Analysis of the scintillation light production and propagation in the WA105 Dual-Phase demonstrator

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Físicas, leída el 17-12-2020Los experimentos de oscilaciones de neutrinos de proxima generacion, longbaseline, tienen como objetivo responder las mayores preguntas en la física de neutrinos, como la observacion de la violacion de la fase CP en el sector leptonico y la determinacion del orden de la masa de neutrinos. El experimento Deep Underground Neutrino Experiment (DUNE) es uno de estos proyectos, cuyo diseño final esta todavía por definir. Su detector lejano (DL), situado a 1300 km de distancia de la produccion del haz de neutrinos, en Fermilab, esta destinado a tener cuatro camaras de proyeccion temporales (TPC) de argon lquido (LAr) de 10 kilotoneladas, que utilizaran tecnologías de una unica y de doble fase (DP)...The next-generation long-baseline neutrino oscillation experiments aim to answer most of the unsolved questions in neutrino physics as the observation of the CP violation in the leptonic sector and the determination of the neutrino mass ordering. The Deep Underground Neutrino Experiment (DUNE) is one of these projects, whose final design is currently to be de ned. In particular, the far detector (FD) site is intended to have four 10-kton Liquid Argon (LAr) Time Projection Chambers, using both the single and dual-phase (DP) technologies...Fac. de Ciencias FísicasTRUEunpu

Survival analysis of a multicentre, randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in patients with metastatic colorectal cancer (mCRC)

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A randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in the treatment of patients with metastatic colorectal cancer-OBELICS (Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme).

BACKGROUND: Despite the improvements in diagnosis and treatment, colorectal cancer (CRC) is the second cause of cancer deaths in both sexes. Therefore, research in this field remains of great interest. The approval of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with a fluoropyrimidine-based chemotherapy in the treatment of metastatic CRC has changed the oncology practice in this disease. However, the efficacy of bevacizumab-based treatment, has thus far been rather modest. Efforts are ongoing to understand the better way to combine bevacizumab and chemotherapy, and to identify valid predictive biomarkers of benefit to avoid unnecessary and costly therapy to nonresponder patients. The BRANCH study in high-risk locally advanced rectal cancer patients showed that varying bevacizumab schedule may impact on the feasibility and efficacy of chemo-radiotherapy. METHODS/DESIGN: OBELICS is a multicentre, open-label, randomised phase 3 trial comparing in mCRC patients two treatment arms (1:1): standard concomitant administration of bevacizumab with chemotherapy (mFOLFOX/OXXEL regimen) vs experimental sequential bevacizumab given 4 days before chemotherapy, as first or second treatment line. Primary end point is the objective response rate (ORR) measured according to RECIST criteria. A sample size of 230 patients was calculated allowing reliable assessment in all plausible first-second line case-mix conditions, with a 80% statistical power and 2-sided alpha error of 0.05. Secondary endpoints are progression free-survival (PFS), overall survival (OS), toxicity and quality of life. The evaluation of the potential predictive role of several circulating biomarkers (circulating endothelial cells and progenitors, VEGF and VEGF-R SNPs, cytokines, microRNAs, free circulating DNA) as well as the value of the early [(18)F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) response, are the objectives of the traslational project. DISCUSSION: Overall this study could optimize bevacizumab scheduling in combination with chemotherapy in mCRC patients. Moreover, correlative studies could improve the knowledge of the mechanisms by which bevacizumab enhance chemotherapy effect and could identify early predictors of response. EudraCT Number: 2011-004997-27 TRIAL REGISTRATION: ClinicalTrials.gove number, NCT01718873

Association of Upfront Peptide Receptor Radionuclide Therapy With Progression-Free Survival Among Patients With Enteropancreatic Neuroendocrine Tumors

