Extensive screening strategies to detect occult cancer in patients with unprovoked venous thromboembolism (VTE) are complex and no benefit in terms of survival has been reported. FDG-PET/CT (2-[F-18] fluoro-2-deoxy-D-glucose positron emission tomography combined with computed tomography), a noninvasive technique for the diagnosis and staging of malignancies, could be useful in this setting. Consecutive patients 50 years with a first unprovoked VTE episode were prospectively included. Screening with FDG-PET/CT was performed 3-4 weeks after the index event. If positive, appropriate diagnostic work-up was programmed. Clinical follow-up continued for 2 years. Blood samples were collected to assess coagulation biomarkers. FDG-PET/CT was negative in 68/99 patients (68.7%), while suspicious FDG uptake was detected in 31/99 patients (31.3%). Additional diagnostic work-up confirmed a malignancy in 7/31 patients (22.6%), with six of them at early stage. During follow-up, two patients with negative FDG-PET/CT were diagnosed with cancer. Sensitivity (S), positive (PPV) and negative predictive values (NPV) of FDG-PET/CT as single tool for the detection of occult malignancy were 77.8% (95% CI: 0.51-1), 22.6% (95% CI: 0.08-0.37) and 97.1% (95% CI: 0.93-1), respectively. Median tissue factor (TF) activity in patients with occult cancer was 5.38 pM vs. 2.40 pM in those without cancer (p 5 0.03). Limitation of FDG-PET/CT screening to patients with TF activity > 2.8 pM would improve the PPV to 37.5% and reduce the costs of a single cancer diagnosis from 20,711e to 11,670e. FDG-PET/CT is feasible for the screening of occult cancer in patients with unprovoked VTE, showing high S and NPV. The addition of TF activity determination may be useful for patient selection.Cancer patients have an increased risk of venous thromboembolism (VTE), either deep vein thrombosis (DVT) or pulmonary embolism (PE), through different mechanisms, including tumor-and treatment-induced hypercoagulability, endothelial damage (chemotherapy toxicity and use of venous catheters) or venous stasis due to bed rest or surgical immobilization.

Identification of new markers associated with long-term efficacy in patients treated with CAR T cells is a current medical need, particularly in diseases such as multiple myeloma. In this study we address the impact of CAR density on the functionality of BCMA-CAR T cells. Functional and transcriptional studies demonstrate that CAR T cells with high expression of the CAR construct show an increased tonic signaling with upregulation of exhaustion markers, increased in vitro cytotoxicity but a decrease in in vivo BM infiltration. Characterization of Gene Regulatory Networks using scRNA-seq identified regulons associated to activation and exhaustion upregulated in CARHigh T cells, providing mechanistic insights behind differential functionality of these cells. Finally, we demonstrate that patients treated with CAR T cell products enriched in CARHigh T cells show a significantly worse clinical response in several hematological malignancies. In summary, our work demonstrates that CAR density plays an important role in CAR T activity with significant impact on clinical response.