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In recent years, there is an emerging interest in the prognostic role of chemistry blood biomarkers in oncological patients but their role in adenoid cystic carcinomas (ACCs) is still unknown. This study aims to assess the prognostic significance of baseline neutrophil-to-lymphocyte ratio (NLR) and blood chemistry in a series of head and neck ACC patients treated with carbon ion radiotherapy (CIRT).We retrospectively retrieved the data of 49 consecutive head and neck ACC patients treated with CIRT. Univariable and multivariable Cox proportional hazard regression (Cox-ph) analyses were performed to look for a potential association of NLR, and other blood biomarker values, with disease-free survival (DFS), Local Control (LC), Metastasis Free Survival (MFS) and overall survival (OS).No significant association between NLR 2,5 and DFS, LC, MFS and OS was found with univariable analysis although a trend was reported for DFS (Hazard ratio [HR]: 2,10, 95 % CI: 0,85 - 5,08, p-value = 0,11). Patients with hemoglobin (hb) ≤ 14 g/dL showed significantly better DFS, MFS and OS. Multivariable regression Cox-ph analysis for DFS, adjusted for margin status, clinical target volume and Absolute Number of Monocytes, reported the following statistically significant HRs, for both NLR 2,5 and hb 14 g/dL respectively: 4,850 (95 % CI = 1,408 - 16,701, p = 0,012) and 3,032 (95 % CI = 1,095 - 8,393, p = 0,033). Moreover, hb 14 with HR = 3,69 (95 % CI: 1,23 - 11,07, p-value = 0,02), was a negative independent prognostic predictor for MFS.Pre-treatment NLR and hb values seem to be independent prognostic predictor for clinical outcomes in head and neck ACC patients. If their role will be validated in a larger prospective cohort, they might be worthwhile for a pre-treatment risk stratification in patients treated with CIRT.

Aim: To evaluate the association between pretreatment diffusion-weighted MRI (DW-MRI) and 12-month radiological response in locally recurrent rectal cancer treated with carbon ion radiotherapy. Methods: Histogram analysis was performed on pretreatment DW-MRI for patients re-irradiated with carbon ion radiotherapy for local recurrence of rectal cancer. Results: A total of 17 patients were enrolled in the study. Pretreatment DW-MRI b-value of 1000 s/mm2 (b1000) and apparent diffusion coefficient (ADC) lesion median values for 1-year nonresponders (six patients) and responders (11 patients) demonstrated a median (interquartile of median values) of 62.5 (23.9) and 34.0 (13.0) and 953.0 (277.0) and 942.5 (339.0) μm2/s, respectively. All b1000 histogram features (h-features) and ADC h-kurtosis showed statistically significant differences, whereas only b1000 h-median, b1000 h-interquartile range and ADC h-kurtosis demonstrated remarkable diagnostic accuracy. Conclusion: DW-MRI showed promising results in predicting carbon ion radiotherapy outcome in local recurrence of rectal cancer, particularly with regard to b1000 h-median, b1000 h-interquartile range and ADC h-kurtosis.

In this study, we investigate the use of magnetic resonance imaging (MRI) for the clinical evaluation of gating treatment robustness in carbon-ion radiotherapy (CIRT) of pancreatic cancer. Indeed, MRI allows radiation-free repeated scans and fast dynamic sequences for time-resolved (TR) imaging (cine-MRI), providing information on inter- and intra-fraction cycle-to-cycle variations of respiratory motion. MRI can therefore support treatment planning and verification, overcoming the limitations of the current clinical standard, that is, four-dimensional computed tomography (4DCT), which describes an "average" breathing cycle neglecting breathing motion variability.We integrated a technique to generate a virtual CT (vCT) from 3D MRI with a method for 3D reconstruction from 2D cine-MRI, to produce TR vCTs for dose recalculations. For eight patients, the method allowed evaluating inter-fraction variations at end-exhale and intra-fraction cycle-to-cycle variability within the gating window in terms of tumor displacement and dose to the target and organs at risk.The median inter-fraction tumor motion was in the range 3.33-12.16 mm, but the target coverage was robust (-0.4% median DThis study proposed a method for the generation of TR vCTs from MRI, which enabled an off-line evaluation of gating treatment robustness and suggested its feasibility to support treatment planning of pancreatic tumors in CIRT.