open57noIMPORTANCE Data about the optimal timing for the initiation of peptide receptor radionuclide therapy (PRRT) for advanced, well-differentiated enteropancreatic neuroendocrine tumors are lacking. OBJECTIVE To evaluate the association of upfront PRRT vs upfront chemotherapy or targeted therapy with progression-free survival (PFS) among patients with advanced enteropancreatic neuroendocrine tumors who experienced disease progression after treatment with somatostatin analogues (SSAs). DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study analyzed the clinical records from 25 Italian oncology centers for patients aged 18 years or older who had unresectable, locally advanced or metastatic, well-differentiated, grades 1 to 3 enteropancreatic neuroendocrine tumors and received either PRRT or chemotherapy or targeted therapy after experiencing disease progression after treatment with SSAs between January 24, 2000, and July 1, 2020. Propensity score matching was done to minimize the selection bias. EXPOSURES Upfront PRRT or upfront chemotherapy or targeted therapy. MAIN OUTCOMES AND MEASURES The main outcome was the difference in PFS among patients who received upfront PRRT vs among those who received upfront chemotherapy or targeted therapy. A secondary outcome was the difference in overall survival between these groups. Hazard ratios (HRs) were fitted in a multivariable Cox proportional hazards regression model to adjust for relevant factors associated with PFS and were corrected for interaction with these factors. RESULTS Of 508 evaluated patients (mean ([SD] age, 55.7 [0.5] years; 278 [54.7%] were male), 329 (64.8%) received upfront PRRT and 179 (35.2%) received upfront chemotherapy or targeted therapy. The matched group included 222 patients (124 [55.9%] male; mean [SD] age, 56.1 [0.8] years), with 111 in each treatment group. Median PFS was longer in the PRRT group than in the chemotherapy or targeted therapy group in the unmatched (2.5 years [95%CI, 2.3-3.0 years] vs 0.7 years [95%CI, 0.5-1.0 years]; HR, 0.35 [95%CI, 0.28-0.44; P < .001]) and matched (2.2 years [95% CI, 1.8-2.8 years] vs 0.6 years [95%CI, 0.4-1.0 years]; HR, 0.37 [95%CI, 0.27-0.51; P < .001]) populations. No significant differences were shown in median overall survival between the PRRT and chemotherapy or targeted therapy groups in the unmatched (12.0 years [95%CI, 10.7-14.1 years] vs 11.6 years [95%CI, 9.1-13.4 years]; HR, 0.81 [95%CI, 0.62-1.06; P = .11]) and matched (12.2 years [95% CI, 9.1-14.2 years] vs 11.5 years [95%CI, 9.2-17.9 years]; HR, 0.83 [95%CI, 0.56-1.24; P = .36]) populations. The use of upfront PRRT was independently associated with improved PFS (HR, 0.37; 95%CI, 0.26-0.51; P < .001) in multivariable analysis. After adjustment of values for interaction, upfront PRRT was associated with longer PFS regardless of tumor functional status (functioning: adjusted HR [aHR], 0.39 [95%CI, 0.27-0.57]; nonfunctioning: aHR, 0.29 [95%CI, 0.16-0.56]), grade of 1 to 2 (grade 1: aHR, 0.21 [95%CI, 0.12-0.34]; grade 2: aHR, 0.52 [95%CI, 0.29-0.73]), and site of tumor origin (pancreatic: aHR, 0.41 [95%CI, 0.24-0.61]; intestinal: aHR, 0.19 [95%CI, 0.11-0.43]) (P < .001 for all). Conversely, the advantage was not retained in grade 3 tumors (aHR, 0.31; 95%CI, 0.12-1.37; P = .13) or in tumors with a Ki-67 proliferation index greater than 10% (aHR, 0.73; 95%CI, 0.29-1.43; P = .31). CONCLUSIONS AND RELEVANCE In this cohort study, treatment with upfront PRRT in patients with enteropancreatic neuroendocrine tumors who had experienced disease progression with SSA treatment was associated with significantly improved survival outcomes compared with upfront chemotherapy or targeted therapy. Further research is needed to investigate the correct strategy, timing, and optimal specific sequence of these therapeutic options.openPusceddu, Sara; Prinzi, Natalie; Tafuto, Salvatore; Ibrahim, Toni; Filice, Angelina; Brizzi, Maria Pia; Panzuto, Francesco; Baldari, Sergio; Grana, Chiara M.; Campana, Davide; Davì, Maria Vittoria; Giuffrida, Dario; Zatelli, Maria Chiara; Partelli, Stefano; Razzore, Paola; Marconcini, Riccardo; Massironi, Sara; Gelsomino, Fabio; Faggiano, Antongiulio; Giannetta, Elisa; Bajetta, Emilio; Grimaldi, Franco; Cives, Mauro; Cirillo, Fernando; Perfetti, Vittorio; Corti, Francesca; Ricci, Claudio; Giacomelli, Luca; Porcu, Luca; Di Maio, Massimo; Seregni, Ettore; Maccauro, Marco; Lastoria, Secondo; Bongiovanni, Alberto; Versari, Annibale; Persano, Irene; Rinzivillo, Maria; Pignata, Salvatore Antonio; Rocca, Paola Anna; Lamberti, Giuseppe; Cingarlini, Sara; Puliafito, Ivana; Ambrosio, Maria Rosaria; Zanata, Isabella; Bracigliano, Alessandra; Severi, Stefano; Spada, Francesca; Andreasi, Valentina; Modica, Roberta; Scalorbi, Federica; Milione, Massimo; Sabella, Giovanna; Coppa, Jorgelina; Casadei, Riccardo; Di Bartolomeo, Maria; Falconi, Massimo; de Braud, FilippoPusceddu, Sara; Prinzi, Natalie; Tafuto, Salvatore; Ibrahim, Toni; Filice, Angelina; Brizzi, Maria Pia; Panzuto, Francesco; Baldari, Sergio; Grana, Chiara M.; Campana, Davide; Davì, Maria Vittoria; Giuffrida, Dario; Zatelli, Maria Chiara; Partelli, Stefano; Razzore, Paola; Marconcini, Riccardo; Massironi, Sara; Gelsomino, Fabio; Faggiano, Antongiulio; Giannetta, Elisa; Bajetta, Emilio; Grimaldi, Franco; Cives, Mauro; Cirillo, Fernando; Perfetti, Vittorio; Corti, Francesca; Ricci, Claudio; Giacomelli, Luca; Porcu, Luca; Di Maio, Massimo; Seregni, Ettore; Maccauro, Marco; Lastoria, Secondo; Bongiovanni, Alberto; Versari, Annibale; Persano, Irene; Rinzivillo, Maria; Pignata, Salvatore Antonio; Rocca, Paola Anna; Lamberti, Giuseppe; Cingarlini, Sara; Puliafito, Ivana; Ambrosio, Maria Rosaria; Zanata, Isabella; Bracigliano, Alessandra; Severi, Stefano; Spada, Francesca; Andreasi, Valentina; Modica, Roberta; Scalorbi, Federica; Milione, Massimo; Sabella, Giovanna; Coppa, Jorgelina; Casadei, Riccardo; Di Bartolomeo, Maria; Falconi, Massimo; de Braud, Filipp

