Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device - the SERCA-LVAD TRIAL.

The SERCA-LVAD trial was a phase 2a trial assessing the safety and feasibility of delivering an adeno-associated vector 1 carrying the cardiac isoform of the sarcoplasmic reticulum calcium ATPase (AAV1/SERCA2a) to adult chronic heart failure patients implanted with a left ventricular assist device. The SERCA-LVAD trial was one of a program of AAV1/SERCA2a cardiac gene therapy trials including CUPID1, CUPID 2 and AGENT trials. Enroled subjects were randomised to receive a single intracoronary infusion of 1 × 1013 DNase-resistant AAV1/SERCA2a particles or a placebo solution in a double-blinded design, stratified by presence of neutralising antibodies to AAV. Elective endomyocardial biopsy was performed at 6 months unless the subject had undergone cardiac transplantation, with myocardial samples assessed for the presence of exogenous viral DNA from the treatment vector. Safety assessments including ELISPOT were serially performed. Although designed as a 24 subject trial, recruitment was stopped after five subjects had been randomised and received infusion due to the neutral result from the CUPID 2 trial. Here we describe the results from the 5 patients at 3 years follow up, which confirmed that viral DNA was delivered to the failing human heart in 2 patients receiving gene therapy with vector detectable at follow up endomyocardial biopsy or cardiac transplantation. Absolute levels of detectable transgene DNA were low, and no functional benefit was observed. There were no safety concerns in this small cohort. This trial identified some of the challenges of performing gene therapy trials in this LVAD patient cohort which may help guide future trial design.

Sleep disorders in myotonic dystrophy type 2: a controlled polysomnographic study and self-reported questionnaires.

BACKGROUND AND PURPOSE: There is a paucity of data available regarding the occurrence of sleep disorders in myotonic dystrophy type 2 (DM2). In this study the sleep-wake cycle and daytime sleepiness were investigated in DM2 patients and compared with results from healthy subjects and myotonic dystrophy type 1 (DM1) patients. METHODS: Twelve DM2 outpatients, 12 age- and sex-matched healthy controls and 18 DM1 patients were recruited. Subjective quality of sleep was assessed by means of the Pittsburgh Sleep Quality Index (PSQI). Both the Epworth Sleepiness Scale and the Daytime Sleepiness Scale were performed in order to evaluate excessive daytime sleepiness (EDS). All participants underwent polysomnographic monitoring over 48 h as well as the Multiple Sleep Latency Test. RESULTS: Sleep efficiency was < 90% in 12/12 DM2 patients, and significantly reduced when compared with controls or with DM1. Decreased sleep efficiency was associated with sleep-disordered breathing in seven out of 12 DM2 patients and/or periodic limbs movements of sleep (PLMS) in three out of eight patients. Six DM2 patients showed REM sleep without atonia, whereas none of the controls or DM1 patients showed REM sleep dysregulation. The global PSQI score was higher in DM2 patients than in controls and DM1 patients. CONCLUSIONS: Sleep quality in DM2 patients is poorer than in DM1 patients and controls. Sleep apnea is the most common sleep disorder in DM2 patients. Obstructive sleep apnea and sleep fragmentation may represent the main cause of EDS, whereas PLMS is a frequent finding in DM1.

Differential features of muscle fiber atrophy in osteoporosis and osteoarthritis.

UNLABELLED: We demonstrated that osteoporosis is associated with a preferential type II muscle fiber atrophy, which correlates with bone mineral density and reduced levels of Akt, a major regulator of muscle mass. In osteoarthritis, muscle atrophy is of lower extent and related to disease duration and severity. INTRODUCTION: Osteoarthritis (OA) and osteoporosis (OP) are associated with loss of muscle bulk and power. In these diseases, morphological studies on muscle tissue are lacking, and the underlying mechanisms of muscle atrophy are not known. The aim of our study was to evaluate the OP- or OA-related muscle atrophy and its correlation with severity of disease. Muscle levels of Akt protein, a component of IGF-1/PI3K/Akt pathway, the main regulator of muscle mass, have been determined. METHODS: We performed muscle biopsy in 15 women with OP and in 15 women with OA (age range, 60-85 years). Muscle fibers were counted, measured, and classified by ATPase reaction. By statistical analysis, fiber-type atrophy was correlated with bone mineral density (BMD) in the OP group and with Harris Hip Score (HHS) and disease duration in the OA group. Akt protein levels were evaluated by Western blot analysis. RESULTS: Our findings revealed in OP a preferential type II fiber atrophy that inversely correlated with patients' BMD. In OA, muscle atrophy was of lower extent, homogeneous among fiber types and related to disease duration and HHS. Moreover, in OP muscle, the Akt level was significantly reduced as compared to OA muscles. CONCLUSIONS: This study shows that in OP, there is a preferential and diffuse type II fiber atrophy, proportional to the degree of bone loss, whereas in OA, muscle atrophy is connected to the functional impairment caused by the disease. A reduction of Akt seems to be one of the mechanisms involved in OP-related muscle atrophy.

