An age‐adapted approach for the use of D‐dimers in the exclusion of deep venous thrombosis

A normal D‐dimer (DD) concentration for the exclusion of deep venous thrombosis (DVT) has a low specificity in older patients and compression ultrasonography is often required. Three D‐dimer assays, STA Liatest, Tina‐quant, and Innovance, are evaluated in symptomatic outpatients suspected for DVT with emphasis on its performance in older patients by using different cut‐off levels. This study includes 466 outpatients suspected for having DVT. The diagnostic accuracy, measured as sensitivity and area under the curve of the receiver operation characteristic curve is good for all DD assays. The specificity of the DD assays combined with a low pretest probability varies from 42.6 to 51.5%. The specificity of the three DD assays in patients ≥60 years varies, however, between 24.6 and 40.9%. Several cut‐off values in different age‐subgroups are studied. For patients <60 years, the most accurate cut‐off value is 500 μg/L for all DD assays. For patients ≥60 years, a threshold of 750 μg/L has the best results with NPV of 100% for all assays and specificity of 48.5% (STA Liatest), 60.6% (Tina‐quant), and 49.2% (Innovance), respectively. For the three assays, the number needed to test (NNT) decreases in both subgroups of patients compared to the standard algorithm. A cut‐off level of 750 μg/L for patients ≥60 years improves the clinical performance of DD assays in combination with the PTP score without the loss of NPV. The NNT improves substantially with an age‐adapted algorithm. Am. J. Hematol., 2009. © 2009 Wiley‐Liss, Inc.     

Optimization of the diagnostic management of clinically suspected pulmonary embolism in hospitalized patients

Identical diagnostic algorithms for suspected pulmonary embolism (PE) are used for hospitalized patients and outpatients, while D‐dimer levels, risk factors and pre‐test probability for PE differ, and the percentage of patients managed without computerized tomography pulmonary angiography (CTPA) is lower in hospitalized patients. We aimed to improve the efficiency of the diagnostic algorithm by increasing the threshold of the D‐dimer, the threshold of the Wells rule and by adjustments of the Wells rule. Six‐hundred and twenty‐four hospitalized patients from two previously performed management studies with a PE prevalence of 26% were studied. Adjustments were considered to be safe when the failure rate remained <2%. By applying standard management, 8% (49/624) were managed without CTPA with a failure rate of 0·0% (0/49; 95% confidence interval [CI] 0·0–7·3), and it was 1·7% (8/465; 95%CI 0·8–3·4) for all patients in whom PE was excluded at baseline. All evaluated adjustments resulted in an increase of the failure rate with very small improvements of the efficiency. Given these potentially small improvements and the increasing complexity of clinical practice if adjusted diagnostic algorithms for specific patient categories were introduced, we do not recommend further evaluation of any of the adjustments; we recommend that the standard diagnostic algorithm should continue to be applied.     

Recent developments in the diagnosis and treatment of pulmonary embolism

Due to the nonspecific symptoms of the condition, a diagnosis of acute pulmonary embolism (PE) is frequently considered. However, PE will only be confirmed in 10–20% of patients. Because the imaging test of choice, computed tomography pulmonary angiography (CTPA), is costly and associated with radiation exposure and other complications, a validated diagnostic algorithm consisting of a clinical decision rule and D‐dimer test should be used to safely exclude PE in 20–30% of patients without the need for CTPA. Recently, the age‐adjusted D‐dimer threshold has been validated, and this has increased the proportion of patients at older age in whom PE can be excluded without CTPA. Initial therapeutic management of PE depends on the risk of short‐term PE‐related mortality. Haemodynamically unstable patients should be closely monitored and receive thrombolytic therapy unless contraindicated because of an unacceptably high bleeding risk, whereas patients with low‐risk PE may be safely discharged early from hospital or receive only outpatient treatment. The PESI score and Hestia decision rule are available to select patients in whom early discharge or outpatient treatment will be safe, although the safety of these strategies should be confirmed in additional studies. Standard PE therapy consists of low molecular weight heparin (LMWH) followed by vitamin K antagonists (VKAs). Recently, several nonvitamin K‐dependent oral anticoagulants have been shown to be as effective as LMWH/VKAs, and maybe safer. Determining the optimal duration of treatment for a first unprovoked PE remains a challenge, although clinical prediction rules for estimating the risk of recurrence of venous thromboembolism and anticoagulation‐associated haemorrhage are under investigation. Using these prediction rules may lead to both more standardized and more individualized long‐term treatment of PE.     

