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Experimental evidence is growing, supporting the evidence of a considerable normal tissue sparing effect when treatments are delivered with dose rates much larger with respect to the conventional ones [1]. In particular, an increasing of the therapeutic window has been demonstrated for dose rates over 50 Gy/s, over a large variety of in-vivo experiments [2]. If confirmed, the ‘FLASH effect’ has the potential to re-shape the future of radiation treatments, with a significant impact on many oncology patients [3]. Ultra-high dose rate (UHDR) beams for FLASH radiotherapy present significant dosimetric challenges [4]. Ionization chambers are affected by ion recombination effects, although novel approaches for decreasing or correcting for this effect are being proposed [5]. Passive dosimeters, as radiochromic films and alanine [6], could be used for UHDR measurements, although dose determination is typically time consuming. Solid state detectors, such as diamond or Silicon Carbide (SiC) detectors, have been also recently investigated, as a valuable alternative for real-time measurements. In this work we analysed the response of alanine pellets to UHDR electron beams. Irradiations of alanine pellets with electron beams at 7 and 9 MeV, accelerated by a SIT-Sordina ElectronFlash Linac, at conventional and UHDR regimes have been carried out. Average dose rates up several hundreds of Gy/s were used for the experimental campaign, with instantaneous dose rate even more two orders of magnitudes larger. Indeed, pulse structure of the used accelerator is characterized by a pulse duration between 1-4 us and a frequency up to hundreds of Hz. The analysis of the depth dose profile performed by stacking alanine pellets along the electron beam direction allowed to evaluate whether a dependence on the dose rate is present for these UHDR beams. The experimental results were aided by computational analyses. The results will be presented and discussed in details.

In this paper, a complete methodology to design a modular brushless wound rotor synchronous machine is proposed. From a schedule of conditions and a chosen structure (with 7 phases, 7 slots and 6 poles), a non-linear and non-convex optimization problem is defined and solved using NOMAD (a derivative free local optimization code): the external volume is minimized under some constraints, which are the average torque equal to 5 Nm, the torque ripple less than 5%, the efficiency greater than 94%, and the surface temperature less than 85 °C. The constraints have to be computed using 2D-finite element simulations in order to reduce the CPU-time consumption for each NOMAD iteration. Moreover, a relaxation of this optimization problem makes it possible to provide an efficient starting point for NOMAD. Thus, a good optimal design is obtained, and it is then validated by using 3D electromagnetic and thermic numerical methods. These numerical verifications show that, inside the end-winding, the leakage flux is high. This yields a lot of iron losses in this machine. Moreover, the surface and coil temperature differences between the 2D and 3D numerical approaches are discussed. Finally, the machine prototype is built following the optimal dimensions and a POKI-POKITM assembly technology. Preliminary experimental tests are carried out, and the results are devoted to the comparison of measured and predicted 3D numerical results.

Ultra-high dose rate (UHDR) beams for FLASH radiotherapy present significant dosimetric challenges. Although novel approaches for decreasing or correcting ion recombination in ionization chambers are being proposed, applicability of ionimetric dosimetry to UHDR beams is still under investigation. Solid-state sensors have been recently investigated as a valuable alternative for real-time measurements, especially for relative dosimetry and beam monitoring. Among them, Silicon Carbide (SiC) represents a very promising candidate, compromising between the maturity of Silicon and the robustness of diamond. Its features allow for large area sensors and high electric fields, required to avoid ion recombination in UHDR beams. In this study, we present simulations and experimental measurements with the low energy UHDR electron beams accelerated with the ElectronFLASH machine developed by the SIT Sordina company (IT). The response of a newly developed 1 × 1 cm2 SiC sensor in charge as a function of the dose-per-pulse and its radiation hardness up to a total delivered dose of 90 kGy, was investigated during a dedicated experimental campaign, which is, to our knowledge, the first characterization ever done of SiC with UHDR-pulsed beams accelerated by a dedicated ElectronFLASH LINAC. Results are encouraging and show a linear response of the SiC detector up to 2 Gy/pulse and a variation in the charge per pulse measured for a cumulative delivered dose of 90 kGy, within ±0.75%.

