Recent guidelines recommend consideration of the use of oral edoxaban or rivaroxaban for the treatment of venous thromboembolism in patients with cancer. However, the benefit of these oral agents is ...limited by the increased risk of bleeding associated with their use.
This was a multinational, randomized, investigator-initiated, open-label, noninferiority trial with blinded central outcome adjudication. We randomly assigned consecutive patients with cancer who had symptomatic or incidental acute proximal deep-vein thrombosis or pulmonary embolism to receive oral apixaban (at a dose of 10 mg twice daily for the first 7 days, followed by 5 mg twice daily) or subcutaneous dalteparin (at a dose of 200 IU per kilogram of body weight once daily for the first month, followed by 150 IU per kilogram once daily). The treatments were administered for 6 months. The primary outcome was objectively confirmed recurrent venous thromboembolism during the trial period. The principal safety outcome was major bleeding.
Recurrent venous thromboembolism occurred in 32 of 576 patients (5.6%) in the apixaban group and in 46 of 579 patients (7.9%) in the dalteparin group (hazard ratio, 0.63; 95% confidence interval CI, 0.37 to 1.07; P<0.001 for noninferiority). Major bleeding occurred in 22 patients (3.8%) in the apixaban group and in 23 patients (4.0%) in the dalteparin group (hazard ratio, 0.82; 95% CI, 0.40 to 1.69; P = 0.60).
Oral apixaban was noninferior to subcutaneous dalteparin for the treatment of cancer-associated venous thromboembolism without an increased risk of major bleeding. (Funded by the Bristol-Myers Squibb-Pfizer Alliance; Caravaggio ClinicalTrials.gov number, NCT03045406.).
Predicting human mobility is a key element in the development of intelligent transport systems. Current digital technologies enable capturing a wealth of data on mobility flows between geographic ...areas, which are then used to train machine learning models to predict these flows. However, most works have only considered a single data source for building these models or different sources but covering the same spatial area. In this paper we propose to augment a macro open-data mobility study based on cellular phones with data from a road traffic sensor located within a specific motorway of one of the mobility areas in the study. The results show that models trained with the fusion of both types of data, especially long short-term memory (LSTM) and Gated Recurrent Unit (GRU) neural networks, provide a more reliable prediction than models based only on the open data source. These results show that it is possible to predict the traffic entering a particular city in the next 30 minutes with an absolute error less than 10%. Thus, this work is a further step towards improving the prediction of human mobility in interurban areas by fusing open data with data from IoT systems.
SEQUOIA compared efficacy and safety of adding pegilodecakin (PEG), a pegylated recombinant human interleukin (IL)-10, with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) in patients following ...progression on first-line gemcitabine-containing therapy with metastatic pancreatic ductal adenocarcinoma (PDAC).
SEQUOIA, a randomized, global phase III study, compared FOLFOX with PEG + FOLFOX as second line in gemcitabine-refractory PDAC. Patients were randomly assigned 1:1 (PEG + FOLFOX:FOLFOX) and stratified by prior gemcitabine and region. Eligible patients had only one prior gemcitabine-containing treatment. Primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), response evaluation per Response Evaluation Criteria in Solid Tumor (RECIST) 1.1, and safety. Exploratory analyses included biomarkers related to immune activation.
Between March 1, 2017, and September 9, 2019, 567 patients were randomly assigned PEG + FOLFOX (n = 283) or FOLFOX (n = 284). Most (94.7%) patients received prior gemcitabine plus nab paclitaxel. OS was similar comparing PEG + FOLFOX versus FOLFOX (median: 5.8
6.3 months; hazard ratio = 1.045; 95% CI, 0.863 to 1.265). Also, PFS (median 2.1
2.1 months; hazard ratio = 0.981; 95% CI, 0.808 to 1.190) and objective response rate (4.6%
5.6%) were similar between the treatment arms. Most common (≥ 35%) treatment-emergent adverse events in PEG + FOLFOX versus FOLFOX were thrombocytopenia (55%
20%), anemia (40%
16%), fatigue (61%
45%), neutropenia (39%
28%), abdominal pain (37%
29%), nausea (45%
41%), neuropathy (37%
38%), and decreased appetite (35%
31%). Exploratory analyses revealed increases in total IL-18, interferon (IFN)-γ, and granzyme B and decreases in transforming growth factor (TGF)-β with the addition of PEG.