Elevated d‐Dimer Level is a Risk Factor for Coronary Artery Lesions Accompanying Intravenous Immunoglobulin‐Unresponsive Kawasaki Disease

Although there are many reports on the resistance of Kawasaki disease (KD) to initial intravenous immunoglobulin (IVIg) therapy, risk factors for coronary artery lesions in such cases remain to be established. The objective of this study was to explore when additional therapies should be administered and to identify factors helpful for selecting a therapeutic option. Based on their written clinical records, we performed a retrospective review of KD patients who did not respond to initial IVIg therapy and who therefore then underwent plasma exchange (PE) therapy. This was a case‐control study to compare the presence or absence of acute coronary lesions in patients treated by PE for IVIg‐unresponsive KD at Yokohama City University Hospital or at Yokohama City University Medical Center. Fifteen of 44 patients had acute coronary artery lesions (CAL) correlating with high levels of white blood cells (WBC) (P = 0.045), d ‐dimer (P = 0.008), and fibrin/fibrinogen degradation products (P = 0.009) and lower levels of fibrinogen (P = 0.013) prior to PE therapy. There was a strong correlation between pre‐PE levels of albumin and d ‐dimer (Pearson's correlation coefficient of 0.610). Multivariate analyses revealed that the odds ratio for CAL when d ‐dimer was ≥ 4.5 μg/mL was 25.06 (95% CI, 2.56–244.91, P = 0.006). d ‐dimer elevation and albumin decline in IVIg‐unresponsive KD patients could be risk factors for acute CAL, suggesting the possibility that angitis has spread throughout the arterial system, as far as the coronary artery.     

Transthoracic Sonography in Comparison to Multislice Computed Tomography in Detection of Peripheral Pulmonary Embolism

The aim of the study was to compare transthoracic sonography (TS) with multislice computed tomography (MSCT) in the detection of peripheral pulmonary embolism (PE). In addition, the study verified peripheral parenchymal findings visualized by TS and MSCT. A total of 33 patients (16 females, 17 males; mean age = 65.4 years) with symptoms of suspected PE were enrolled in the study. TS and MSCT were undertaken within 24 h of the beginning of clinical PE signs. Ten patients suffered from PE as visualized by MSCT. The sensitivity of TS for detecting PE was 70.0% and the specificity was 69.6%. Preferentially, PE and peripheral parenchymal findings were situated in the lower lobes. Oligemia was the main parenchymal alteration detected by MSCT. TS demonstrated that wedge-shaped consolidations were frequently associated with PE. In addition, localized pleural effusion was a typical finding in the presence of PE for both TS and MSCT. TS had moderate sensitivity and specificity compared with MSCT. Furthermore, the study revealed that PE is often associated with peripheral parenchymal changes, both of which are detectable by TS and MSCT. In case of contraindication with MSCT, TS is a potential technique for diagnosing PE-related parenchymal findings and can serve as an alternative method in the diagnosis of PE. However, a negative result with TS does not rule out a PE.     

Long‐term results of high‐dose imatinib in children and adolescents with chronic myeloid leukaemia in chronic phase: the Italian experience

Imatinib mesylate (IM) is used for the management of childhood chronic myeloid leukaemia (CML). The most effective dosage of IM and its long‐term efficacy in children are not well defined. The purpose of this multicentre study is to report on the long‐term results of high‐dose IM (340 mg/m²/d) in CML patients in chronic phase (CP‐CML) aged <18 years at diagnosis. A total of 47 CP‐CML patients with a median age at diagnosis of 11 years 9 months were enrolled in nine Italian centres. Complete cytogenetic response was achieved in 91·5% of the evaluable patients at a median time of 6 months. BCR‐ABL1 International Scale ≤ 0·1% (major molecular response; MMR) and ≤0·01% (molecular response; MR) at 12 months were 66·6% and 33%, respectively. During follow‐up, MMR and MR were achieved in 78·6% and 61% of children, respectively. IM was safely discontinued in 3 long‐term treated children with a durable MR. Twelve patients (eight cytogenetic/molecular responders) underwent stem cell transplantation. The progression‐free survival probabilities at 96 months for responding patients who continued IM and for those transplanted were 60% and 50%, respectively. After a median follow‐up of 52 months (range 3–146), all patients are alive . High‐dose IM is a long‐term effective therapy in children and adolescents with CP‐CML.     