Living myocardial slices for the study of nucleic acid-based therapies.

Gene therapy based on viral vectors offers great potential for the study and the treatment of cardiac diseases. Here we explore the use of Living Myocardial Slices (LMS) as a platform for nucleic acid-based therapies. Rat LMS and Adeno-Associated viruses (AAV) were used to optimise and analyse gene transfer efficiency, viability, tissue functionality, and cell tropism in cardiac tissue. Human cardiac tissue from failing (dilated cardiomyopathy) hearts was also used to validate the model in a more translational setting. LMS were cultured at physiological sarcomere length for 72-h under electrical stimulation. Two recombinant AAV serotypes (AAV6 and AAV9) at different multiplicity of infection (MOI) expressing enhanced green fluorescent protein (eGFP) were added to the surface of rat LMS. AAV6 at 20,000 MOI proved to be the most suitable serotype without affecting LMS contractility or kinetics and showing high transduction and penetrability efficiency in rat LMS. This serotype exhibited 40% of transduction efficiency in cardiomyocytes and stromal cells while 20% of the endothelial cells were transduced. With great translational relevance, this protocol introduces the use of LMS as a model for nucleic acid-based therapies, allowing the acceleration of preclinical studies for cardiac diseases.

Calculation of electron interaction models in N2 and O2.

Cosmic rays have the potential to significantly affect the atmospheric composition by increasing the rate and changing the types of chemical reactions through ion production. The amount and states of ionization, and the spatial distribution of ions produced are still open questions for atmospheric models. To precisely estimate these quantities, it is necessary to simulate particle-molecule interactions, down to very low energies. Models enabling such simulations require interaction probabilities over a broad energy range and for all energetically allowed scattering processes. In this paper, we focus on electron interaction with the two most abundant molecules in the atmosphere, i.e., N2 and O2, as an initial step. A set of elastic and inelastic cross section models for electron transportation in oxygen and nitrogen molecules valid in the energy range 10 eV - 1 MeV, is presented. Comparison is made with available theoretical and experimental data and a reasonable good agreement is observed. Stopping power is calculated and compared with published data to assess the general consistency and reliability of our results. Good overall agreement is observed, with relative differences lower than 6% with the ESTAR database.

Experimental validation of an innovative approach in biokinetics study for personalised dosimetry of molecular radiation therapy treatments.

One of today's main challenges in molecular radiation therapy is to assess an individual dosimetry that allows treatment to be tailored to the specific patient, in accordance with the current paradigm of 'personalized medicine'. The evaluation of the absorbed doses for tumor and organs at risk in molecular radiotherapy is typically based on MIRD schema acquiring few experimental points for the assessement of biokinetic parameters. WIDMApp, the wearable individual dose monitoring apparatus, is an innovative approach for internal dosimetry based on a wearable radiation detecting system for individual biokinetics sampling, a Monte Carlo simulation for particle interaction, and an unfolding algorithm for data analysis and integrated activity determination at organ level. A prototype of a WIDMApp detector element was used to record the photon emissions in a body phantom containing 3 spheres with liquid sources (18F,64Cu and99mTc) to simulate organs having different washout. Modelling the phantom geometry on the basis of a CT scan imaging, the Monte Carlo simulation computed the contribution of each emitting sphere to the signal detected in 3 positions on the phantoms surface. Combining the simulated results with the data acquired for 120 h, the unfolding algorithm deconvolved the detected signal and assessed the decay half-life (T1/2) and initial activity values (A(0)) that best reproduces the observed exponential decays. A 3%-18% level of agreement is found between the actualA(0) andT1/2values and those obtained by means of the minimization procedure based on the Monte Carlo simulation. That resulted in an estimation of the cumulated activity <15%. Moreover, WIDMApp data redundancy has been used to mitigate some experimental occurrences that happened during data taking. A first experimental test of the WIDMApp approach to internal radiation dosimetry is presented. Studies with patients are foreseen to validate the technique in a real environment.