For permissionless blockchains, scalability is paramount. While current technologies still fail to address this problem fully, many research works propose sharding or other techniques that extensively adopt parallel processing of transactions. In these approaches, a potentially large number of committees of nodes independently perform consensus and process new transactions. Hence, in addition to regular intra-committee communication, (1) new transactions have to be delivered to the right committee, (2) committees need to communicate to process inter-shard transactions or (3) to exchange intermediate results. To contrast slowly adaptive adversaries, committees should be frequently changed. However, efficient communication to frequently-changing committees is hard. We propose a simple approach that allows us to implicitly select committee members and effectively deliver messages to all members of a specific committee, even when committees are changed frequently. The aim of our design is to provide a committee selection procedure and a committee-targeted communication primitive to be applied in most of the scalable blockchain architectures that are currently proposed in literature. We provide a theoretical proof of the security of our approach and first experimental results that shows that our approach might be feasible in practice.

The origin of radiotherapy dates back to 1895-immediately after the discovery of X-rays. Since the beginning, efforts were focused on developing ways to improve the accuracy of radiation delivery. Molecular imaging allows the visualization of surrogates of several pathophysiological characteristics of tumor tissue (e.g., proliferation, metabolism, hypoxia, perfusion), allowing tailoring of dose distribution based on the tissue's features and biological patterns within the tumor. A significant improvement in the ability of modern radiotherapy to precisely target tumor while avoiding irradiating normal tissues can be achieved by integrating molecular imaging into an individualized radiation treatment planning. PET data are the most common molecular images used for tumor volume delineation and assessment of pathophysiological characteristics of tissue. The type of radiopharmaceutical used allows visualization and understanding of different pathophysiologic information. The most commonly used among all PET tracers is the 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG). [18F]FDG is currently the mainstay of PET use in radiotherapy. With the aim of identifying specific biological tumor processes and offering valuable information that can assist radiation oncologist to modulate radiotherapy's doses and volumes, several other molecular imaging tracers emerged in the last few years. Non-[18F]FDG tracers commonly used in radiation oncology include [11C]Methionine ([11C]MET) for brain tumors; [18F]FDOPA for brain and neuroendocrine tumors; radiolabeled somatostatin analogs for somatostatin-receptor positive tumors; 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) and 18F-fluoromisonidazole (18F-FMISO) to identify regions of radiation resistance within the tumor; and [11C]/[18F]Choline, [18F]/68Ga-PSMA, and 18F-Fluciclovine for prostate cancer.

The armamentarium of approved radiopharmaceuticals for either diagnosis or therapy is at the core of the clinical practice of today's nuclear medicine. Nevertheless, both because the currently approved agents do not meet all the clinical needs for radionuclide targeting and because advancing knowledge in the pathophysiology of tissues/organs opens in turn new opportunities, investigations continue at the preclinical and clinical validation level for the development of new radiopharmaceuticals, most of which are not approved yet for commercial use. Concerning in particular the diagnostic applications of nuclear medicine to oncology, ongoing investigations in the search for tumor-targeting agents with better specificity and sensitivity are countless, possibly within the scenario of theranostics-that is, with the dual potential for imaging and for therapy, depending on the specific radionuclide employed for radiolabeling. We will focus this chapter on the most promising imaging agents labeled with single-photon-emitting radionuclides based on some of the mechanisms that are typical for tumor cells/tissues.

Monoclonal antibodies (MAbs) raised against cancer antigens may mediate antibody-dependent cell-mediated cytotoxicity. This form of cancer control arises from cytolysis of a target cell by effector lymphocytes, such as cytotoxic T lymphocytes or natural killer cells. However, most of these antibodies have low/moderate efficacy in the tumor control. Antibodies targeting hormone receptors expressed by cancer have shown greater tumor control compared with other cell membrane targets. Moreover, the labeling of these antibodies with a toxin can potentiate their efficacy in the tumor control. In this way, the antibody becomes an invaluable targeting vector for delivery of the toxin to the cancer cells. The toxin/antibody complex is called the immunoconjugate. Different molecules, chemicals, or radioisotopes can serve themselves as toxins; toxins may have long half-lives in the body (e.g., ricin), thus increasing the toxicity to both the cancer and normal tissues. However, the different radioisotopes (e.g., iodine-131, lutetium-177) have a wide range of half-lives and radiation decay that make them useful for different applications. Beta-emitting radioisotopes, predominantly I-131, have had only modest success in radioimmunotherapy. More recently, high linear energy transfer (LET) radiation in the form of alpha particles has been studied: alpha radiation is ideal for killing isolated cancer cells in transit in the vascular and lymphatic systems and regressing tumors by disruption of tumor capillary networks by targeting and killing tumor capillary endothelial cells. Over the past 20 years the development of alpha-immunoconjugates has enabled targeted alpha therapy (TAT) to progress from in vitro studies, through in vivo experiments, to clinical trials. The dose to normal tissues always provides a limitation to the injected dose and that received by the tumor. However, TAT can achieve cancer regression within the maximum tolerance dose for normal tissue. TAT was originally thought to be an ideal therapy for "liquid" cancers, e.g., leukemia and micro-metastases, as the short half-lives of the radioisotopes were sufficient to target these cancer cells and the short range ensured that the targeted cancer cells received the highest radiation dose. Different antibodies have been developed and tested in clinical trials as conditioning treatment, but none of them have yet been approved for radioimmunotherapy (RIT) in multiple myeloma (MM). Addiotinally, bone-seeking radiopharmaceuticals are being evaluated in MM patients in the transplant setting.