Evaluation of an automated latex D‐dimer immunoassay in the clinical assessment of suspected venous thromboembolism

Because the reliability of clinical signs in venous thromboembolism (VTE) is poor, a highly sensitive, non‐invasive test may improve the selection of patients requiring further investigation. We assessed the sensitivity and negative predictive value of an automated D ‐dimer latex immunoassay (IL‐Test?) in 68 patients presenting with suspected VTE. The plasma D ‐dimer concentration was estimated and an appropriate diagnostic radiological investigation performed. Control values were obtained from healthy young and elderly volunteers. Using a cut‐off value of 330 ng/ml, the assay had a sensitivity of 100% and negative predictive value of 100% for VTE. We conclude that the IL‐Test^TM. automated D ‐dimer assay has a suitably high sensitivity and adequate negative predictive value to be included in a pre‐test clinical probability protocol for the evaluation of patients with suspected VTE.     

Effects of 18 months of l-T4 replacement in women with subclinical hypothyroidism

Context Some of the cardiovascular and renal abnormalities seen in overt hypothyroidism have also been reported in subclinical hypothyroidism (SCH). Short‐term l ‐T4 replacement in SCH improves cardiovascular risk markers and reduces carotid intima‐media thickness (CIMT), a surrogate marker of atherosclerosis. The haemodynamic and renal effects of l ‐T4 replacement in SCH are poorly understood. Objectives To compare cardiovascular risk factors and renal variables in women with SCH and normal women. To study the effects of l ‐T4 replacement in SCH subjects on these variables and on structural and functional changes in common carotid and brachial arteries. Design Fifty‐six women with SCH before and after l ‐T4 replacement for 18 months and 56 normal women of similar age distribution were studied. Blood Pressure (BP), plasma lipids and homocysteine were measured and renal function evaluated [estimation of glomerular filtration rate (eGFR) using standard equations and measurement of serum Cystatin‐C] in women with SCH before and after 18 months of l ‐T4, and in healthy women. CIMT and endothelial function (using brachial artery ultrasound) were studied before and after l‐ T4 in a subgroup of women with SCH. Results Systolic and diastolic BP, total cholesterol, triglyceride, LDL‐cholesterol, lipoprotein(a) and homocysteine were greater in SCH (P < 0·05), and following l‐ T4 replacement decreased (P < 0·05) to levels that no longer differed from normal subjects. Estimated GFR was reduced and serum Cystatin‐C increased (P < 0·05) in SCH. These variables also normalized following l ‐T4. Following l ‐T4 replacement the carotid artery baseline diameter increased by 7·1% and CIMT decreased by a mean value of 13%, while brachial artery diameter increased basally by 12·5% and following endothelium‐dependent vasodilatation by 17·5% (P < 0·05). However, the increment following reactive hyperaemia did not differ before or following l‐ T4 replacement. Conclusion Normalization of cardiovascular risk factors following l‐ T4 replacement in SCH potentially explains reduced CIMT. Increased carotid and brachial artery diameters and normalized eGFR indicates a haemodynamic effect of l‐ T4 replacement, the importance of which requires further investigation.     

Non-invasive exclusion and diagnosis of pulmonary embolism by sequential use of the rapid ELISA D-dimer assay, clinical score and spiral CT.

Pulmonary angiography is the gold standard for segmental pulmonary embolism (PE) but no longer for its subsegmental PE, because the inter-observer agreement for angiographically documented subsegmental PE is only 60%. Two non-invasive tools exclude PE with a negative predictive value of > 99%: a normal perfusion lung scan and a normal rapid ELISA VIDAS D-dimer test. The positive predictive value of a high probability ventilation-perfusion lung scan (VP-scan) is only 85% to 87%. The combination of a low clinical score and a non-diagnostic VP-scan safely exclude PE without the need of angiography. The prevalence of PE and that of an alternative diagnosis in symptomatic patients with a non-diagnostic VP-scan are 10% to 20% and 30% to 45%, respectively. Helical spiral computed tomography (CT) detects all clinically relevant PE and a large number of alternative diagnoses in symptomatic patients with a non-diagnostic or high probability VP-scan. The positive predictive value of the spiral CT is > 95%. Single-slice helical CT as the primary diagnostic test in patients with suspected PE in retrospective outcome studies and in prospective multicenter management studies indicate that the negative predictive value of a negative spiral CT preceded or followed by a negative compression ultrasonography (CUS) is > 99%. Therefore, a helical spiral CT can replace both the VP-scan and pulmonary angiography to safely rule in and out PE. A negative rapid ELISA VIDAS D-dimer test result will reduce the need for helical spiral CT by 25% to 35%.     