Aberrant splicing and expression of the non muscle myosin heavy-chain gene MYH14 in DM1 muscle tissues.

Myotonic dystrophy type 1 (DM1) is a complex multisystemic disorder caused by an expansion of a CTG repeat located at the 3' untranslated region (UTR) of DMPK on chromosome 19q13.3. Aberrant messenger RNA (mRNA) splicing of several genes has been reported to explain some of the symptoms of DM1 including insulin resistance, muscle wasting and myotonia. In this paper we analyzed the expression of the MYH14 mRNA and protein in the muscle of DM1 patients (n=12) with different expansion lengths and normal subjects (n=7). The MYH14 gene is located on chromosome 19q13.3 and encodes for one of the heavy chains of the so called class II "nonmuscle" myosins (NMHCII). MYH14 has two alternative spliced isoforms: the inserted isoform (NMHCII-C1) which includes 8 amino acids located in the globular head of the protein, not encoded by the non inserted isoform (NMHCII-C0). Results showed a splicing unbalance of the MYH14 gene in DM1 muscle, with a prevalent expression of the NMHCII-C0 isoform more marked in DM1 patients harboring large CTG expansions. Minigene assay indicated that levels of the MBNL1 protein positively regulates the inclusion of the MYH14 exon 6. Quantitative analysis of the MYH14 expression revealed a significant reduction in the DM1 muscle samples, both at mRNA and protein level. No differences were found between DM1 and controls in the skeletal muscle localization of MYH14, obtained through immunofluorescence analysis. In line with the thesis of an "RNA gain of function" hypothesis described for the CTG mutation, we conclude that the alterations of the MYH14 gene may contribute to the DM1 molecular pathogenesis.

Label-free quantitative SWATH-MS proteomic analysis of adult myocardial slices in vitro after biomimetic electromechanical stimulation.

A special in vitro model maintained with ultrathin cardiac slices with a preserved architecture, multi-cellularity, and physiology of the heart tissue was used. In our experiments, we performed label-free quantitative SWATH-MS proteomic analysis of the adult myocardial slices in vitro after biomimetic electromechanical stimulation. Rat myocardial slices were stretched to sarcomere lengths (SL) within the physiological range of 1.8-2.2 µm. Electromechanically stimulated slices were compared with slices cultured without electromechanical stimulation (unloaded and nonstimulated-TW) on a liquid-air interface and with fresh myocardial slices (0 h-C). Quantitative (relative) proteomic analyses were performed using a label-free SWATH-MS technique on a high-resolution microLC-MS/MS TripleTOF 5600+ system (SCIEX). The acquired MS/MS spectra from the DDA LC-MS/MS analyses of the rat heart samples were searched against the UniProt Rattus norvegicus database (version of 15.05.2018) using the Paragon algorithm incorporated into ProteinPilot 4.5 (SCIEX) software. The highest number of differential proteins was observed in the TW group-121 when compared to the C group. In the 1.8 and 2.2 groups, 79 and 52 proteins present at a significantly different concentration from the control samples were found, respectively. A substantial fraction of these proteins were common for two or more comparisons, resulting in a list of 169 significant proteins for at least one of the comparisons. This study found the most prominent changes in the proteomic pattern related to mitochondrial respiration, energy metabolism, and muscle contraction in the slices that were stretched and fresh myocardial slices cultured without electromechanical stimulation.

