METHODS: Subjects were enrolled in the three large prospective multicentre studies: PROLONG (NEJM 2006) PROLONG II (Blood 2010) and DULCIS (Blood 2014). Women whose index event was hormone related were excluded from the analysis. The development of cancer was recorded during a 2-year follow-up. RESULTS: 1,805 patients were enrolled (M/F: 510/453), mean age: 62, median: 67; range:18-87 years). Cancer developed in 55 patients (3% ; 1.7% pt-years) of whom 15 (2.0%; 1.1% pt-years) had PE with or without DVT and 40 (3.8%; 2.1% pt-years) had DVT without PE (p=0.03). The development of cancer was associated with DVT without PE (HR:1.8; 95% CI: 1.1-3.3) and age >65 (HR: 2.5; 95%: 1.3-4.9). Among patients with DVT, with or without PE, the development of cancer was associated with the presence of residual vein obstruction>4mm (RVO) at compression ultrasound (HR: 1.8, 95% CI: 1.1-3.3) and age>65 (HR: 2.8; 95% CI: 1.3-6.2). CONCLUSIONS: Age>65 years, DVT without PE and the presence of RVO are significantly associated with the risk of developing cancer after a first episode of idiopathic VTE over a two-year follow-up.
ABSTRACT
INTRODUCTION: D-dimer assay, generally evaluated according to cutoff points calibrated for VTE exclusion, is used to estimate the individual risk of recurrence after a first idiopathic event of venous thromboembolism (VTE). METHODS: Commercial D-dimer assays, evaluated according to predetermined cutoff levels for each assay, specific for age (lower in subjects <70 years) and gender (lower in males), were used in the recent DULCIS study. The present analysis compared the results obtained in the DULCIS with those that might have been had using the following different cutoff criteria: traditional cutoff for VTE exclusion, higher levels in subjects aged ≥60 years, or age multiplied by 10. RESULTS: In young subjects, the DULCIS low cutoff levels resulted in half the recurrent events that would have occurred using the other criteria. In elderly patients, the DULCIS results were similar to those calculated for the two age-adjusted criteria. The adoption of traditional VTE exclusion criteria would have led to positive results in the large majority of elderly subjects, without a significant reduction in the rate of recurrent event. CONCLUSION: The results confirm the usefulness of the cutoff levels used in DULCIS.
Subject(s)
Fibrin Fibrinogen Degradation Products , Venous Thromboembolism/blood , Venous Thromboembolism/diagnosis , Aged , Aged, 80 and over , Anticoagulants/therapeutic use , Female , Humans , Male , Middle Aged , Recurrence , Reference Values , Risk Factors , Venous Thromboembolism/drug therapyABSTRACT
The aim of this work was to evaluate the oxidative damage to nucleic acids in children (5-11 years) associated with exposure to environmental pollutants and tobacco smoke (ETS). For each subject, urinary sampling was done twice (evening and next morning) to measure by tandem LC-MS-MS such oxidated products of nucleic acids as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo), 8-oxo-7,8-dihydroguanosine (8-oxoGuo), and 8-oxo-7,8-dihydroguanine (8-oxoGua). Methyl tert-butyl ether (U-MTBE), benzene (U-Benz), and its metabolites (t,t-muconic and S-phenylmercapturic acids, t,t-MA and S-PMA, respectively) were determined as biomarkers of exposure to air pollution, and cotinine as a biomarker of exposure to ETS. Biomarkers of exposure (S-PMA and U-MTBE) and of DNA oxidation (8-oxodGuo) were dependent on the urbanization and industrialization levels and increased in the evening sample as compared to next morning (p<0.05). In both evening and next morning samples, 8-oxodGuo and 8-oxoGuo correlated with each other (r=0.596 and r=0.537, respectively, p<0.01) and with biomarkers of benzene exposure, particularly S-PMA (r=0.59 and r=0.45 for 8-oxodGuo and r=0.411 and r=0.383 for 8-oxoGuo, p<0.01). No such correlations were observed for U-MTBE and cotinine. Multiple linear regression analyses showed that 8-oxodGuo was positively associated with S-PMA at both sampling times (ß=0.18 and ß=0.14 for evening and next morning sampling, respectively; p<0.02) and weakly with U-MTBE (ß=0.07, p=0.020) only in the evening urines. These results suggest that the selected biomarkers of exposure to benzene, particularly S-PMA, are good tracers of exposure to complex mixtures of oxidative pollutants and that the associated oxidative damage to nucleic acids is detectable even at very low levels of exposure.
