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Space Telescopes and Instrumentation 2022: Ultraviolet to Gamma Ray (2022), Montreal, Jul 17-22, 2022.--Proceedings of SPIE - The International Society for Optical Engineering vol. 12181 Article number 1218126.-- Full list of authors: Amati, Lorenzo; Labanti, Claudio; Mereghetti, Sandro; Frontera, Filippo; Campana, Riccardo; Auricchio, Natalia; Baldazzi, Giuseppe; Bellutti, Pierluigi; Bertuccio, Giuseppe; Branchesi, Marica; Butler, Reginald C.; Caballero-Garcia, Maria D.; Camisasca, Anna E.; Castro-Tirado, Alberto J.; Cavazzini, Leo; Ciolfi, Riccardo; De Rosa, Adriano; Evangelisti, Federico; Farinelli, Ruben; Ferro, Lisa; Ficorella, Francesco; Fiorini, Mauro; Fuschino, Fabio; Gasent-Blesa, Jose L.; Ghirlanda, Giancarlo; Grassi, Marco; Guidorzi, Cristiano; Hedderman, Paul; Kuvvetli, Irfan; La Rosa, Giovanni; Lorenzi, Paolo; Malcovati, Piero; Marchesini, Ezequiel; Marisaldi, Martino; Melchiorri, Michele; Mele, Filippo; Mikhalska, Malgorzata; Orlandini, Mauro; Orleanski, Piotr; Pedersen, Soren M.; Pizzolla, Raffaele; Rachevski, Alexandre; Rashevskaya, Irina; Rosati, Piero; Reglero, Victor; Ronchini, Samuele; Santangelo, Andrea; Salvaterra, Ruben; Sarra, Paolo; Sortino, Francesca; Sottile, Giuseppe; Stratta, Giulia; Squerzanti, Stefano; Stephen, John B.; Tenzer, Chris; Terenzi, Luca; Trois, Alessio; Vacchi, Andrea; Virgilli, Enrico; Volpe, Angela; Winkler, Marek; Zampa, Gianluigi; Zampa, Nicola; Zdziarski, Andrzej, We describe the science case, design and expected performances of the X/Gamma-ray Imaging Spectrometer (XGIS), a GRB and transients monitor developed and studied for the THESEUS mission project, capable of covering an exceptionally wide energy band (2 keV – 10 MeV), with imaging capabilities and location accuracy, With funding from the Spanish government through the Severo Ochoa Centre of Excellence accreditation SEV-2017-0709

PURPOSE Patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) have a poor prognosis, and their treatment represents an urgent and unmet need. Because PMBCL is associated with genetic aberrations at 9p24 and overexpression of programmed cell death-1 (PD-1) ligands (PD-L1), it is hypothesized to be susceptible to PD-1 blockade. METHODS In the phase IB KEYNOTE-013 (ClinicalTrials.gov identifier: NCT01953692 ) and phase II KEYNOTE-170 (ClinicalTrials.gov identifier: NCT02576990 ) studies, adults with rrPMBCL received pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity. The primary end points were safety and objective response rate in KEYNOTE-013 and objective response rate in KEYNOTE-170. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Exploratory end points included association between biomarkers and pembrolizumab activity. RESULTS The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival. CONCLUSION Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.

Currently, no information is available regarding the influence of the different CD34+ cell subsets infused on the haematopoietic recovery, following non-myeloablative allogeneic peripheral blood stem cell transplantation (allo-PBSCT). We have explored, in a group of 13 patients receiving non-myeloablative allo-PBSCT from human leucocyte antigen-identical sibling donors, the influence of the total dose of CD34+ haematopoietic progenitor cells (HPC) infused, compared with that of the different CD34+ HPC and CD34- leucocyte subsets in the leukapheresis samples, on both engraftment and clinical outcome. The overall numbers of total CD34+ HPC (P = 0.002) and myelomonocytic-committed CD34+ HPC infused (P = 0.0002) were strongly associated with neutrophil recovery (1 x 109 neutrophils/l), the latter being the only independent parameter influencing neutrophil recovery. Regarding long-term engraftment, only the number of immature CD34+ HPC infused/kg correlated with the duration of hospitalization in the first 2 years after discharge (r = -0.75, P = 0.005). Both the overall amount of CD34+ HPC and the number of myelomonocytic CD34+ HPC infused showed a significant influence on the risk of graft-versus-host disease (GVHD). Thus, the overall probability of GVHD was 100%vs 25% for patients receiving/= 5 x 106 CD34+ HPC or/= 3.5 x 106 of myelomonocytic-committed CD34+ HPC vs lower doses (P = 0.013). None of the other CD34+ and CD34- cell subsets analysed correlated with development of GVHD. In summary, our results suggest that in non-myeloablative allo-PBSCT, high numbers of CD34+ HPC, especially the myelomonocytic-committed CD34+ progenitors, lead to rapid neutrophil engraftment. However, they also strongly impair clinical outcome by increasing the incidence of GVHD.

In order to gain further insights into the role of the p16 gene in cell cycle regulation and the prognostic implications of its inactivation, we investigated the methylation status of the p16 gene in 98 untreated patients using a polymerase chain reaction assay based on the inability of some restriction enzymes to digest methylated sequences. Forty-one patients showed a p16 methylated gene (42%). The percentage of S-phase plasma cells (PC) in these patients was almost three times higher than in those with an unmethylated p16 gene (4.16% +/- 3.37%vs 1.5% +/- 1.41%, P0.001). The presence of p16 methylation also correlated with both elevated beta2-microglobulin serum levels and high C-reactive protein values. Patients with a p16 methylated gene had shorter overall and progression-free survival than those patients without p16 methylation. However, this feature did not retain independent prognostic influence on multivariate analysis, probably due to its association with the S-phase PC, which had more potent statistical significance in the Cox model. These findings showed methylation of the p16 gene was a frequent event inMM patients at diagnosis, and was associated with an increased proliferative rate of plasma cells and a poor prognosis, indicating an important role for p16 gene in the cell cycle regulation of multiple myeloma tumour cells, and thus in the clinical outcome of the disease.