Early subclinical cochlear dysfunction in myotonic dystrophy type 1.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is an autosomal-dominant inherited disorder clinically characterized by variable systemic manifestations. Among clinical features of the disease, 'precocious presbyacusis' has been previously reported. The underlying mechanism of this auditory impairment remains still poorly understood. Hearing is an active process located in the cochlea, where the outer hair cells (OHCs) play an important role in sound perception through a 'contractile' like movement resembling skeletal muscle fibers dynamics. OHCs status has not yet been investigated in DM1 patients. OHCs integrity can be assessed by measuring transient-evoked otoacoustic emissions (TEOAE), a non-invasive, repeatable, and objective quantitative tool. METHODS: We recruited 25 patients with a genetically confirmed diagnosis of DM1, and 28 age-matched control subjects. All of them underwent a routine audiological evaluation and TEOAE recordings. RESULTS: We detected a high prevalence of sensorineural high-frequency hearing loss (HFHL) in DM1 patients, significantly different if compared to control subjects. Interestingly, the accurate analysis of DM1 recorded data showed a marked impairment of TEOAE both in HFHL+ and unexpectedly in HFHL- group. Cochlear dysfunction was restricted to frequencies above 2000 Hz in the HFHL- group, but it extended to 1000 Hz in HFHL+ DM1 patients. CONCLUSIONS: Our study indicates that cochlear impairment in DM1 is present, even in patients without evidence of hearing loss at a standard audiometric analysis. Hence, in the current clinical practice, an assessment of cochlear function by TEOAE recording may be useful in DM1 patients to identify precocious signs of cochlear dysfunction.

Report on G4-Med, a Geant4 benchmarking system for medical physics applications developed by the Geant4 Medical Simulation Benchmarking Group.

BACKGROUND: Geant4 is a Monte Carlo code extensively used in medical physics for a wide range of applications, such as dosimetry, micro- and nanodosimetry, imaging, radiation protection, and nuclear medicine. Geant4 is continuously evolving, so it is crucial to have a system that benchmarks this Monte Carlo code for medical physics against reference data and to perform regression testing. AIMS: To respond to these needs, we developed G4-Med, a benchmarking and regression testing system of Geant4 for medical physics. MATERIALS AND METHODS: G4-Med currently includes 18 tests. They range from the benchmarking of fundamental physics quantities to the testing of Monte Carlo simulation setups typical of medical physics applications. Both electromagnetic and hadronic physics processes and models within the prebuilt Geant4 physics lists are tested. The tests included in G4-Med are executed on the CERN computing infrastructure via the use of the geant-val web application, developed at CERN for Geant4 testing. The physical observables can be compared to reference data for benchmarking and to results of previous Geant4 versions for regression testing purposes. RESULTS: This paper describes the tests included in G4-Med and shows the results derived from the benchmarking of Geant4 10.5 against reference data. DISCUSSION: Our results indicate that the Geant4 electromagnetic physics constructor G4EmStandardPhysics_option4 gives a good agreement with the reference data for all the tests. The QGSP_BIC_HP physics list provided an overall adequate description of the physics involved in hadron therapy, including proton and carbon ion therapy. New tests should be included in the next stage of the project to extend the benchmarking to other physical quantities and application scenarios of interest for medical physics. CONCLUSION: The results presented and discussed in this paper will aid users in tailoring physics lists to their particular application.

The myotonic dystrophy type 2 (DM2) gene product zinc finger protein 9 (ZNF9) is associated with sarcomeres and normally localized in DM2 patients' muscles.

AIMS: Myotonic dystrophy type 2 (DM2) is caused by a [CCTG]n intronic expansion in the zinc finger protein 9 (ZNF9) gene. As for DM1, sharing with DM2 a similar phenotype, the pathogenic mutation involves a transcribed but untranslated genomic region, suggesting that RNA toxicity may have a role in the pathogenesis of these multisystem disorders by interfering with common cellular mechanisms. However, haploinsufficiency has been described in DM1 and DM2 animal models, and might contribute to pathogenesis. The aim of the present work was therefore to assess ZNF9 protein expression in rat tissues and in human muscle, and ZNF9 subcellular distribution in normal and DM2 human muscles. METHODS: Polyclonal anti-ZNF9 antibodies were obtained in rabbit, high pressure liquid chromatography-purified, and used for Western blot, standard and confocal immunofluorescence and immunogold labelling electron microscopy on a panel of normal rat tissues and on normal and DM2 human muscles. RESULTS: Western blot analysis showed that ZNF9 is ubiquitously expressed in mammalian tissues, and that its signal is not substantially modified in DM2 muscles. Immunofluorescence studies showed a myofibrillar distribution of ZNF9, and double staining with two non-repetitive epitopes of titin located it in the I bands. This finding was confirmed by the visualization of ZNF9 in close relation with sarcomeric thin filaments by immunogold labelling electron microscopy. ZNF9 distribution was unaltered in DM2 muscle fibres. CONCLUSIONS: ZNF9 is abundantly expressed in human myofibres, where it is located in the sarcomeric I bands, and no modification of this pattern is observed in DM2 muscles.