Multiple myeloma (MM) represents about 1.8% of all cancers and 10% of all hematologic malignancies. MM is the most common primary bone cancer. The clonal proliferation of malignant plasma cells in the bone marrow may result both in local growth and in systemic effects due to the overproduction of a monoclonal protein (M-protein). Plasma cell proliferation is linked to a variety of clinical presentations of the disease, ranging from simple monoclonal gammopathy of undetermined significance (MGUS) to smoldering myeloma (SMM) to full-blown "malignant" MM. MM differs from MGUS and SMM by the presence of the end-organ damage associated with a complex syndrome named CRAB. However, in the updated version of the criteria for the diagnosis of plasma cell proliferative disorders established by the International Myeloma Working Group (IMWG), more specific criteria have been established to define MM, MGUS, and SMM. Excess bone marrow plasma cells, M-protein, osteolytic bone lesions, renal disease, and immunodeficiency constitute the pathophysiologic bases of the clinical manifestations of MM. Severe bone pain, pathologic fractures, spinal cord compression, and hypercalcemia are caused by lytic bone lesions. The course of MM is highly variable, and the clinical behavior is remarkably heterogeneous. Many studies have identified prognostic factors capable of predicting this heterogeneity in survival (serum β2-microglobulin, albumin, C-reactive protein, and lactate dehydrogenase). The standard workup of MM is based on a number of laboratory tests that are utilized for risk stratification. The International Staging System (ISS) is a powerful and reproducible three-stage classification in which the ISS3 class is associated with the poorest outcome. Imaging studies demonstrate the extent and severity of bone involvement (intramedullary/extramedullary, site and number of lesions) at baseline, including disease-related complications, such as pathologic fractures; they also serve to assess response to treatment and provide follow-up surveillance. The ISS introduced over 25 years ago is mainly based on serum β2-microglobulin and albumin levels, without any reference to the presence of bone lesions or to the methodology employed for their evaluation. Although the ISS serves as a prognostic indicator rather than as an accurate scoring system, it adequately estimates tumor burden and risk stratification, allowing differentiation of MGUS and SMM from MM. In 1975, Durie and Salmon introduced a clinical staging system based on the presence of bone lesions to grade the severity of the disease. While the original Durie and Salmon system was essentially based on the use of planar X-ray for evaluating bones, a newer version, the PLUS system, was released in 2005 to improve the accuracy of staging with advanced imaging modalities such as [18F]FDG-PET/CT and MRI.

RationalePulse glucocorticoid therapy is used in hyperinflammation related to coronavirus disease 2019 (COVID-19). We evaluated the efficacy and safety of pulse intravenous methylprednisolone in addition to standard treatment in COVID-19 pneumonia.MethodsIn this multicentre, randomised, double-blind, placebo-controlled trial, 304 hospitalised patients with COVID-19 pneumonia were randomised to receive 1 g of methylprednisolone intravenously for three consecutive days or placebo in addition to standard dexamethasone. The primary outcome was the duration of patient hospitalisation, calculated as the time interval between randomisation and hospital discharge without the need for supplementary oxygen. The key secondary outcomes were survival free from invasive ventilation with orotracheal intubation and overall survival.ResultsOverall, 112 (75.4%) out of 151 patients in the pulse methylprednisolone arm and 111 (75.2%) of 150 in the placebo arm were discharged from hospital without oxygen within 30 days from randomisation. Median time to discharge was similar in both groups (15 days, 95% CI 13.0–17.0 days and 16 days, 95% CI 13.8–18.2 days, respectively; hazard ratio (HR) 0.92, 95% CI 0.71–1.20; p=0.528). No significant differences between pulse methylprednisolone and placebo arms were observed in terms of admission to intensive care unit with orotracheal intubation or death (20.0%versus16.1%; HR 1.26, 95% CI 0.74–2.16; p=0.176) or overall mortality (10.0%versus12.2%; HR 0.83, 95% CI 0.42–1.64; p=0.584). Serious adverse events occurred with similar frequency in the two groups.ConclusionsMethylprenisolone pulse therapy added to dexamethasone was not of benefit in patients with COVID-19 pneumonia.