Imaging tests in the diagnosis of pulmonary embolism

Imaging modalities play an essential role in diagnosing pulmonary embolism (PE). Clinical outcome studies demonstrated that PE can be safely ruled out in patients with unlikely clinical probability in combination with a normal D-dimer test result; in all other patients additional imaging is needed. The aim is to accurately confirm or rule out the diagnosis of PE, after which, if indicated, anticoagulant treatment can be initiated. Various diagnostic tests are available, and this article reviews the different imaging techniques in patients with suspected PE. Computed tomographic pulmonary angiography (CTPA) is the imaging test of choice because of its high sensitivity and specificity. Compression ultrasonography and ventilation perfusion scintigraphy are reserved for patients with concomitant suspicion of deep vein thrombosis or contraindication for CTPA. Furthermore the diagnostic process in patients with clinically suspected recurrent PE, PE during pregnancy, and PE in the elderly and in patients with malignancy are discussed.     

Identification of novel diagnostic biomarkers for deep venous thrombosis

The combination of a negative D‐dimer and a Wells score can rule out, but not confirm, a diagnosis of deep venous thrombosis (DVT). We aimed to identify new diagnostic biomarkers for DVT and to investigate their relationship with hypercoagulability markers [D‐dimer and activated protein C‐protein C inhibitor (APC‐PCI) complex]. We screened 92 cardiovascular‐specific proteins in plasma samples from 45 confirmed DVT patients and 45 age‐ and sex‐matched non‐DVT patients selected from a prospective multicentre diagnostic management study (SCORE) by Proseek Multiplex CVDIII^96×96. Plasma levels of 30 proteins were significantly different between DVT and non‐DVT patients. After Bonferroni correction, plasma levels of seven proteins: P‐selectin, transferrin receptor protein 1, von Willebrand factor, tissue factor pathway inhibitor, osteopontin (OPN), bleomycin hydrolase and ST2 protein remained significantly different. The area under curve (AUC) for these proteins ranged from 0·70 to 0·84. Furthermore, all seven identified proteins were significantly associated with markers of hypercoagulability. A combination of OPN and APC‐PCI had the best ability to discriminate DVT from non‐DVT patients (AUC = 0·94; sensitivity = 89% and specificity = s84%). In conclusion, we identified multiple proteins associated with markers of hypercoagulability and with a potential to become novel diagnostic biomarkers for DVT.     

Serum levels of the adipokine visfatin are increased in pre-eclampsia

Objective Pre‐eclampsia (PE) is a serious cardiovascular complication in pregnancy which shares risk factors with the metabolic syndrome including insulin resistance and obesity. Recently, visfatin was introduced as a novel insulin‐mimetic adipokine which is up‐regulated when weight is gained. In the current study, we investigated visfatin serum levels in pre‐eclamptic patients as compared to healthy gestational age‐matched controls. Patients and measurements Visfatin was quantified by ELISA in control (n = 20) and PE (n = 15) patients. Furthermore, visfatin was correlated to clinical and biochemical measures of renal function, glucose and lipid metabolism, as well as inflammation. Results Mean maternal visfatin serum levels adjusted for maternal age were about twofold up‐regulated in PE (31·1 ± 23·4 µg/l) as compared to controls (15·7 ± 23·1 µg/l). Furthermore, visfatin concentrations correlated positively with age, blood pressure, creatinine, free fatty acids (FFA), IL‐6 and C reactive protein (CRP), whereas a negative correlation was found with fasting insulin and the HOMA‐insulin resistance index (HOMA‐IR). In multivariate analyses, HOMA‐IR and CRP remained independently associated with visfatin serum levels and explained 58% of the variation in visfatin concentrations. Conclusions We show that maternal visfatin levels are significantly increased in PE patients. Furthermore, insulin sensitivity and inflammatory status independently predict serum visfatin levels.     

