A fast - Monte Carlo toolkit on GPU for treatment plan dose recalculation in proton therapy

In the context of the particle therapy a crucial role is played by Treatment Planning Systems (TPSs), tools aimed to compute and optimize the tratment plan. Nowadays one of the major issues related to the TPS in particle therapy is the large CPU time needed. We developed a software toolkit (FRED) for reducing dose recalculation time by exploiting Graphics Processing Units (GPU) hardware. Thanks to their high parallelization capability, GPUs significantly reduce the computation time, up to factor 100 respect to a standard CPU running software. The transport of proton beams in the patient is accurately described through Monte Carlo methods. Physical processes reproduced are: Multiple Coulomb Scattering, energy straggling and nuclear interactions of protons with the main nuclei composing the biological tissues. FRED toolkit does not rely on the water equivalent translation of tissues, but exploits the Computed Tomography anatomical information by reconstructing and simulating the atomic composition of each crossed tissue. FRED can be used as an efficient tool for dose recalculation, on the day of the treatment. In fact it can provide in about one minute on standard hardware the dose map obtained combining the treatment plan, earlier computed by the TPS, and the current patient anatomic arrangement

An 81-Year-Old Man with a 6-Year History of Chronic Lymphocytic Leukemia Presenting with Disease Flare Following Ibrutinib Discontinuation

Patient: Male, 81-year-old Final Diagnosis: Chronic lymphocytic leukemia Symptoms: Fever Medication: — Clinical Procedure: — Specialty: Hematology Objective: Background: Case Report: Conclusions: Unusual clinical course Chronic lymphocytic leukemia (CLL) is a mature B-cell neoplasm and the most common leukemia in adults in Western countries. Novel agents, including BTK inhibitors and the BCL2 inhibitor venetoclax, have dramati-cally changed the treatment landscape. Moreover, a disease flare, characterized by sudden worsening of clinical symptoms, radiographic findings of rapidly worsening splenomegaly or lymphadenopathy, and laboratory changes (increased absolute lymphocyte count or lactate dehydrogenase), is a phenomenon described in up to 25% of patients with CLL after ibrutinib discontinuation. We describe a patient with CLL with disease flare after ibrutinib discontinuation due to disease progression and describe the subsequent management of vene-toclax initial treatment in the course of the disease flare. We describe the case of an 81-year-old man with a 6-year history of CLL who was treated with multiple lines of therapy and developed worsening of disease-related signs and symptoms with fever, marked increase of lym-phocyte count, acute worsening of renal function, and increase in lymph nodes and spleen size following ces-sation of targeted therapy with ibrutinib at the time of disease progression. There was subsequent overlap-ping of ibrutinib during the venetoclax dose escalation period to prevent disease flare recurrence. Our report highlights the problem of disease flare after ibrutinib discontinuation in order to avoid associated patient morbidity, underscoring the importance of awareness of this phenomenon and focusing on the addition of venetoclax at time of progression in ibrutinib-treated patients, as a temporary overlap strategy, to prevent disease flare

A fast - Monte Carlo toolkit on GPU for treatment plan dose recalculation in proton therapy

In the context of the particle therapy a crucial role is played by Treatment Planning Systems (TPSs), tools aimed to compute and optimize the tratment plan. Nowadays one of the major issues related to the TPS in particle therapy is the large CPU time needed. We developed a software toolkit (FRED) for reducing dose recalculation time by exploiting Graphics Processing Units (GPU) hardware. Thanks to their high parallelization capability, GPUs significantly reduce the computation time, up to factor 100 respect to a standard CPU running software. The transport of proton beams in the patient is accurately described through Monte Carlo methods. Physical processes reproduced are: Multiple Coulomb Scattering, energy straggling and nuclear interactions of protons with the main nuclei composing the biological tissues. FRED toolkit does not rely on the water equivalent translation of tissues, but exploits the Computed Tomography anatomical information by reconstructing and simulating the atomic composition of each crossed tissue. FRED can be used as an efficient tool for dose recalculation, on the day of the treatment. In fact it can provide in about one minute on standard hardware the dose map obtained combining the treatment plan, earlier computed by the TPS, and the current patient anatomic arrangement