Minimally invasive surgery (MIS) is a widespread approach in general surgery. Computer guiding software, such as the augmented reality (AR), the virtual reality (VR) and mixed reality (MR), has been proposed to help surgeons during MIS. This study aims to report these technologies' current knowledge and diffusion during surgical training in Italy. A web-based survey was developed under the aegis of the Italian Society of Endoscopic Surgery (SICE). Two hundred and seventeen medical doctors' answers were analyzed. Participants were surgeons (138, 63.6%) and residents in surgery (79, 36.4%). The mean knowledge of the role of the VR, AR and MR in surgery was 4.9 ± 2.4 (range 1-10). Most of the participants (122, 56.2%) did not have experience with any proposed technologies. However, although the lack of experience in this field, the answers about the functioning of the technologies were correct in most cases. Most of the participants answered that VR, AR and MR should be used more frequently for the teaching and training and during the clinical activity (170, 80.3%) and that such technologies would make a significant contribution, especially in training (183, 84.3%) and didactic (156, 71.9%). Finally, the main limitations to the diffusion of these technologies were the insufficient knowledge (182, 83.9%) and costs (175, 80.6%). Based on the present study, in Italy, the knowledge and dissemination of these technologies are still limited. Further studies are required to establish the usefulness of AR, VR and MR in surgical training.

Quantitative imaging such as Diffusion-Weighted MRI (DW-MRI) can be exploited to non-invasively derive patient-specific tumour microstructure information for tumour characterization and local recurrence risk prediction in radiotherapy.To characterize tumour microstructure according to proliferative capacity and predict local recurrence through microstructural markers derived from pre-treatment conventional DW-MRI, in skull-base chordoma (SBC) patients treated with proton (PT) and carbon ion (CIRT) radiotherapy.Forty-eight patients affected by SBC, who underwent conventional DW-MRI before treatment and were enrolled for CIRT (n = 25) or PT (n = 23), were retrospectively selected. Clinically verified local recurrence information (LR) and histological information (Ki-67, proliferation index) were collected. Apparent diffusion coefficient (ADC) maps were calculated from pre-treatment DW-MRI and, from these, a set of microstructural parameters (cellular radius R, volume fraction vf, diffusion D) were derived by applying a fine-tuning procedure to a framework employing Monte Carlo simulations on synthetic cell substrates. In addition, apparent cellularity (ρRefined microstructural markers revealed optimal capabilities in discriminating patients according to cell proliferation, achieving best results with mean values (p-values were 0.0383, 0.0284, 0.0284, 0.0468 and 0.0088 for ADC, R, vf, D, and ρPatient-specific microstructural information was non-invasively derived providing potentially useful tools for SBC treatment personalization and optimization in particle therapy. This article is protected by copyright. All rights reserved.

Background Studies have reported a strong association between children's early literacy skills at preschool and their reading and writing skills at primary school. However, it is unclear whether this association is affected by language and curriculum practices. Objective The study investigates (i) whether early literacy skills are influenced by orthographic consistency and by preschool curriculum, and (ii) how early skills are related to later literacy skills across countries. Method Three countries, Italy (n = 73), Romania (n = 65), and Belgium (n = 109) were involved in the study, for a total of 247 children. Language and early literacy in preschool were assessed using a novel assessment tool (the ‘Talk’). Early visual-phonological and manual aspects integration were investigated using rapid automatized naming and grapho-motor tasks. The children’s reading and writing skills nine months later were assessed using standardized tests. Results Results showed higher early literacy scores for the groups of children speaking languages with more transparent orthographic systems and for the group taking part in preschool activities designed to enhance literacy acquisition. Later reading and writing skills were predicted by early competences, albeit with differences across countries. Conclusions Findings suggest that literacy acquisition trajectories are not only associated with early skills but are also influenced by language characteristics and curriculum practices. The study also presents preliminary findings relative to the ‘Talk’, an assessment tool that may have important implications for early identification and intervention of language and literacy difficulties, as well as for improving cross-country curriculum practices.