Leukemias are a group of acute and chronic hematological neoplasias characterized by the dissemination of cancer cells originating in the bone marrow via the bloodstream. In 2016, the estimated number of new leukemia cases was more than 110,000 in all of Europe and 47,000 in the USA. Leukemia is the cause of 4% of all cancer deaths and accounts for 3.6% of all cancers. Historically, leukemias have been divided into four major categories further classified into subtypes based on specific features of cells: acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML). A revised classification of myeloid/lymphoid neoplasms and leukemias has recently been published to better characterize each disease. This updated classification incorporated new scientific and clinical information to refine diagnostic criteria for previously described neoplasms and introduced newly recognized disease entities. In this chapter, the main entities of leukemia, with specific regard to imaging for diagnosis, treatment response assessment, and follow-up, will be treated according to what is reported in the clinical guidelines.

Molecular targeting requires assessing several factors that come into play such as the location of the target, the choice of radionuclide, the inertness of the bifunctional chelate and stability of the covalently bound halogens, matching the residence time in the tumor with the physical half-life of the radionuclide, the scale and scope of the disease, and the absorbed dose sensitivity of the targeted tumor compared to normal tissue. The principles of molecular targeting are well established, but a paradigm shift from designing a medium-affinity radiotracer used to determine target density to designing a high-affinity, high-target density radioligand to maximize the target-to-nontarget ratio should increase the probability of detecting lesions smaller than the instrument resolution. Developing and validating a therapeutic radiopharmaceutical for a single target is necessary, but often not sufficient to produce a toxic event because of other mechanisms that are only partially understood. These include nontargeted effects due to radiation emitted from neighboring, targeted cells as well as bystander effects produced by the cellular processing of radiation not necessarily impinging on DNA. Both of these indirect consequences of cellular radiation could make a substantial contribution to the efficacy of targeted radionuclide therapy. These mechanisms should be exploited to optimize the efficacy of targeted radiotherapy and overcome the inefficiency of tumor control due to nonuniform distribution of radiation dose. The design approach to take advantage of the indirect consequences of cellular radiation depends heavily on further elucidation of the indirect effect. The successful combination of these two should lead to more effective nuclear radiotherapy.

Radiopharmaceuticals contain a radionuclide and an agent to direct the radionuclide to a receptor, antigen, ionic pump, or other sites of interest. Some radiopharmaceuticals are simple, such as the ionic form of the radionuclide, while most radiopharmaceuticals have a complex chemical structure where the radionuclide provides a signal, indicating the site of localization of the carrier molecule. Common single-photon radiopharmaceuticals used for oncological diagnosis include the agents labeled with 99mTc such as 99mTc-bisphosphonates (that accumulate at sites of bone mineral deposition), 99mTc-labeled colloids (that are used for lymphoscintigraphy and for imaging of the liver and spleen), 99mTc-hexakis-methoxy-isobutyl-isonitrile, and 99mTc-tetrofosmin (initially employed for myocardial perfusion imaging, and also used for localization of parathyroid adenomas and for identification of other malignant tumors). The most commonly used radiopharmaceuticals labeled with radioiodine (123I or 131I) include iodide itself (for localization of thyroid tissue) and the catecholamine analog metaiodobenzylguanidine (MIBG, for localizing pheochromocytoma and neuroblastoma). Thallium-201 chloride (201Tl) is used for myocardial perfusion imaging as well as tumor perfusion imaging, while 111In-pentetreotide detects overexpression of somatostatin receptors, especially in neuroendocrine tumors and in lesions arising from the neural crest, such as carcinoid, paragangliomas, and medullary thyroid carcinomas. 111In-capromab pendetide is a murine monoclonal antibody recognizing a transmembrane glycoprotein expressed by poorly differentiated and metastatic prostate adenocarcinomas. 67Ga-citrate receptors are overexpressed on membranes of both tumor and inflammatory cells.