Subject(s)
Air Pollutants/toxicity , Benzene/toxicity , 8-Hydroxy-2'-Deoxyguanosine , Acetylcysteine/analogs & derivatives , Acetylcysteine/urine , Air Pollutants/urine , Biomarkers/urine , Child , Child, Preschool , Cotinine/urine , DNA/metabolism , DNA Damage , Deoxyguanosine/analogs & derivatives , Deoxyguanosine/urine , Environmental Monitoring , Female , Guanine/analogs & derivatives , Guanine/urine , Guanosine/analogs & derivatives , Guanosine/urine , Humans , Male , Methyl Ethers/urine , Oxidation-Reduction , SicilyABSTRACT
BACKGROUND: The treatment of splanchnic vein thrombosis (SVT) is challenging, due to the increased risk of bleeding and potentially life-threatening complications. Current recommendations are based on evidence from the treatment of venous thrombosis in usual sites, but small observational studies in SVT population suggest that the bleeding risk may offset the benefit of anticoagulant treatment in this setting. The aim of this study was to evaluate the safety of vitamin K antagonists (VKAs) in SVT patients. METHODS: We retrospectively included SVT patients treated with VKAs followed by 37 Italian anticoagulation clinics, until June 2013. The primary outcome was the incidence of major bleeding (MB), according to the ISTH definition, during VKA treatment. Vascular events, including both arterial and venous thrombosis, and mortality were also documented. RESULTS: Three hundred and seventy-five patients were included (median age 53 years; 54.7% males). During a median VKA treatment duration of 1.98 years, 15 MB events occurred, corresponding to an incidence rate of 1.24 (95% confidence interval [CI], 0.75-2.06) per 100 patient-years. Gastrointestinal bleeding represented 40% of all MB events. At multivariate analysis, the presence of esophageal varices emerged as independent predictor of MB (hazard ratio 5.4; 95% CI, 1.4-21.1). The incidence rate of vascular events on treatment was 1.37 (95% CI, 0.84-2.23) per 100 patient-years and the mortality rate was 0.83 (95% CI, 0.44-1.54) per 100 patient-years. CONCLUSIONS: Selected SVT patients followed by anticoagulation clinics for the management of VKA treatment show a low rate of major bleeding and vascular events.
Subject(s)
Anticoagulants/administration & dosage , Splanchnic Circulation , Venous Thrombosis/drug therapy , Vitamin K/antagonists & inhibitors , Administration, Oral , Adolescent , Adult , Aged , Aged, 80 and over , Anticoagulants/adverse effects , Chi-Square Distribution , Esophageal and Gastric Varices/mortality , Female , Gastrointestinal Hemorrhage/chemically induced , Gastrointestinal Hemorrhage/mortality , Humans , Incidence , Italy/epidemiology , Kaplan-Meier Estimate , Male , Middle Aged , Multivariate Analysis , Patient Safety , Proportional Hazards Models , Retrospective Studies , Risk Factors , Time Factors , Treatment Outcome , Venous Thrombosis/diagnosis , Venous Thrombosis/mortality , Venous Thrombosis/physiopathology , Young AdultABSTRACT
BACKGROUND: In order to stratify patients with a first unprovoked venous thromboembolism (VTE) according to their recurrence risk and to identify those who would actually benefit from indefinite anticoagulation, three prediction models have been developed so far; none of them has been yet externally validated. OBJECTIVE: To externally validate the Vienna Prediction Model (VPM), a prediction guide for estimating the recurrence risk after a first unprovoked VTE developed through Cox modeling and including sex, D-dimer and index VTE site as predictors. PATIENTS/METHODS: Nine hundred and four patients pooled from five prospective studies evaluating the prognostic value of D-dimer for VTE recurrence served as the validation cohort. The validity of the VPM in stratifying patients according to their relative recurrence risk (discrimination) and in predicting the absolute recurrence risk (calibration) was tested with survival analysis methods. RESULTS: The ability of the VPM to distinguish patients' risk for recurrent VTE in the validation cohort was at least as good as in the original cohort, with a calibration slope of 1.17 (95% confidence interval 0.71-1.64; P = 0.456 for the hypothesis of a significant difference from 1), and a c-statistic of 0.626 (vs. 0.651 in the original derivation cohort). The VPM absolute predictions in terms of cumulative rates tended to underestimate the observed recurrence rates at 12 months. CONCLUSIONS: By using a pooled individual patient database as a validation cohort, we confirmed the ability of the VPM to stratify patients with a first unprovoked VTE according to their risk of recurrence.