Scintillation light production, propagation, and detection in the 4-ton dual-phase LAr-TPC demonstrator (data analysis and simulations)

The Deep Underground Neutrino Experiment (DUNE) Far Detector (FD) will be formed by four 10-kton Liquid Argon (LAr) Time Projection Chambers (TPC) using both single and dual-phase technology. The dual-phase technology foreseen the charge amplification in the gas phase before the signal collection and is following a staged approach to demonstrate its feasibility at the DUNE FD scale. In 2017, a 4-ton demonstrator of 3x1x1 m$^3$ volume was exposed to cosmic muons and demonstrated expected performance in terms of charge extraction and light collection. A bigger prototype (ProtoDUNE-DP), with an active volume of 6x6x6 m$^3$, is currently under commissioning at CERN. The photon detection system in these detectors is crucial to provide the trigger signal giving an absolute time reference for the charge acquisition system of rare non-beam events and to provide complementary calorimetry. An overview of the analysis of the light collected in the 4-ton demonstrator has been presented. These prototypes confirmed the performance of the light detection system to provide trigger based on the scintillation light signal, to characterize the LAr response to the crossing muons and to monitor the LAr purity. The analyzed data are compared with MC simulations to improve the values of less understood LAr optical parameters such as the Rayleigh scattering length.The Deep Underground Neutrino Experiment (DUNE) Far Detector (FD) will be formed by four 10-kton Liquid Argon (LAr) Time Projection Chambers (TPC) using both single and dual-phase technology. The dual-phase technology foreseen the charge amplification in the gas phase before the signal collection and is following a staged approach to demonstrate its feasibility at the DUNE FD scale. In 2017, a 4-ton demonstrator of 3x1x1 m$^3$ volume was exposed to cosmic muons and demonstrated expected performance in terms of charge extraction and light collection. A bigger prototype (ProtoDUNE-DP), with an active volume of 6x6x6 m$^3$, is currently under commissioning at CERN. The photon detection system in these detectors is crucial to provide the trigger signal giving an absolute time reference for the charge acquisition system of rare non-beam events, and to provide complementary calorimetry. An overview of the analysis of the light collected in the 4-ton demonstrator has been presented. These prototypes confirmed the performance of the light detection system to provide trigger based on the scintillation light signal, to characterize the LAr response to the crossing muons and to monitor the LAr purity. The analyzed data are compared with MC simulations to improve the values of less understood LAr optical parameters such as the Rayleigh scattering length