Introduction Respiratory motion models establish a correspondence between respiratory‐correlated (RC) 4‐dimensional (4D) imaging and respiratory surrogates, to estimate time‐resolved (TR) 3D breathing motion. To evaluate the performance of motion models on real patient data, a validation framework based on magnetic resonance imaging (MRI) is proposed, entailing the use of RC 4DMRI to build the model, and on both (i) TR 2D cine‐MRI and (ii) additional 4DMRI data for testing intra‐/inter‐fraction breathing motion variability. Methods Repeated MRI data were acquired in 7 patients with abdominal lesions. The considered model relied on deformable image registration (DIR) for building the model and compensating for inter‐fraction baseline variations. Both 2D and 3D validation were performed, by comparing model estimations with the ground truth 2D cine‐MRI and 4DMRI respiratory phases, respectively. Results The median DIR error was comparable to the voxel size (1.33 × 1.33 × 5 mm3), with higher values in the presence of large inter‐fraction motion (median value: 2.97 mm). In the 2D validation, the median estimation error on anatomical landmarks’ position resulted below 4 mm in every scenario, whereas in the 3D validation it was 1.33 mm and 4.21 mm when testing intra‐ and inter‐fraction motion, respectively. The range of motion described in the cine‐MRI was comparable to the motion of the building 4DMRI, being always above the estimation error. Overall, the model performance was dependent on DIR error, presenting reduced accuracy when inter‐fraction baseline variations occurred. Conclusions Results suggest the potential of the proposed framework in evaluating global motion models for organ motion management in MRI‐guided radiotherapy.

Multiparametric MRI is a remarkable imaging method for the assessment of patho-physiological processes. In particular, brain tumor characterization has taken advantage of the development of advanced techniques such as Diffusion- (DWI) and Perfusion- (PWI) Weighted Imaging, but a thorough analysis of meningiomas is still lacking despite the variety of computational methods proposed. We compute perfusion and diffusion parametric maps relying on a well-defined methodological workflow, investigating possible correlations between pure and diffusion-based perfusion parameters in a cohort of 26 patients before proton therapy. A preliminary investigation of meningioma staging biomarkers based on IntraVoxel Incoherent Motion and Dynamic Susceptibility Contrast is also reported. We observed significant differences between the gross target volume and the normal appearing white matter for every investigated parameter, confirming the higher vascularization of the neoplastic tissue. DWI and PWI parameters appeared to be weakly correlated and we found that diffusion parameters - the perfusion fraction in particular - could be promising biomarkers for tumor staging.

Skull-base chordoma (SBC) can be treated with carbon ion radiotherapy (CIRT) to improve local control (LC). The study aimed to explore the role of multi-parametric radiomic, dosiomic and clinical features as prognostic factors for LC in SBC patients undergoing CIRT. Before CIRT, 57 patients underwent MR and CT imaging, from which tumour contours and dose maps were obtained. MRI and CT-based radiomic, and dosiomic features were selected and fed to two survival models, singularly or by combining them with clinical factors. Adverse LC was given by in-field recurrence or tumour progression. The dataset was split in development and test sets and the models&rsquo, performance evaluated using the concordance index (C-index). Patients were then assigned a low- or high-risk score. Survival curves were estimated, and risk groups compared through log-rank tests (after Bonferroni correction &alpha, = 0.0083). The best performing models were built on features describing tumour shape and dosiomic heterogeneity (median/interquartile range validation C-index: 0.80/024 and 0.79/0.26), followed by combined (0.73/0.30 and 0.75/0.27) and CT-based models (0.77/0.24 and 0.64/0.28). Dosiomic and combined models could consistently stratify patients in two significantly different groups. Dosiomic and multi-parametric radiomic features showed to be promising prognostic factors for LC in SBC treated with CIRT.