Feasibility study on the use of CMOS sensors as detectors in radioguided surgery with ß-- emitters.

Radioguided surgery (RGS) is a medical practice which thanks to a radiopharmaceutical tracer and a probe allows the surgeon to identify tumor residuals up to a millimetric resolution in real-time. The employment of ß- emitters, instead of γ or ß+, reduces background from healthy tissues, administered activity to the patient, and medical exposure. In a previous work the possibility of using a CMOS Imager (Aptina MT9V011), initially designed for visible light imaging, to detect ß- from 90Y or 90Sr sources has been established. Because of its possible application as counting probe in RGS, the performances of MT9V011 in clinical-like conditions were studied.1 Through horizontal scans on a collimated 90Sr source of different sizes (1, 3, 5, 7 mm), we have determined relationships between scan fit parameters and the source dimension, namely A quadratic correlation and a linear dependency of, respectively, signal integrated over scan interval, and maximum signal against source diameter, are determined. Horizontal scan measurements on a source, interposing collimators of different size, aim to determine relationships or correlations between scan fit parameters and source dimension. A quadratic correlation and a linear dependency of, respectively, signal integrated over scan interval, and maximum signal against source diameter are determined. In order to get closer to clinical conditions, agar-agar phantoms containing 90Y with different dimensions and activities were prepared. A 90Y phantom is characterized by a central spot and a ring all around, for simulating both signal (tumor) and background (surrounding healthy tissue). The relationship found between scan maximum and 90Sr source diameter is then exploited to extract the concentration ratio between spot and external ring of the 90Y phantom. This observable, defined as the ratio between the tumor and the nearby healthy tissues uptake simulates the Tumor-to-Non-tumor Ratio (TNR). With the aim of evaluating the sensor's ability to discriminate signal from background relying on the significance parameter, a further 90Y phantom, featuring a well-known and clinical-like activity will mimic the signal only condition. This result is used to extrapolate to different source sizes, after having estimated the background for various TNR. The obtained significance values suggest that the MT9V011 sensor is capable of distinguishing a signal from an estimated background, depending on the interplay among TNR, acquisition time and tumor diameter.

Preliminary results in using Deep Learning to emulate BLOB, a nuclear interaction model.

PURPOSE: A reliable model to simulate nuclear interactions is fundamental for Ion-therapy. We already showed how BLOB ("Boltzmann-Langevin One Body"), a model developed to simulate heavy ion interactions up to few hundreds of MeV/u, could simulate also 12C reactions in the same energy domain. However, its computation time is too long for any medical application. For this reason we present the possibility of emulating it with a Deep Learning algorithm. METHODS: The BLOB final state is a Probability Density Function (PDF) of finding a nucleon in a position of the phase space. We discretised this PDF and trained a Variational Auto-Encoder (VAE) to reproduce such a discrete PDF. As a proof of concept, we developed and trained a VAE to emulate BLOB in simulating the interactions of 12C with 12C at 62 MeV/u. To have more control on the generation, we forced the VAE latent space to be organised with respect to the impact parameter (b) training a classifier of b jointly with the VAE. RESULTS: The distributions obtained from the VAE are similar to the input ones and the computation time needed to use the VAE as a generator is negligible. CONCLUSIONS: We show that it is possible to use a Deep Learning approach to emulate a model developed to simulate nuclear reactions in the energy range of interest for Ion-therapy. We foresee the implementation of the generation part in C++ and to interface it with the most used Monte Carlo toolkit: Geant4.

Tumor-non-tumor discrimination by a ß- detector for Radio Guided Surgery on ex-vivo neuroendocrine tumors samples.

This paper provides a first insight of the potential of the ß- Radio Guided Surgery (ß--RGS) in a complex surgical environment like the abdomen, where multiple sources of background concur to the signal at the tumor site. This case is well reproduced by ex-vivo samples of 90Y-marked Gastro-Entero-Pancreatic Neuroendocrine Tumors (GEP NET) in the bowel. These specimens indeed include at least three wide independent sources of background associated to three anatomical districts (mesentery, intestine, mucose). The study is based on the analysis of 37 lesions found on 5 samples belonging to 5 different patients. We show that the use of electrons, a short range particle, instead of γ particles, allows to limit counts read on a lesion to the sum of the tumor signal plus the background generated by the sole hosting district.The background on adjacent districts in the same specimen/patient is found to differ up to a factor 4, showing how the specificity and sensitivity of the ß--RGS technique can be fully exploited only upon a correct measurement of the contributing background. This locality has been used to set a site-specific cut-off algorithm to discriminate tumor and healthy tissue with a specificity of 100% and a sensitivity, on this test data sample, close to 100%. Factors influencing the sensitivity are also discussed. One of the specimens set allowed us evaluate the volume of the lesions, thus concluding that the probe was able to detect lesions as small as 0.04 mL in that particular case.