Subject(s)
Venous Thromboembolism/epidemiology , Cohort Studies , Female , Humans , Male , Middle Aged , Recurrence , Risk FactorsABSTRACT
Lung cancer is one of the most frequently diagnosed cancers worldwide and is still the leading cause of cancer-related deaths. There is a considerable interest in finding diagnostic methods in the disease's earliest stages. A complementary approach to imaging techniques could be provided by exhaled breath gas phase and exhaled breath condensate (EBC) analysis. The aim of this study was to quantify various biomarkers in the exhaled breath gas phase and EBC in suspected cases of non-small-cell lung cancer (NSCLC). The study involved 138 subjects with suspected lung cancer, 71 of whom had a subsequent diagnosis of NSCLC. The diagnostic power of a combination of hydrogen peroxide (H2O2)-EBC, and exhaled pentane, 2-methyl pentane, hexane, ethyl benzene, heptanal, trans-2-nonenal in distinguishing NSCLC and non-NSCLC subjects was poor-to-fair (area under the curve (AUC) = 0.68), similar to that of smoking history alone (expressed as pack-years, AUC = 0.70); a further improvement was observed when smoking history was combined with exhaled compounds (AUC = 0.80). The diagnostic power was increased in those patients with little or no past smoke exposure (AUC = 0.92) or where past smoke exposure was up to 30 pack-years (AUC = 0.85). Exhaled substances had a good accuracy in discriminating suspected cancerous cases only in those subjects with a modest smoking history (≤ 30 pack-years), but the inclusion of other exhaled biomarkers may increase the overall accuracy, regardless of tobacco smoke.
Subject(s)
Breath Tests/methods , Carcinoma, Non-Small-Cell Lung/diagnosis , Exhalation , Lung Neoplasms/diagnosis , Aged , Aldehydes/analysis , Area Under Curve , Biomarkers/analysis , Confidence Intervals , Cross-Sectional Studies , Female , Humans , Hydrogen Peroxide/analysis , Logistic Models , Male , Middle Aged , Multivariate Analysis , ROC CurveABSTRACT
BACKGROUND: Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. PATIENTS AND METHODS: Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m(2) day 1, LV 100 mg/m(2) as 2 h infusion and 5-FU 400 mg/m(2) as bolus, days 1 and 2 followed by 600 mg/m(2)/day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). RESULTS: From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85-1.17; P = 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82-1.18; P = 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. CONCLUSIONS: A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01640782.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Camptothecin/analogs & derivatives , Stomach Neoplasms/drug therapy , Camptothecin/administration & dosage , Chemotherapy, Adjuvant , Cisplatin/administration & dosage , Combined Modality Therapy , Docetaxel , Fluorouracil/administration & dosage , Humans , Leucovorin/administration & dosage , Stomach Neoplasms/surgery , Taxoids/administration & dosageABSTRACT
BACKGROUND: The optimal duration of anticoagulant treatment after venous thromboembolism (VTE) should be evaluated in relation to bleeding risk. This assessment is particularly difficult with elderly patients, because of their increased risk of both recurrences and hemorrhages. Bleeding risk stratification models have been proposed, but their predictive ability in very elderly patients is unknown. We aimed to assess six bleeding stratification models in this setting, by using information available in our dataset. PATIENTS AND METHODS: Patients aged ≥ 80 years receiving vitamin K antagonists (VKAs) for the secondary prevention of VTE were eligible for this prospective cohort study. All patients were followed at Italian anticoagulation clinics for monitoring of VKA treatment. Risk factors for bleeding were collected, and major bleeding events and mortality were documented during follow-up. The association of bleeding events with the available risk factors was tested by means of Cox regression analysis; the c-statistic was used to quantify the predictive validity of the classification schemes. RESULTS: A total of 1078 patients (37.2% males; mean age, 84 years) were enrolled in the study, for a total observation period of 1981 patient-years. The rate of major bleeding was 2.4 per 100 patient-years (47 events; one was fatal). The mortality rate was 5.2 per 100 patient-years. None of the considered risk factors were significantly associated with bleeding events. The predictive validity of the risk stratification models was low, and the most accurate model was not specifically developed for VTE patients (HEMORR2 HAGES, c-statistic 0.60, 95% confidence interval 0.49-0.70). CONCLUSIONS: Bleeding risk stratification models appear to have little accuracy in very elderly VTE patients.