PEG added to FOLFOX did not improve efficacy in advanced gemcitabine-refractory PDAC. Safety findings were consistent as previously observed from PEG with chemotherapy; toxicity was manageable and tolerable. Exploratory pharmacodynamic results were consistent with immunostimulatory signals of the IL-10R pathway.
Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining ...immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC.
Multicenter, single-arm, phase II study to evaluate the safety and efficacy of motixafortide and pembrolizumab combined with chemotherapy in patients with
metastatic PDAC and disease progression on front-line gemcitabine-based therapy (NCT02826486). Subjects received a priming phase of motixafortide daily on days 1-5, followed by repeated cycles of motixafortide twice a week; pembrolizumab every 3 weeks; and nanoliposomal irinotecan, fluorouracil, and leucovorin every 2 weeks (NAPOLI-1 regimen). The primary objective was objective response rate (ORR). Secondary objectives included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), safety, and tolerability.
A total of 43 patients were enrolled. The ORR according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The DCR was 63.2% with median duration of clinical benefit of 5.7 months. In the intention-to-treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated, with toxicity comparable with the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection was 7%, lower than expected for this chemotherapy regimen.
Triple combination of motixafortide, pembrolizumab, and chemotherapy was safe and well tolerated, and showed signs of efficacy in a population with poor prognosis and aggressive disease.
Programmed cell death 1 (PD-1) inhibitors have limited effect in pancreatic ductal adenocarcinoma (PDAC), underscoring the need to co-target alternative pathways. CXC chemokine receptor 4 (CXCR4) ...blockade promotes T cell tumor infiltration and is synergistic with anti-PD-1 therapy in PDAC mouse models. We conducted a phase IIa, open-label, two-cohort study to assess the safety, efficacy and immunobiological effects of the CXCR4 antagonist BL-8040 (motixafortide) with pembrolizumab and chemotherapy in metastatic PDAC (NCT02826486). The primary outcome was objective response rate (ORR). Secondary outcomes were overall survival (OS), disease control rate (DCR) and safety. In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The DCR was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8
effector T cell tumor infiltration, decreased myeloid-derived suppressor cells (MDSCs) and further decreased circulating regulatory T cells. In cohort 2, 22 patients received BL-8040 and pembrolizumab with chemotherapy, with an ORR, DCR and median duration of response of 32%, 77% and 7.8 months, respectively. These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in PDAC and warrants confirmation in subsequent randomized trials.
Patients with cancer and venous thromboembolism (VTE) show a high risk of VTE recurrence during anticoagulant treatment. This study aimed to develop a predictive model to assess the risk of VTE ...recurrence within 6 months at the moment of primary VTE diagnosis in these patients.
Using the EHRead® technology, based on Natural Language Processing (NLP) and machine learning (ML), the unstructured data in electronic health records from 9 Spanish hospitals between 2014 and 2018 were extracted. Both clinically- and ML-driven feature selection were performed to identify predictors for VTE recurrence. Logistic regression (LR), decision tree (DT), and random forest (RF) algorithms were used to train different prediction models, which were subsequently validated in a hold-out data set.
A total of 16,407 anticoagulated cancer patients with diagnosis of VTE were identified (54.4 % male and median age 70). Deep vein thrombosis, pulmonary embolism and metastases were observed in 67.2 %, 26.6 %, and 47.7 % of the patients, respectively. During the study follow-up, 11.4 % of the patients developed a recurrent VTE, being more frequent in patients with lung cancer. Feature selection and model training based on ML identified primary pulmonary embolism, deep vein thrombosis, metastasis, adenocarcinoma, hemoglobin and serum creatinine levels, platelet and leukocyte count, family history of VTE, and patients' age as predictors of VTE recurrence within 6 months of VTE diagnosis. The LR model had an AUC-ROC (95 % CI) of 0.66 (0.61, 0.70), the DT of 0.69 (0.65, 0.72) and the RF of 0.68 (0.63, 0.72).
