Addition of the nuclear export inhibitor selinexor to standard intensive treatment for elderly patients with acute myeloid leukemia and high risk myelodysplastic syndrome.

Treatment results of AML in elderly patients are unsatisfactory. In an open label randomized phase II study, we investigated whether addition of the XPO1 inhibitor selinexor to intensive chemotherapy would improve outcome in this population. 102 AML patients > 65 years of age (median 69 (65-80)) were randomly assigned to standard chemotherapy (3 + 7) with or without oral selinexor 60 mg twice weekly (both arms n = 51), days 1-24. In the second cycle, cytarabine 1000 mg/m2 twice daily, days 1-6 with or without selinexor was given. CR/CRi rates were significantly higher in the control arm than in the investigational arm (80% (95% C.I. 69-91%) vs. 59% (45-72%; p = 0.018), respectively). At 18 months, event-free survival was 45% for the control arm versus 26% for the investigational arm (Cox-p = 0.012) and overall survival 58% vs. 33%, respectively (p = 0.009). AML and infectious complications accounted for an increased death rate in the investigational arm. Irrespective of treatment, MRD status after two cycles appeared to be correlated with survival. We conclude that the addition of selinexor to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients. (Netherlands Trial Registry number NL5748 (NTR5902), www.trialregister.nl ).

Endogenous activated protein C is essential for immune-mediated cancer cell elimination from the circulation.

Fibrinogen and platelets play an important role in cancer cell survival in the circulation by protecting cancer cells from the immune system. Moreover, endogenous activated protein C (APC) limits cancer cell extravasation due to sphingosine-1-phosphate receptor-1 (S(1)P(1)) and VE-cadherin-dependent vascular barrier enhancement. We aimed to study the relative contribution of these two mechanisms in secondary tumor formation in vivo. We show that fibrinogen depletion limits pulmonary tumor foci formation in an experimental metastasis model in C57Bl/6 mice but not in NOD-SCID mice lacking a functional immune system. Moreover, we show that in the absence of endogenous APC, fibrinogen depletion does not prevent cancer cell dissemination and secondary tumor formation in immune-competent mice. Overall, we thus show that endogenous APC is essential for immune-mediated cancer cell elimination.

Accuracy of diagnostic tests for clinically suspected upper extremity deep vein thrombosis: a systematic review.

BACKGROUND: The best available test for the diagnosis of upper extremity deep venous thrombosis (UEDVT) is contrast venography. The aim of this systematic review was to assess whether the diagnostic accuracy of other tests for clinically suspected UEDVT is high enough to justify their use in clinical practise and to evaluate if any test can replace venography. METHODS: MEDLINE and EMBASE databases were searched from inception to June 2009. Two reviewers independently evaluated study eligibility, extracted data, and assessed study quality. RESULTS: We identified 17 papers, reporting on 793 patients. Overall, the methodological quality was poor, sample sizes were small, and large between-study differences were observed in spectrum and design. The summary estimates of sensitivity (95% confidence interval) were 97% (90-100%) for compression ultrasonography, 84% (72-97%) for Doppler ultrasonography, 91% (85-97%) for Doppler ultrasonography with compression, and 85% (72-99%) for phleboreography. The corresponding summary estimates of specificity were, respectively, 96% (87-100%), 94% (86-100%), 93% (80-100%), and 87% (71-100%). Clinical findings, a clinical score, D-dimer, magnetic resonance imaging, rheography and plethysmography were evaluated in one study each, involving a median number of 46 patients (range 21-214). Sensitivity and specificity ranged from 0% to 100% and from 14% to 100%. CONCLUSIONS: Methodological limitations, large between-study differences and small sample sizes limit the evidence of tests for clinically suspected UEDVT. Compression ultrasonography may be an acceptable alternative to venography. The addition of (color) Doppler does not seem to improve the accuracy. Adequately designed studies are warranted to confirm these findings.

Cancer and thrombosis: from molecular mechanisms to clinical presentations.

Although the bidirectional association between cancer and venous thromboembolism (VTE) has been known for almost two centuries, recent advances in our understanding of the clinical, laboratory, and epidemiologic aspects of this association have created a renewed interest in this topic. This review consists of two parts. The first part discusses the occurrence, determinants and significance of VTE in those with cancer, as well as the risk of developing and the possible need to detect cancer in those presenting with VTE. The second part reviews the role of hemostatic constituents (coagulation and fibrinolytic proteins and platelets) in promoting growth and progression of cancer, as well as the effects and possible mechanisms of the low molecular weight heparins (LMWH) in this process.

Family history and inherited thrombophilia.

BACKGROUND: It is a common belief that patients with venous thrombosis and a positive family history for venous thromboembolism (VTE) have an increased likelihood of having an inherited thrombophilic defect. METHODS: We analyzed the relation between family history, qualified with three different methods, and thrombophilic status in 314 patients with proven VTE. A positive family history (one or more first-degree relatives with VTE) and a strongly positive family history (two or more first-degree relatives with VTE). In 118 of the patients a third, more precise method was analyzed: the family history score, which compares the observed and the expected number of first-degree family members with VTE. RESULTS: Patients with a positive or strongly positive family history had a slightly increased chance of having inherited thrombophilia compared to those without a positive family history. For positive family history this was 42% vs. negative 32%, likelihood ratio 1.3 (95% confidence interval; CI 0.9-2.1) and for strongly positive family history this was 46% vs. negative 34%, likelihood ratio 1.6 (95% CI 0.7-3.3). The family history score correlated with the chance of having inherited thrombophilia [OR 1.23 per score point (95% CI 1.01-1.48)]. However, even with this method the chance of having inherited thrombophilia is lower than 50% in 97% of the cases. CONCLUSIONS: Family history of VTE is not a precise tool in clinical practice to identify patients with inherited thrombophilia among patients with VTE. The family history score is more precise, but probably only useful for research purposes and not for daily practice.