Utilización de un ciclotrón para la producción de radionucleidos emisores de positrones

The experience acquired by our center during the first two years of using cyclotron 18/9 (IBA) dedicated to the production of clinical positron emission radionuclides is described. The cyclotron performance characteristics, production yields, quality control and synthesized radiotracers are analyzed. Cyclotron makes it possible to produce up to 3,300 mCi of 18F-, 270 mCi of 18F2, 3,100 mCi of 11C, 502 mCi of 13N (in 120, 60, 35 and 20 minutes respectively) and 540 mCi/min of 15O. In our center, about 85% of the PET studies are performed with 18F-FDG, whereas the remaining are done with 15O-water, 11C-bicarbonate, 11C-methionine, 13N-ammonia or 18F-. Cyclotron is included in the Radiopharmacy Unit of our PET facility and is subjected to a global quality control program. Follow-up of the bombardment parameters and periodic verifications of the cyclotron performance have made it possible to prevent equipment functioning problems, increase mean time between stoppage and decrease downtime. We conclude that cyclotron has high production capabilities and allows enough flexibility for a clinical and research positron emission tomography center; furthermore, it can also be used for regional distribution of 18F-FDG to satellite PET centers

Dissecting the role of the NADPH oxidase NOX4 in TGF-beta signaling in hepatocellular carcinoma

The NADPH oxidase NOX4 has been proposed as necessary for the apoptosis induced by the Transforming Growth Factor-beta (TGF-I3) in hepatocytes and hepatocellular carcinoma (HCC) cells. However, whether NOX4 is required for TGF-I3-induced canonical (SMADs) or non-canonical signals is not fully understood yet, neither its potential involvement in other parallel actions induced by TGF-I3. In this work we have used CRISPR Cas9 technology to stable attenuate NOX4 expression in HCC cells. Results have indicated that NOX4 is required for an efficient SMAD2/3 phosphorylation in response to TGF-I3, whereas non-canonical signals, such as the phos-phorylation of the Epidermal Growth Receptor or AKT, are higher in NOX4 silenced cells. TGF-I3-mediated in-hibition of cell proliferation and viability is attenuated in NOX4 silenced cells, correlating with decreased response in terms of apoptosis, and maintenance of high expression of MYC and CYCLIN D1. These results would indicate that NOX4 is required for all the tumor suppressor actions of TGF-I3 in HCC. However, analysis in human HCC tumors has revealed a worse prognosis for patients showing high expression of TGF-I31-related genes concomitant with high expression of NOX4. Deepening into other tumorigenic actions of TGF-I3 that may contribute to tumor progression, we found that NOX4 is also required for TGF-I3-induced migratory effects. The Epithelial-Mesenchymal transition (EMT) program does not appear to be affected by attenuation of NOX4 levels. However, TGF-I3-mediated regulation of cytoskeleton dynamics and focal adhesions require NOX4, which is necessary for TGF-I3-induced increase in the chaperone Hsp27 and correct subcellular localization of Hic-5 within focal adhesions, as well for upregulation of the metalloprotease MMP9. All these results together point to NOX4 as a key element in the whole TGF-I3 signaling in HCC cells, revealing an unknown role for NOX4 as tumor promoter in HCC patients presenting activation of the TGF-I3 pathway

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

Utilización de un ciclotrón para la producción de radionucleidos emisores de positrones

The experience acquired by our center during the first two years of using cyclotron 18/9 (IBA) dedicated to the production of clinical positron emission radionuclides is described. The cyclotron performance characteristics, production yields, quality control and synthesized radiotracers are analyzed. Cyclotron makes it possible to produce up to 3,300 mCi of 18F-, 270 mCi of 18F2, 3,100 mCi of 11C, 502 mCi of 13N (in 120, 60, 35 and 20 minutes respectively) and 540 mCi/min of 15O. In our center, about 85% of the PET studies are performed with 18F-FDG, whereas the remaining are done with 15O-water, 11C-bicarbonate, 11C-methionine, 13N-ammonia or 18F-. Cyclotron is included in the Radiopharmacy Unit of our PET facility and is subjected to a global quality control program. Follow-up of the bombardment parameters and periodic verifications of the cyclotron performance have made it possible to prevent equipment functioning problems, increase mean time between stoppage and decrease downtime. We conclude that cyclotron has high production capabilities and allows enough flexibility for a clinical and research positron emission tomography center; furthermore, it can also be used for regional distribution of 18F-FDG to satellite PET centers

Diagnostic trajectories of mental disorders in children and adolescents: a cohort study.

Mental disorders in children and adolescents may follow different trajectories, such as remission, change of diagnosis, or addition of two or more comorbid diagnoses, showing a heterotypic pattern. This study aims to describe the main diagnostic trajectories across a broad range of mental disorder diagnostic categories, from childhood to adolescence and from adolescence to young adulthood in a clinical population. A prospective study was conducted among a clinical sample of children and adolescents who were aged 3-17 years at the face-to-face baseline interview. Electronic health records of these participants were reviewed 10 years later. The diagnostic stability over time was examined using the kappa coefficient, and factors associated with stability were explored using simple logistic regression. The study included a sample of 691 participants. The kappa coefficient for diagnostic stability across all diagnoses was 0.574 for the transition from childhood to adulthood, 0.614 from childhood to adolescence, and 0.733 from adolescence to adulthood. Neurodevelopmental diagnoses had the highest stability. Factors associated with higher diagnostic stability included family history of mental disorders, receiving psychopharmacological treatment, and symptom severity at baseline. We found a variable diagnostic stability across different diagnoses and age categories. The different life transitions represent complex periods that should not be overlooked from a clinical standpoint. An appropriate transition from child and adolescent mental health services to adult mental health services may have a positive impact on children and adolescents with mental disorders