Orientadora: Prof.ª Dr.ª Melina Girardi Fachin Coorientadora: Prof.ª Dr.ª Danielle Anne Pamplona Dissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências Jurídicas, Programa de Pós-Graduação em Direito. Defesa : Curitiba, 19/07/2021 Inclui referências: p. 166-180 Área de concentração: Direito Humanos e Democracia Resumo: A relação entre a igualdade de gênero, direitos humanos, empresas e práticas fiscais tem ponto de contato no desenho de políticas fiscais e planejamento tributário que aumentam o poder econômico de empresas ao passo que oneram desproporcionalmente as mulheres. A presente dissertação tem como objetivo investigar, a partir do marco conceitual de Direitos Humanos e Empresas, os efeitos da perda de recursos dos Estados por ausência de pagamento de impostos de empresas, seja em razão de abusos fiscais cometidos por corporações, ou por benefícios fiscais concedidos por países visando atrair investimento. O fio condutor da análise será a igualdade substancial de gênero, compreendida como a igualdade social política e econômica entre homens e mulheres. Neste sentido, busca demonstrar a necessidade de uma dimensão de gênero aos Princípios Orientadores sobre Empresas e Direitos Humanos em razão do impacto desproporcional sofrido por mulheres, como resultado das práticas tributárias adotadas pela atividade empresarial transnacional, devido à discriminação interseccional. A realização da igualdade substancial demanda, portanto, investimentos de políticas públicas, as quais são majoritariamente custeadas pelo pagamento de impostos. De igual sorte, a ausência de políticas públicas impactará em maior medida as mulheres. A partir desta ligação que o direito tributário servirá de ferramenta de análise, lido a partir do human rights approach. Desta sorte, a análise proposta será conduzida a partir de levantamento bibliográfico que permita a conciliação das três temáticas propostas. Palavras-chave: Direitos Humanos e Empresas; Igualdade de gênero; Políticas fiscais e tributárias; Abusos fiscais; Privilégios fiscais. Abstract: The relation between gender equality, human rights, corporations and tax resides on the design of fiscal policies and tax planning that increases the economic power of companies however, diminishes women's rights. The present dissertation investigates, parting from the conceptual mark of Business and Human Rights, the effects of the loss of resources by the States due to the lack of tax payments by corporations because of tax abuse or tax incentives given by States to attract investment. The guiding thread of the analysis will be substantial gender equality, meaning the social, political and economic equality between man and women. Thus, the objective is to demonstrate the necessity of a gender dimension of the Guiding Principles for Business and Human Rights because of the disproportional impact suffered by women, because of intersectional discrimination and tax practices adopted by the transnational business activity. The realization of substantial equality demands, therefore, investment in public policies, which are mostly funded by tax payment. Likewise, the lack of public policies will affect women to a greater extent. Tax law with serve as an instrument of analysis based on this connection, interpreted from a human rights approach. For this means, the proposed analyses will be conducted by bibliographical research that enables the connection of the three proposed themes. Keywords: Business and Human Rights; Gender equality; Fiscal and tax policies; Tax abuse; Tax privilege.