Diagnosing pulmonary embolism: a comparison of clinical probability scores

Pulmonary embolism (PE) is a major cause of community and in‐hospital mortality. This study aimed to compare the performance of the British Thoracic Society (BTS) score to the Wells’ score in diagnosing PE. Data from two separate prospective diagnostic PE studies were analysed. All patients underwent gold standard investigation to determine the presence or absence of PE, together with a 3‐month follow‐up. The posttest prevalence of PE was compared using both scores and the receiver operating characteristic (ROC) curves. Seven hundred and seventy‐nine patients were consented and investigated for PE. In patients with pleuritic chest pain, respiratory rate <20 breaths/min and absence of dyspnoea, 4·0% [95% confidence interval (CI) 1·9–7·9%] had PE. The BTS score allocated 463/779 patients as low probability, compared to 565/779 according to the Wells’ score. Both scores identified a low risk group in the Manchester Investigation of Pulmonary Embolism Diagnosis cohort, however the BTS low probability group in the Thromboembolism Assessment and Diagnosis study had a prevalence of 9·7% (95% CI 5·8–15·9%). For the BTS score, the areas under the ROC curves were 0·67 (95% CI 0·61–0·72) and 0·71 (95% CI 0·61–0·75). For the Wells’ score these were 0·76 (95%CI 0·71–0·81) and 0·68 (95%CI 0·64–0·73). Given the lack of BTS validation studies to date, the Wells’ score appears to be the safer assessment option.     

Clinical usefulness and safety of an age-adjusted D-dimer cutoff levels to exclude pulmonary embolism: a retrospective analysis

Age-adjusted D-dimer (AADD) appears to increase the proportion of patients in whom pulmonary embolism (PE) can safely be excluded compared with conventional D-dimer (CDD), according to a limited number of studies. The aim if this study was to assess whether the use of an AADD might safely increase the clinical usefulness of CDD for the diagnosis of PE in our setting. Three hundred and sixty two consecutive outpatients with clinically suspected PE in whom plasma samples were obtained to measure D-dimer were included in this post hoc analysis of a previous study. CDD cutoff value was 500 ng/mL and AADD was calculated as (patient’s age × 10) ng/mL in patients aged >50. Sensitivity, specificity, clinical usefulness (i.e., proportion of true-negative tests among all patients with suspected PE), and the proportion of false negatives were calculated for both AADD and CDD among patients with low-to-moderate clinical probability of PE according to Well’s criteria. PE was confirmed in 98 patients (27 %). Among 331 patients with low-to-moderate clinical probability of PE, sensitivity and clinical usefulness were 100 and 27.8 % for CDD, respectively, and 100 and 36.5 % for AADD, respectively. In 29 patients aged >50 with CDD >500 ng/mL, AADD showed values under its normal cutoff point, without false negatives for the diagnosis of PE (0 %, 95 % CI 0–11 %). AADD increases clinical usefulness notably with respect to that of CDD in patients with clinical suspected PE without losing sensitivity in our cohort. The use of AADD apparently does not reduce the safety of CDD for the exclusion of PE.     

Can procalcitonin tests aid in identifying bacterial infections associated with influenza pneumonia? A systematic review and meta‐analysis

Objective To summarize evidence for the diagnostic accuracy of procalcitonin (PCT) tests for identifying secondary bacterial infections in patients with influenza. Methods Major databases, including MEDLINE, EMBASE, and the Cochrane Library, were searched for studies published between January 1966 and May 2009 that evaluated PCT as a marker for diagnosing bacterial infections in patients with influenza infections and that provided sufficient data to construct two‐by‐two tables. Results Six studies were selected that included 137 cases with bacterial coinfection and 381 cases without coinfection. The area under a summary ROC curve was 0·68 (95% CI: 0·64–0·72). The overall sensitivity and specificity estimates for PCT tests were 0·84 (95% CI: 0·75–0·90) and 0·64 (95% CI: 0·58–0·69), respectively. These studies reported heterogeneous sensitivity estimates ranging from 0·74 to 1·0. The positive likelihood ratio for PCT (LR+ = 2·31; 95% CI: 1·93–2·78) was not sufficiently high for its use as a rule‐in diagnostic tool, while its negative likelihood ratio was reasonably low for its use as a rule‐out diagnostic tool (LR? = 0·26; 95% CI: 0·17–0·40). Conclusions Procalcitonin tests have a high sensitivity, particularly for ICU patients, but a low specificity for identifying secondary bacterial infections among patients with influenza. Because of its suboptimal positive likelihood ratio and good negative likelihood ratio, it can be used as a suitable rule‐out test but cannot be used as a standalone rule‐in test.     