This is the first ML-based predictive model designed to predict 6-months VTE recurrence in patients with cancer. These results hold great potential to assist clinicians to identify the high-risk patients and improve their clinical management.
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•Unstructured data from electronic health records were extracted with NLP.•We identified 16,407 adult cancer patients diagnosed of VTE in 9 hospitals.•11.4 % of patients had recurrent VTE, 9.2 % within six months after the primary event.•Machine-learning-based feature selection identified 10 VTE recurrence predictors.•The predictive models of VTE recurrence in cancer patients had an ROC-AUC > 0.7.
Road traffic pollution is one of the key factors affecting urban air quality. There is a consensus in the community that the efficient use of public transport is the most effective solution. In that ...sense, much effort has been made in the data mining discipline to come up with solutions able to anticipate taxi demands in a city. This helps to optimize the trips made by such an important urban means of transport. However, most of the existing solutions in the literature define the taxi demand prediction as a regression problem based on historical taxi records. This causes serious limitations with respect to the required data to operate and the interpretability of the prediction outcome. In this paper, we introduce QUADRIVEN (QUalitative tAxi Demand pRediction based on tIme-Variant onlinE social Network data analysis), a novel approach to deal with the taxi demand prediction problem based on human-generated data widely available on online social networks. The result of the prediction is defined on the basis of categorical labels that allow obtaining a semantically-enriched output. Finally, this proposal was tested with different models in a large urban area, showing quite promising results with an F1 score above 0.8.
International and national guidelines recommend low-molecular-weight heparin for the treatment of venous thromboembolism (VTE) in patients with cancer. The aim of the Caravaggio study is to assess ...whether oral apixaban is non-inferior to subcutaneous dalteparin for the treatment of acute proximal deep vein thrombosis and/or pulmonary embolism in patients with cancer. The study is an investigator-initiated, multi-national, prospective, randomized, open-label with blind end-point evaluation (PROBE), non-inferiority clinical trial (NCT03045406). Consecutive patients are randomized to receive oral apixaban or subcutaneous dalteparin for 6 months. Apixaban is given at a dose of 10 mg twice daily for the first 7 days and then 5 mg twice daily; dalteparin is given at a dose of 200 IU/kg for the first month and then 150 IU/kg once daily. The primary outcome of the study is objectively confirmed recurrent VTE as assessed by a central independent adjudication committee unaware of study treatment allocation. The primary safety outcome is major bleeding defined according to the guidelines of the International Society of Thrombosis and Haemostasis. Assuming a 6-month incidence of the primary outcome of 7% with dalteparin and an upper limit of the two-sided 95% confidence interval of the hazard ratio below the pre-specified margin of 2.00, 1,168 patients will be randomized considering an up to 20% loss in total patient-years (
= 80%;
one-sided = 0.025). The Caravaggio study has the potential, along with other recently performed or on-going studies, to make less cumbersome the management of VTE in patients with cancer by replacing parenteral with oral anticoagulation.
This paper presents a novel measuring system for partial discharge (PD) measurements in Gas Insulated Systems (GIS) using high frequency current transformers (HFCT). The system is based on the ...measurement of the induced PD currents in the GIS enclosure. In opposition to the existing antenna technologies that measure the radiated energy in the very high frequency/ultra-high frequency (VHF/UHF) range, the proposed system measures the PD conducted currents in the high frequency (HF) range and below. The foundation of the measurements together with a detailed explanation of the sensor installed conveniently at the bolts of the GIS spacer are presented. An experimental study on the current distribution in the GIS enclosure is described to evaluate the impact of the sensor on the measurements. Laboratory experiments have been performed that show the suitability of this method to properly measure particle discharges caused by corona, surface and free moving particle discharges in SF₆. Discharges in the range of 1 to 4 pC have been properly measured. An analysis to evaluate the performance of the method is shown, in comparison to VHF/UHF antenna measurements. The potential benefits of this novel technique rely on the small attenuation of PD signals in the GIS components in the HF range and sample rate reductions. Finally, a discussion on the potential applicability of present cluster and charge calculation techniques to the proposed PD GIS measurement using HFCT is presented.
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