Inter-fractional monitoring of [Formula: see text]C ions treatments: results from a clinical trial at the CNAO facility.

The high dose conformity and healthy tissue sparing achievable in Particle Therapy when using C ions calls for safety factors in treatment planning, to prevent the tumor under-dosage related to the possible occurrence of inter-fractional morphological changes during a treatment. This limitation could be overcome by a range monitor, still missing in clinical routine, capable of providing on-line feedback. The Dose Profiler (DP) is a detector developed within the INnovative Solution for In-beam Dosimetry in hadronthErapy (INSIDE) collaboration for the monitoring of carbon ion treatments at the CNAO facility (Centro Nazionale di Adroterapia Oncologica) exploiting the detection of charged secondary fragments that escape from the patient. The DP capability to detect inter-fractional changes is demonstrated by comparing the obtained fragment emission maps in different fractions of the treatments enrolled in the first ever clinical trial of such a monitoring system, performed at CNAO. The case of a CNAO patient that underwent a significant morphological change is presented in detail, focusing on the implications that can be drawn for the achievable inter-fractional monitoring DP sensitivity in real clinical conditions. The results have been cross-checked against a simulation study.

The ß- radio-guided surgery: Method to estimate the minimum injectable activity from ex-vivo test.

PURPOSE: Radio-guided surgery with ß- decays is a novel technique under investigation. One of the main advantages is its capability to detect small (⩽0.1 ml) samples after injecting the patient with low activity of radiopharmaceutical. This paper presents an experimental method to quantify this feature based on ex-vivo tests on specimens from meningioma patients. METHODS: Patients were enrolled on the basis of the standard uptake value (SUV) and the tumour-to-non-tumour activity ratio (TNR) resulted from 68Ga-DOTATOC PET exams. After injecting the patients with 93-167 MBq of 90Y-DOTATOC, 26 samples excised during surgery were analyzed with a ß- probe. The radioactivity expected on the neoplastic specimens was estimated according to the SUV found in the PET scan and the correlation with the measured counts was studied. The doses to surgeon and medical personnel were also evaluated. RESULTS: Even injecting as low as 1.4 MBq/kg of radiotracer, tumour residuals of 0.1 ml can be detected. A negligible dose to the medical personnel was confirmed. CONCLUSIONS: Radio-guided surgery with ß- decays is a feasible technique with a low radiation dose for both personnel and patient, in particular if the patient is injected with the minimum required activity. A correlation greater than 80% was observed between the measured counts and the expected activity for the lesion samples based on the individual SUV and the TNR. This makes identifiable the minimum injectable radiotracer activity for cases where 90Y is the utilized radionuclide.

Preliminary results coupling "Stochastic Mean Field" and "Boltzmann-Langevin One Body" models with Geant4.

PURPOSE: Monte Carlo (MC) simulations are widely used for medical applications and nuclear reaction models are fundamental for the simulation of the particle interactions with patients in ion therapy. Therefore, it is of utmost importance to have reliable models in MC simulations for such interactions. Geant4 is one of the most used toolkits for MC simulation. However, its models showed severe limitations in reproducing the yields measured in the interaction of ion beams below 100 MeV/u with thin targets. For this reason, we interfaced two models, SMF ("Stochastic Mean Field") and BLOB ("Boltzmann-Langevin One Body"), dedicated to simulate such reactions, with Geant4. METHODS: Both SMF and BLOB are semi-classical, one-body approaches to solve the Boltzmann-Langevin equation. They include an identical treatment of the mean-field propagation, on the basis of the same effective interaction, but they differ in the way fluctuations are included. Furthermore, we tested a correction to the excitation energy calculated for the light fragments emerging from the simulations and a simple coalescence model. RESULTS: While both SMF and BLOB have been developed to simulate heavy ion interactions, they show very good results in reproducing the experimental yields of light fragments, up to alpha particles, obtained in the interaction of 12C with a thin carbon target at 62 MeV/u. CONCLUSIONS: BLOB in particular gives promising results and this stresses the importance of integrating it into the Geant4 toolkit.