Analysis of the scintillation light production and propagation in the WA105 Dual-Phase demonstrator

The next-generation long-baseline neutrino oscillation experiments aim to solve the main unanswered questions in neutrino physics, being sensitive to the observation of the CP violation in the lepton sector and the neutrino mass order. The Deep Underground Neutrino Experiment (DUNE) is one of these projects; the final design, still to be defined, consists of a far detector located 1300 km far away from the neutrino beam production at Fermilab and made of four 10-kton liquid argon (LAr) time projection chambers (TPCs), in single and dual-phase (DP) configurations. Although the LAr is a conventional medium for neutrino detectors, none of the two technologies have been worked with such a large volume. Consequently, the operation of small prototypes is crucial for demonstrating their scalability toward the giant scale. In DP LAr-TPCs, a pocket of gas argon (GAr) is kept above the LAr mass, allowing the extraction and amplification of ionization electrons before their collection at the anode plane. This configuration is particularly advantageous in large detectors because the charge amplification helps cover longer drift paths. In order to validate the suitability of the DP technology for DUNE, two prototypes with an increasing LAr active volume have been operated: the WA105-DP demonstrator, of 3x1x1 m3 (~4.2 tons), and ProtoDUNE-DP, of 6x6x6 m3 (~300 tons); both have been operated at CERN and exposed to cosmic muons for several months. The WA105-DP detector demonstrated the operability of the DP LAr-TPC at the ton scale, allowing to achieve important technological milestones, such as the extraction and amplification of ionization electrons over a 3m2 surface. In these kinds of detectors, the photon detection system (PDS) is used for triggering and it is expected to be valuable for discriminating non-beam or low-energy events. This thesis is dedicated to studying the scintillation light collected during the whole operation period of the WA105-DP prototype. The first part of the dissertation is focused on the study of the PDS performance; the main outcomes have been crucial to validating the design of this system for bigger DP LAr-TPC, as ProtoDUNE-DP and the DUNE DP far detector module. The second part of the thesis is devoted to the detailed characterization of the two light signals respectively produced in the liquid (primary scintillation light, S1) and gas (electroluminescence light, S2) Ar phases. Pioneering results have been achieved from the study of the primary scintillation light, which allowed to deepen the understanding of the LAr micro-physics. In particular, a detailed characterization of the scintillation light produced by cosmic muons crossing a DP LAr-TPC operated at the ton scale is presented. For the first time, the dependence of the scintillation time profile parameters on the electric drift field strength has been reported. The thorough knowledge of the S1 production and propagation in the LAr bulk contributed to a good improvement of the current simulations for physics sensitivity studies in big LAr detectors. Ultimately, the development of an algorithm dedicated to the reconstruction of the electroluminescence light signal led to its characterization, allowing the measurement of the drift velocity of ionization electrons, under low electric fields. Finally, for the first time, the impact of the amplification field on the S2 signal has been studied

Tau neutrino appearance measurement in KM3NeT/ORCA 6

International audienceKM3NeT/ORCA is a next-generation water Cherenkov neutrino telescope currently under construction in the Mediterranean Sea. By studying the oscillations of the atmospheric neutrino flux passing through the Earth, thanks to the detector geometry and its unprecedented statistics, KM3NeT/ORCA's primary physics goal is an early measurement of the neutrino mass ordering as well as the direct observation of tau neutrino appearance; the last, allowing for a test of the standard three-neutrino flavours paradigm. Due to the detector's modular structure, neutrino oscillation analyses are already possible with a partially instrumented volume. Given that the neutrino flux composition is dominated by muon neutrinos producing a track-like topology in the detector, the tau neutrinos can be identified as an excess into the shower-like topology, and the tau appearance, quantified in terms of the neutrino tau normalization, can be performed on statistical basis. In this summary, the focus will be given to the analysis of the data collected in the KM3NeT/ORCA 6 geometry (6 Detection Units, equivalent to 5% of the final geometry); the description of a novel Random Grid Search algorithm developed to optimize the track-shower selection will be reported