Pilot clinical trial of type 1 dendritic cells loaded with autologous tumor lysates combined with GM-CSF, pegylated IFN, and cyclophosphamide for metastatic cancer patients

Twenty-four patients with metastatic cancer received two cycles of four daily immunizations with monocyte-derived dendritic cells (DC). DC were incubated with preheated autologous tumor lysate and subsequently with IFN-α, TNF-α, and polyinosinic:polycytidylic acid to attain type 1 maturation. One DC dose was delivered intranodally, under ultrasound control, and the rest intradermally in the opposite thigh. Cyclophosphamide (day -7), GM-CSF (days 1-4), and pegIFN alpha-2a (days 1 and 8) completed each treatment cycle. Pretreatment with cyclophosphamide decreased regulatory T cells to levels observed in healthy subjects both in terms of percentage and in absolute counts in peripheral blood. Treatment induced sustained elevations of IL-12 in serum that correlated with the output of IL-12p70 from cultured DC from each individual. NK activity in peripheral blood was increased and also correlated with the serum concentration of IL-12p70 in each patient. Circulating endothelial cells decreased in 17 of 18 patients, and circulating tumor cells markedly dropped in 6 of 19 cases. IFN-γ-ELISPOT responses to DC plus tumor lysate were observed in 4 of 11 evaluated cases. Tracing DC migration with [(111)In] scintigraphy showed that intranodal injections reached deeper lymphatic chains in 61% of patients, whereas with intradermal injections a small fraction of injected DC was almost constantly shown to reach draining inguinal lymph nodes. Five patients experienced disease stabilization, but no objective responses were documented. This combinatorial immunotherapy strategy is safe and feasible, and its immunobiological effects suggest potential activity in patients with minimal residual disease. A randomized trial exploring this hypothesis is currently ongoing

A novel [89Zr]-anti-PD-1-PET-CT to assess response to PD-1/PD-L1 blockade in lung cancer

Background: Harnessing the anti-tumor immune system response by targeting the program cell death protein (PD-1) and program cell death ligand protein (PD-L1) axis has been a major breakthrough in non-small cell lung cancer (NSCLC) therapy. Nonetheless, conventional imaging tools cannot accurately assess response in immunotherapy-treated patients. Using a lung cancer syngeneic mouse model responder to immunotherapy, we aimed to demonstrate that [89Zr]-anti-PD-1 immuno-PET is a safe and feasible imaging modality to assess the response to PD-1/PD-L1 blockade in NSCLC. Materials and methods: A syngeneic mouse model responder to anti-PD-1 therapy was used. Tumor growth and response to PD-1 blockade were monitored by conventional 2-deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) PET scans. Additionally, tumor lymphocyte infiltration was analyzed by the use of an [89Zr]-labeled anti-PD-1 antibody and measured as 89Zr tumor uptake. Results: Conventional [18F]-FDG-PET scans failed to detect the antitumor activity exerted by anti-PD-1 therapy. However, [89Zr]-anti-PD-1 uptake was substantially higher in mice that responded to PD-1 blockade. The analysis of tumor-infiltrating immune cell populations and interleukins demonstrated an increased anti-tumor effect elicited by activation of effector immune cells in PD-1-responder mice. Interestingly, a positive correlation between [89Zr]-anti-PD-1 uptake and the proportion of tumor-infiltrating lymphocytes (TILs) was found (Cor = 0.8; p = 0.001). Conclusion: Our data may support the clinical implementation of immuno-PET as a promising novel imaging tool to predict and assess the response of PD-1/PD-L1 inhibitors in patients with NSCLC

A novel [89Zr]-anti-PD-1-PET-CT to assess response to PD-1/PD-L1 blockade in lung cancer

Background: Harnessing the anti-tumor immune system response by targeting the program cell death protein (PD-1) and program cell death ligand protein (PD-L1) axis has been a major breakthrough in non-small cell lung cancer (NSCLC) therapy. Nonetheless, conventional imaging tools cannot accurately assess response in immunotherapy-treated patients. Using a lung cancer syngeneic mouse model responder to immunotherapy, we aimed to demonstrate that [89Zr]-anti-PD-1 immuno-PET is a safe and feasible imaging modality to assess the response to PD-1/PD-L1 blockade in NSCLC. Materials and methods: A syngeneic mouse model responder to anti-PD-1 therapy was used. Tumor growth and response to PD-1 blockade were monitored by conventional 2-deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) PET scans. Additionally, tumor lymphocyte infiltration was analyzed by the use of an [89Zr]-labeled anti-PD-1 antibody and measured as 89Zr tumor uptake. Results: Conventional [18F]-FDG-PET scans failed to detect the antitumor activity exerted by anti-PD-1 therapy. However, [89Zr]-anti-PD-1 uptake was substantially higher in mice that responded to PD-1 blockade. The analysis of tumor-infiltrating immune cell populations and interleukins demonstrated an increased anti-tumor effect elicited by activation of effector immune cells in PD-1-responder mice. Interestingly, a positive correlation between [89Zr]-anti-PD-1 uptake and the proportion of tumor-infiltrating lymphocytes (TILs) was found (Cor = 0.8; p = 0.001). Conclusion: Our data may support the clinical implementation of immuno-PET as a promising novel imaging tool to predict and assess the response of PD-1/PD-L1 inhibitors in patients with NSCLC