Characterisation of a ß detector on positron emitters for medical applications.

PURPOSE: Radio Guided Surgery (RGS) is a technique that helps the surgeon to achieve an as complete as possible tumor resection, thanks to the intraoperative detection of particles emitted by a radio tracer that bounds to tumoral cells. In the last years, a novel approach to this technique has been proposed that, exploiting ß- emitting radio tracers, overtakes some limitations of established γ-RGS. In this context, a first prototype of an intraoperative ß particle detector, based on a high light yield and low density organic scintillator, has been developed and characterised on pure ß- emitters, like 90Y. The demonstrated very high efficiency to ß- particles, together with the remarkable transparency to photons, suggested the possibility to use this detector also with ß+ emitting sources, that have plenty of applications in nuclear medicine. In this paper, we present upgrades and optimisations performed to the detector to reveal such particles. METHODS: Laboratory measurement have been performed on liquid Ga68 source, and were used to validate and tune a Monte Carlo simulation. RESULTS: The upgraded detector has an ~80% efficiency to electrons above ~110keV, reaching a plateau value of ~95%. At the same time, the probe is substantially transparent to photons below ~200keV, reaching a plateau value of ~3%. CONCLUSIONS: The new prototype seems to have promising characteristics to perform RGS also with ß+ emitting isotopes.

MR-based artificial intelligence model to assess response to therapy in locally advanced rectal cancer.

PURPOSE: To develop and validate an Artificial Intelligence (AI) model based on texture analysis of high-resolution T2 weighted MR images able 1) to predict pathologic Complete Response (CR) and 2) to identify non-responders (NR) among patients with locally-advanced rectal cancer (LARC) after receiving neoadjuvant chemoradiotherapy (CRT). METHOD: Fifty-five consecutive patients with LARC were retrospectively enrolled in this study. Patients underwent 3 T Magnetic Resonance Imaging (MRI) acquiring T2-weighted images before, during and after CRT. All patients underwent complete surgical resection and histopathology was the gold standard. Textural features were automatically extracted using an open-source software. A sub-set of statistically significant textural features was selected and two AI models were built by training a Random Forest (RF) classifier on 28 patients (training cohort). Model performances were estimated on 27 patients (validation cohort) using a ROC curve and a decision curve analysis. RESULTS: Sixteen of 55 patients achieved CR. The AI model for CR classification showed good discrimination power with mean area under the receiver operating curve (AUC) of 0.86 (95% CI: 0.70, 0.94) in the validation cohort. The discriminatory power for the NR classification showed a mean AUC of 0.83 (95% CI: 0.71,0.92). Decision curve analysis confirmed higher net patient benefit when using AI models compared to standard-of-care. CONCLUSIONS: AI models based on textural features of MR images of patients with LARC may help to identify patients who will show CR at the end of treatment and those who will not respond to therapy (NR) at an early stage of the treatment.

Secondary radiation measurements for particle therapy applications: Charged secondaries produced by 16O ion beams in a PMMA target at large angles.

Particle therapy is a therapy technique that exploits protons or light ions to irradiate tumor targets with high accuracy. Protons and 12C ions are already used for irradiation in clinical routine, while new ions like 4He and 16O are currently being considered. Despite the indisputable physical and biological advantages of such ion beams, the planning of charged particle therapy treatments is challenged by range uncertainties, i.e. the uncertainty on the position of the maximal dose release (Bragg Peak - BP), during the treatment. To ensure correct 'in-treatment' dose deposition, range monitoring techniques, currently missing in light ion treatment techniques, are eagerly needed. The results presented in this manuscript indicate that charged secondary particles, mainly protons, produced by an 16O beam during target irradiation can be considered as candidates for 16O beam range monitoring. Hereafter, we report on the first yield measurements of protons, deuterons and tritons produced in the interaction of an 16O beam impinging on a PMMA target, as a function of detected energy and particle production position. Charged particles were detected at 90° and 60° with respect to incoming beam direction, and homogeneous and heterogeneous PMMA targets were used to probe the sensitivity of the technique to target inhomogeneities. The reported secondary particle yields provide essential information needed to assess the accuracy and resolution achievable in clinical conditions by range monitoring techniques based on secondary charged radiation.