A Compact Neutron Generator for the Niort® Treatment of Severe Solid Cancers

In the last four years, TheranostiCentre S.r.l , Berkion Technology LLC and ENEA have patented and fabricated a first prototype of a Compact Neutron Generator (CNG) currently under testing in the ENEA laboratories. Besides the usual applications in the field of materials irradiation, this CNG - producing neutrons of 2.45 MeV energy through the deuterium-deuterium (DD) fusion reaction - was conceived for the neutron irradiation of the solid cancer’s tumour bed by means of the Intra-Operative Radiotherapy (IORT) technique, the so-called neutron-IORT (nIORT®). The DD-CNG is self-shielded and light-weight (~120 kg) making possible its remote handling by a robotic arm. Accurate Monte Carlo simulations, modelling the CNG and the “open wound” biological tissues near its irradiation window, demonstrated that the apparatus operated at 100 kV-10 mA supplies a neutron flux ~108 cm-2 s-1 and can deliver equivalent dose rates ~2 Gy (RBE)/min. Hence, it can administer very high dose levels in limited treatment times. This article briefly summarizes the main findings of this collaborative research study, the clinical rationales underpinning the nIORT® idea and the potential performances of the DD-CNG for the treatment of solid cancer pathologies. Indeed, the CNG can be installed in an operating room dedicated to nIORT® treatments, without posing any environmental and safety issues. Monte Carlo simulations have been carried out by envisioning the CNG equipped with an IORT applicator, that is an applicator pipe with a tuneable diameter to be inserted in the surgical cavity. By foreseeing the clinical endpoints of the standard IORT protocols, the irradiation performances for potential nIORT® treatments - obtained with an applicator pipe of 6 cm diameter - are here reported for different regimes: from 10 up to 75 Gy (RBE), that can be administered in a single session of about 4 to 30 minutes. Besides the dose peak in the centre of the tumour bed, the almost isotropic neutrons emission allows to irradiate its surroundings side-walls – usually filled by potential quiescent cancer cells – and therefore reducing the chances of local recurrences by improving the local control of the tumour. The rapid decrease in tissues depth of the dose profile (in few centimetres) will spare the neighbouring organs at risk from harmful radiations. Thus, the DD-CNG apparatus developed for nIORT® applications can potentially improve the resectability rate of a given neoadjuvant cancer treatment and, generally, could satisfy all five R’s criteria of radiotherapy. Furthermore, in comparing with the current IORT techniques with electrons or low-keV Xrays, the nIORT® exploiting a high-flux neutrons beam of 2.45 MeV energy could lead to some significant clinical advantages due to its high linear energy transfer (~ 40 keV/mm as average) and significantly higher relative biological effectiveness (@16) than all other forms of ionizing radiation

Design of an epithermal column for BNCT based on D–D fusion neutron facility

Abstract Boron Neutron Capture Therapy (BNCT) is currently performed on patients at nuclear reactors. At the same time the international BNCT community is engaged in the development of alternative facilities for in-hospital treatments. This paper investigates the potential of a novel high-output D–D neutron generator, developed at Lawrence Berkeley National Laboratory (CA, USA), for BNCT. The simulation code MCNP-4C is used to realize an accurate study of the epithermal column in view of the treatment of deep tumours. Different materials and Beam Shaping Assemblies (BSA) are investigated and an optimized configuration is proposed. The neutron beam quality is defined by the standard free beam parameters, calculated averaging over the collimator aperture. The results are discussed and compared with the performances of other facilities