A phase I study of pulse high‐dose vorinostat (V) plus rituximab (R), ifosphamide,carboplatin, and etoposide (ICE) in patients with relapsed lymphoma

Given the poor outcomes of relapsed aggressive lymphomas and preclinical data suggesting that ≥2·5 μmol/l concentrations of vorinostat synergize with both etoposide and platinums, we hypothesized that pulse high‐dose vorinostat could safely augment the anti‐tumour activity of (R)ICE [(rituximab), ifosphamide, carboplatin, etoposide] chemotherapy. We conducted a phase I dose escalation study using a schedule with oral vorinostat ranging from 400 mg/d to 700 mg bid for 5 d in combination with the standard (R)ICE regimen (days 3, 4 and 5). Twenty‐nine patients [median age 56 years, median 2 prior therapies, 14 chemoresistant (of 27 evaluable), 2 prior transplants] were enrolled and treated. The maximally tolerated vorinostat dose was defined as 500 mg twice daily × 5 d. Common dose limiting toxicities included infection (n = 2), hypokalaemia (n = 2), and transaminitis (n = 2). Grade 3 related gastrointestinal toxicity was seen in 9 patients. The median vorinostat concentration on day 3 was 4·5 μmol/l (range 4·2–6·0 μmol/l) and in vitro data confirmed the augmented antitumour and histone acetylation activity at these levels. Responses were observed in 19 of 27 evaluable patients (70%) including 8 complete response/unconfirmed complete response. High‐dose vorinostat can be delivered safely with (R)ICE, achieves potentially synergistic drug levels, and warrants further study, although adequate gastrointestinal prophylaxis is warranted.     

Comparison of the Wells and Revised Geneva Scores for the diagnosis of pulmonary embolism: an Australian experience

Background/Aims: Clinical prediction rules form an integral component of guidelines on the diagnostic approach to pulmonary embolism (PE). The Wells Score is commonly used but is subjective, while the newer Revised Geneva Score is based entirely on objective variables. The aim of this study was to compare the diagnostic accuracy of the Wells and Revised Geneva Scores for the diagnosis of PE. Methods: Patients presenting to the emergency department with clinically suspected PE and referred for CT pulmonary angiogram or ventilation/perfusion scintigraphy were evaluated. The Wells and Revised Geneva Scores were calculated on the same cohort of patients and dichotomized into low and intermediate/high probability groups. The sensitivities and specificities were compared using McNemar's test. Overall accuracy was determined using receiver operator characteristic curve analysis. Results: A total of 98 consecutive patients was included. The overall prevalence of PE was 15.3%. The frequency of PE in the low, intermediate and high probability groups was similar for both clinical prediction rules. Compared with the Revised Geneva Score, the Wells Score showed a lower sensitivity with borderline significance (46.7% vs 80.0%, P= 0.06) and a significantly higher specificity (67.5% vs 47.0%, P= 0.002). The overall accuracy of both rules was similar (P= 0.617). Conclusion: Using the accepted guidelines in which a high pretest probability leads to further imaging and a low probability leads to a D‐dimer blood test, use of the more specific Wells Score could safely reduce the number of unnecessary scans. This would need to be confirmed with larger, prospective trials.     

Different accuracies of rapid enzyme-linked immunosorbent, turbidimetric, and agglutination D-dimer assays for thrombosis exclusion: impact on diagnostic work-ups of outpatients with suspected deep vein thrombosis and pulmonary embolism