A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis

BACKGROUND: Systemic sclerosis (SSc) is a multi-organ autoimmune disease characterized by skin fibrosis. Internal organ involvement is heterogeneous. It is unknown whether disease mechanisms are common across all involved affected tissues or if each manifestation has a distinct underlying pathology. METHODS: We used consensus clustering to compare gene expression profiles of biopsies from four SSc-affected tissues (skin, lung, esophagus, and peripheral blood) from patients with SSc, and the related conditions pulmonary fibrosis (PF) and pulmonary arterial hypertension, and derived a consensus disease-associate signature across all tissues. We used this signature to query tissue-specific functional genomic networks. We performed novel network analyses to contrast the skin and lung microenvironments and to assess the functional role of the inflammatory and fibrotic genes in each organ. Lastly, we tested the expression of macrophage activation state-associated gene sets for enrichment in skin and lung using a Wilcoxon rank sum test. RESULTS: We identified a common pathogenic gene expression signature-an immune-fibrotic axis-indicative of pro-fibrotic macrophages (MØs) in multiple tissues (skin, lung, esophagus, and peripheral blood mononuclear cells) affected by SSc. While the co-expression of these genes is common to all tissues, the functional consequences of this upregulation differ by organ. We used this disease-associated signature to query tissue-specific functional genomic networks to identify common and tissue-specific pathologies of SSc and related conditions. In contrast to skin, in the lung-specific functional network we identify a distinct lung-resident MØ signature associated with lipid stimulation and alternative activation. In keeping with our network results, we find distinct MØ alternative activation transcriptional programs in SSc-associated PF lung and in the skin of patients with an "inflammatory" SSc gene expression signature. CONCLUSIONS: Our results suggest that the innate immune system is central to SSc disease processes but that subtle distinctions exist between tissues. Our approach provides a framework for examining molecular signatures of disease in fibrosis and autoimmune diseases and for leveraging publicly available data to understand common and tissue-specific disease processes in complex human diseases

Delivery status of the ELI-NP gamma beam system

International audienceThe ELI-NP GBS is a high intensity and monochromatic gamma source under construction in Magurele (Romania). The design and construction of the Gamma Beam System complex as well as the integration of the technical plants and the commissioning of the overall facility, was awarded to the Eurogammas Consortium in March 2014. The delivery of the facility has been planned in for 4 stages and the first one was fulfilled in October 31st 2015. The engineering aspects related to the delivery stage 1 are presented

High power test results of the Eli-NP S-Band gun fabricated with the new clamping technology without brazing

High gradient RF photoguns have been a key development to enable several applications of high quality electron beams. They allow the generation of beams with very high peak current and low transverse emittance, thus satisfying the tight demands of free-electron lasers, energy recovery linacs, Compton/Thomson sources and high-energy linear colliders. A new fabrication technique for this type of structures has been recently developed and implemented at the Laboratories of Frascati of the National Institute of Nuclear Physics (INFN-LNF, Italy). It is based on the use of special RF-vacuum gaskets, that allow a brazing-free realization process. The S-band gun of the ELI-NP gamma beam system (GBS) has been fabricated with this new technique. It operates at 100 Hz with 120 MV/m cathode peak field and 1.5 μs long RF pulses to house the 32 bunches necessary to reach the target gamma flux. High gradient tests, performed at full power and full repetition rate, have shown extremely good performances of the structure in terms of breakdown rate. In the paper, we report and discuss all the experimental results, the electromagnetic design and the mechanical realization processes

Beam manipulation for resonant plasma wakefield acceleration

Plasma-based acceleration has already proved the ability to reach ultra-high accelerating gradients. However the step towards the realization of a plasma-based accelerator still requires some e ff ort to guarantee high brightness beams, stability and reliability. A significant improvement in the efficiency of PWFA has been demonstrated so far accelerating a witness bunch in the wake of a higher charge driver bunch. The transformer ratio, therefore the energy transfer from the driver to the witness beam, can be increased by resonantly exciting the plasma with a properly pre-shaped drive electron beam. Theoretical and experimental studies of beam manipulation for resonant PWFA will be presented her

Neoantigen-specific T-cell immune responses: The paradigm of NPM1-mutated acute myeloid leukemia

The C-terminal aminoacidic sequence from NPM1-mutated protein, absent in normal human tissues, may serve as a leukemia-specific antigen and can be considered an ideal target for NPM1-mutated acute myeloid leukemia (AML) immunotherapy. Different in silico instruments and in vitro/ex vivo immunological platforms have identified the most immunogenic epitopes from NPM1-mutated protein. Spontaneous development of endogenous NPM1-mutated-specific cytotoxic T cells has been observed in patients, potentially contributing to remission maintenance and prolonged survival. Genetically engineered T cells, namely CAR-T or TCR-transduced T cells, directed against NPM1-mutated peptides bound to HLA could prospectively represent a promising therapeutic approach. Although either adoptive or vaccine-based immunotherapies are unlikely to be highly effective in patients with full-blown leukemia, these strategies, potentially in combination with immune-checkpoint inhibitors, could be promising in maintaining remission or preemptively eradicat-ing persistent measurable residual disease, mainly in patients ineligible for allogeneic hematopoietic stem cell transplant (HSCT). Alternatively, neoantigen-specific donor lymphocyte infusion derived from healthy donors and targeting NPM1-mutated protein to selectively elicit graft-versus-leukemia effect may represent an attractive option in subjects experiencing post-HSCT relapse. Future studies are warranted to further investigate dynamics of NPM1-mutated-specific immunity and explore whether novel individualized immunotherapies may have potential clinical utility in NPM1-mutated AML patients