Establishment of a patient-derived intrahepatic cholangiocarcinoma xenograft model with KRAS mutation.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is an aggressive, highly lethal tumors and lacks of effective chemo and targeted therapies. Cell lines and animal models, even partially reflecting tumor characteristics, have limits to study ICC biology and drug response. In this work, we created and characterized a novel ICC patient-derived xenograft (PDX) model of Italian origin. METHODS: Seventeen primary ICC tumors derived from Italian patients were implanted into NOD (Non-Obese Diabetic)/Shi-SCID (severe combined immunodeficient) mice. To verify if the original tumor characteristics were maintained in PDX, immunohistochemical (cytokeratin 7, 17, 19, and epithelial membrane antigen) molecular (gene and microRNA expression profiling) and genetic analyses (comparative genomic hybridization array, and mutational analysis of the kinase domain of EGFR coding sequence, from exons 18 to 21, exons 2 to 4 of K-RAS, exons 2 to 4 of N-RAS, exons 9 and 20 of PI3KCA, and exon 15 of B-RAF) were performed after tumor stabilization. RESULTS: One out of 17 (5.8 %) tumors successfully engrafted in mice. A high molecular and genetic concordance between primary tumor (PR) and PDX was confirmed by the evaluation of biliary epithelial markers, tissue architecture, genetic aberrations (including K-RAS G12D mutation), and transcriptomic and microRNA profiles. CONCLUSIONS: For the first time, we established a new ICC PDX model which reflects the histology and genetic characteristics of the primary tumor; this model could represent a valuable tool to understand the tumor biology and the progression of ICC as well as to develop novel therapies for ICC patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-016-2136-1) contains supplementary material, which is available to authorized users

Pursuit of Gene Fusions in Daily Practice: Evidence from Real-World Data in Wild-Type and Microsatellite Instable Patients

Agnostic biomarkers such as gene fusions allow to address cancer patients to targeted therapies; however, the low prevalence of these alterations across common malignancies poses challenges and needs a feasible and sensitive diagnostic process. RNA-based targeted next generation sequencing was performed on 125 samples of patients affected either by colorectal carcinoma, melanoma, or lung adenocarcinoma lacking genetic alterations in canonical driver genes, or by a colorectal carcinoma with microsatellite instability. Gene fusion rates were compared with in silico data from MSKCC datasets. For NTRK gene fusion detection we also employed a multitarget qRT-PCR and pan-TRK immunohistochemistry. Gene fusions were detected in 7/55 microsatellite instable colorectal carcinomas (12.73%), and in 4/70 of the “gene driver free” population (5.71%: 3/28 melanomas, 10.7%, and 1/12 lung adenocarcinomas, 8.3%). Fusion rates were significantly higher compared with the microsatellite stable and “gene driver positive” MSKCC cohorts. Pan-TRK immunohistochemistry showed 100% sensitivity, 91.7% specificity, and the occurrence of heterogeneous and/or subtle staining patterns. The enrichment of gene fusions in this “real-world” cohort highlights the feasibility of a workflow applicable in clinical practice. The heterogeneous expression in NTRK fusion positive tumours unveils challenging patterns to recognize and raises questions on the effective translation of the chimeric protein

Targeting EGFR/HER2 pathways enhances the antiproliferative effect of gemcitabine in biliary tract and gallbladder carcinomas

<p>Abstract</p> <p>Background</p> <p>Advanced biliary tract carcinomas (BTCs) have poor prognosis and limited therapeutic options. Therefore, it is crucial to combine standard therapies with molecular targeting. In this study EGFR, HER2, and their molecular transducers were analysed in terms of mutations, amplifications and over-expression in a BTC case series. Furthermore, we tested the efficacy of drugs targeting these molecules, as single agents or in combination with gemcitabine, the standard therapeutic agent against BTC.</p> <p>Methods</p> <p>Immunohistochemistry, FISH and mutational analysis were performed on 49 BTC samples of intrahepatic (ICCs), extrahepatic (ECCs), and gallbladder (GBCs) origin. The effect on cell proliferation of different EGFR/HER2 pathway inhibitors as single agents or in combination with gemcitabine was investigated on BTC cell lines. Western blot analyses were performed to investigate molecular mechanisms of targeted drugs.</p> <p>Results</p> <p>EGFR is expressed in 100% of ICCs, 52.6% of ECCs, and in 38.5% of GBCs. P-MAPK and p-Akt are highly expressed in ICCs (>58% of samples), and to a lower extent in ECCs and GBCs (<46%), indicating EGFR pathway activation. HER2 is overexpressed in 10% of GBCs (with genomic amplification), and 26.3% of ECCs (half of which has genomic amplification). EGFR or its signal transducers are mutated in 26.5% of cases: 4 samples bear mutations of PI3K (8.2%), 3 cases (6.1%) in K-RAS, 4 (8.2%) in B-RAF, and 2 cases (4.1%) in PTEN, but no loss of PTEN expression is detected. EGI-1 cell line is highly sensitive to gemcitabine, TFK1 and TGBC1-TKB cell lines are responsive and HuH28 cell line is resistant. In EGI-1 cells, combination with gefitinib further increases the antiproliferative effect of gemcitabine. In TFK1 and TGBC1-TKB cells, the efficacy of gemcitabine is increased with addiction of sorafenib and everolimus. In TGBC1-TKB cells, lapatinib also has a synergic effect with gemcitabine. HuH28 becomes responsive if treated in combination with erlotinib. Moreover, HuH28 cells are sensitive to lapatinib as a single agent. Molecular mechanisms were confirmed by western blot analysis.</p> <p>Conclusion</p> <p>These data demonstrate that EGFR and HER2 pathways are suitable therapeutic targets for BTCs. The combination of gemcitabine with drugs targeting these pathways gives encouraging results and further clinical studies could be warranted.</p