The requirement for a safe diagnostic strategy should be based on an overall posttest incidence of venous thromboembolism (VTE) of less than 1%, with a negative predictive value of more than 99 to 100% during 3-month follow-up. Compression ultrasonography (CUS) and spiral computed tomography (CT) currently are the methods of choice to confirm or rule out deep venous thrombosis (DVT) and pulmonary embolism (PE), respectively. CUS has a negative predictive value (NPV) of 97 to 98%, indicating the need to improve the diagnostic work-up of patients with suspected DVT by clinical score assessment and D-dimer testing. Spiral CT as a stand-alone method detects all clinically relevant PEs and a large number of alternative diagnoses. It rules out PE with a NPV of 98 to 99%. Spiral CT is expensive, emphasizing the need to improve the diagnostic work-up of patients with suspected PE by the use of clinical score assessment and D-dimer testing. Clinical score assessment for DVT and PE has not safely ruled out VTE in multicenter studies and in routine daily practices. Modification of the Wells clinical score assessment for DVT by elimination of the "minus 2 points" for alternative diagnosis will improve the reproducibility of the clinical score assessment. The combination of a first negative CUS and a negative SimpliRed or an enzyme-linked immunosorbent assay (ELISA) VIDAS D-dimer of < 1,000 ng/mL safely exclude DVT (NPV > 99%) irrespective of clinical score assessment and without the need to repeat CUS in approximately 60 to 70% of patients. The rapid quantitative and qualitative agglutination D-dimer assays for the exclusion of VTE are not sensitive enough as stand-alone tests and should be used in combination with clinical score assessment. A normal rapid ELISA VIDAS D-dimer test as a stand-alone test safely excludes DVT and PE, with a NPV of 99 to 100%, irrespective of clinical score, without the need of CUS or spiral CT. The combined strategy of a rapid ELISA VIDAS D-dimer followed by objective testing with CUS for DVT and by spiral CT for PE will reduce the need for noninvasive imaging techniques by 40 to 50%.     

The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized,double‐blind,double‐dummy,symptom study (RELIEF)

The randomized, double‐blind, double‐dummy, phase 3b RELIEF trial evaluated polycythaemia vera (PV )‐related symptoms in patients who were well controlled with a stable dose of hydroxycarbamide (also termed hydroxyurea) but reported PV ‐related symptoms. Patients were randomized 1:1 to ruxolitinib 10 mg BID (n  = 54) or hydroxycarbamide (prerandomization dose/schedule; n  = 56); crossover to ruxolitinib was permitted after Week 16. The primary endpoint, ≥50% improvement from baseline in myeloproliferative neoplasm ‐symptom assessment form total symptom score cytokine symptom cluster (TSS ‐C; sum of tiredness, itching, muscle aches, night sweats, and sweats while awake) at Week 16, was achieved by 43·4% vs. 29·6% of ruxolitinib‐ and hydroxycarbamide‐treated patients, respectively (odds ratio, 1·82; 95% confidence interval, 0·82–4·04; P  =  0·139). The primary endpoint was achieved by 34% of a subgroup who maintained their hydroxycarbamide dose from baseline to Weeks 13–16. In a post hoc analysis, the primary endpoint was achieved by more patients with stable screening‐to‐baseline TSS ‐C scores (ratio ≤ 2) receiving ruxolitinib than hydroxycarbamide (47·4% vs. 25·0%; P  =  0·0346). Ruxolitinib treatment after unblinding was associated with continued symptom score improvements. Adverse events were primarily grades 1/2 with no unexpected safety signals. Ruxolitinib was associated with a nonsignificant trend towards improved PV ‐related symptoms versus hydroxycarbamide, although an unexpectedly large proportion of patients who maintained their hydroxycarbamide dose reported symptom improvement.     

The survival outcome of patients with relapsed/refractory peripheral T‐cell lymphoma‐not otherwise specified and angioimmunoblastic T‐cell lymphoma

Survival outcome of patients with peripheral T‐cell lymphoma‐not otherwise specified (PTCL ‐NOS ) and angioimmunoblastic T‐cell lymphoma (AITL ) who experience disease progression/relapse remains very poor. A total of 321 patients, newly diagnosed with PTCL ‐NOS (n  = 180) or AITL (n  = 141) between 1999 and 2015, were analysed. Failure‐free survival (FFS ) and overall survival (OS ) were calculated from the time of first disease progression (FFS 1, OS 1), from second disease progression (FFS 2, OS 2) and from third progression (FFS 3, OS 3). With a median follow‐up duration of 52 months, 240 patients (135 PTCL ‐NOS , 105 AITL ) experienced progression/relapse. In patients with PTCL ‐NOS , the median durations of FFS 1, FFS 2 and FFS 3 were 3·1, 2·5 and 2·1 months, respectively. In patients with AITL , they were 5·5, 2·9 and 2·3 months, respectively. There was no improvement in FFS 1 and OS 1 by the time of recurrence during this period (1999–2004, 2005–2009 and 2010–2015). The median FFS after pralatrexate and romidepsin was only 3·0 and 2·5 months, respectively. The 5‐year OS rates after salvage autologous and allogeneic transplant were 32% and 52%, respectively; while the 5‐year OS rates for patients who did not undergo transplant was 10%. Further research for novel therapeutic approaches with higher efficacy and better safety profile are needed.