Neutrons propagation in Lead: A feasibility study for experiments in the RSV TAPIRO fast research reactor

The increasing worldwide interest in Lead-cooled Fast Reactors (LFRs) substantiates the need to validate the analytical codes and methods used to support their design. For neutronic analyses, this is chiefly reflected in assessing the impact of nuclear data uncertainties on the integral and local parameters resulting from such analyses. The aim of refining nuclear data moves continuous efforts for more accurate measurements, be them differential or integral, for which adequate facilities are required. The availability at the ENEA's Casaccia research center of a fast source reactor – RSV TAPIRO – provides a unique opportunity to perform new integral experiments in support of fast reactors, including LFRs, owing to the well-characterized neutron spectrum of the thermal column. A series of experiments has been envisaged, dealing with the use of Lead in a reactor. The experiments concern the propagation of neutrons through blocks of materials representing relevant elements of a reactor core, and ranging from pure Lead to mixtures reproducing portions of the reflector and shield in LFRs. The paper is focused on the feasibility study of some of these experiments in which Lead and mixture blocks are inserted in the so-called thermal column of the RSV TAPIRO reactor and irradiated by the neutron flux emerging from the Copper reflector surrounding the reactor core

Additional file 3: Table S3. of Establishment of a patient-derived intrahepatic cholangiocarcinoma xenograft model with KRAS mutation

Overlapped deregulated genes obtained comparing differentially expressed genes (GEP) with the list of genes allocated in amplified or deleted regions (aCGH) found in PDX. (XLSX 13 kb

Additional file 2: Table S2. of Establishment of a patient-derived intrahepatic cholangiocarcinoma xenograft model with KRAS mutation

Differentially expressed genes in PDX versus primary tumor (PR). (XLSX 22 kb

Analysis of C/E results of fission rate ratio measurements in several fast lead VENUS-F cores

During the GUINEVERE FP6 European project (2006–2011), the zero-power VENUS water-moderated reactor was modified into VENUS-F, a mock-up of a lead cooled fast spectrum system with solid components that can be operated in both critical and subcritical mode. The Fast Reactor Experiments for hybrid Applications (FREYA) FP7 project was launched in 2011 to support the designs of the MYRRHA Accelerator Driven System (ADS) and the ALFRED Lead Fast Reactor (LFR). Three VENUS-F critical core configurations, simulating the complex MYRRHA core design and one configuration devoted to the LFR ALFRED core conditions were investigated in 2015. The MYRRHA related cores simulated step by step design peculiarities like the BeO reflector and in pile sections. For all of these cores the fuel assemblies were of a simple design consisting of 30% enriched metallic uranium, lead rodlets to simulate the coolant and Al2O3 rodlets to simulate the oxide fuel. Fission rate ratios of minor actinides such as Np-237, Am-241 as well as Pu-239, Pu-240, Pu-242 and U-238 to U-235 were measured in these VENUS-F critical assemblies with small fission chambers in specially designed locations, to determine the spectral indices in the different neutron spectrum conditions. The measurements have been analyzed using advanced computational tools including deterministic and stochastic codes and different nuclear data sets like JEFF-3.1, JEFF-3.2, ENDF/B7.1 and JENDL-4.0. The analysis of the C/E discrepancies will help to improve the nuclear data in the specific energy region of fast neutron reactor spectra