One of the most studied metabolic routes is the biosynthesis of histidine, especially in enterobacteria where a single compact operon composed of eight adjacent genes encodes the complete set of biosynthetic enzymes. It is still not clear how his genes were organized in the genome of the last universal common ancestor community. The aim of this work was to analyze the structure, organization, phylogenetic distribution, and degree of horizontal gene transfer (HGT) of his genes in the Bacteroidota-Rhodothermota-Balneolota-Chlorobiota superphylum, a group of phylogenetically close bacteria with different surviving strategies. The analysis of the large variety of his gene structures and organizations revealed different scenarios with genes organized in more or less compact—heterogeneous or homogeneous—operons, in suboperons, or in regulons. The organization of his genes in the extant members of the superphylum suggests that in the common ancestor of this group, genes were scattered throughout the chromosome and that different forces have driven the assembly of his genes in compact operons. Gene fusion events and/or paralog formation, HGT of single genes or entire operons between strains of the same or different taxonomic groups, and other molecular rearrangements shaped the his gene structure in this superphylum.

To assess early microstructural changes of meningiomas treated with proton therapy through quantitative analysis of intravoxel incoherent motion (IVIM) and diffusion-weighted imaging (DWI) parameters. Seventeen subjects with meningiomas that were eligible for proton therapy treatment were retrospectively enrolled. Each subject underwent a magnetic resonance imaging (MRI) including DWI sequences and IVIM assessments at baseline, immediately before the 1st (t0), 10th (t10), 20th (t20), and 30th (t30) treatment fraction and at follow-up. Manual tumor contours were drawn on T2-weighted images by two expert neuroradiologists and then rigidly registered to DWI images. Median values of the apparent diffusion coefficient (ADC), true diffusion (D), pseudo-diffusion (D*), and perfusion fraction (f) were extracted at all timepoints. Statistical analysis was performed using the pairwise Wilcoxon test. Statistically significant differences from baseline to follow-up were found for ADC, D, and D* values, with a progressive increase in ADC and D in conjunction with a progressive decrease in D*. MRI during treatment showed statistically significant differences in D values between t0 and t20 (p = 0.03) and t0 and t30 (p = 0.02), and for ADC values between t0 and t20 (p = 0.04), t10 and t20 (p = 0.02), and t10 and t30 (p = 0.035). Subjects that showed a volume reduction greater than 15% of the baseline tumor size at follow-up showed early D changes, whereas ADC changes were not statistically significant. IVIM appears to be a useful tool for detecting early microstructural changes within meningiomas treated with proton therapy and may potentially be able to predict tumor response.

An Eye Tracking System (ETS) is used at CNAO for providing a stable and reproducible ocular proton therapy (OPT) set-up, featuring a fixation light (FL) and monitoring stereo-cameras embedded in a rigid case. The aim of this work is to propose an ETS set-up simulation algorithm, that automatically provides the FL positioning in space, according to patient-specific gaze direction and avoiding interferences with patient, beam and collimator. Two configurations are provided: one in the CT room for acquiring images required for treatment planning with the patient lying on a couch, and one related to the treatment room with the patient sitting in front of the beam. Algorithm validation was performed reproducing ETS simulation (CT) and treatment (room) set-up for 30 patients previously treated at CNAO. The positioning accuracy of the device was quantified through a set of 14 control points applied to the ETS case and localizable both in the CT volume and in room X-ray images. Differences between the position of ETS reference points estimated by the algorithm and those measured by imaging systems are reported. The corresponding gaze direction deviation is on average 0.2° polar and 0.3° azimuth for positioning in CT room and 0.1° polar and 0.4° azimuth in the treatment room. The simulation algorithm was embedded in a clinically usable software application, which we assessed as capable of ensuring ETS positioning with an average accuracy of 2 mm in CT room and 1.5 mm in treatment room, corresponding to gaze direction deviations consistently lower than 1°.

BACKGROUND AND PURPOSE To compare RECIST 1.1 with volume modifications in patients with sacral chordoma not suitable for surgery treated with carbon ions radiotherapy (CIRT) alone. To evaluate patients pain before and after CIRT. To detect if baseline Apparent Diffusion Coefficient values (ADC) from Diffusion Weighted sequences could predict response to treatment. MATERIAL AND METHODS Patients included had one cycle of CIRT and underwent MRI before and after treatment. For each MRI, lesion maximum diameter and volume were obtained, and ADC values were analyzed within the whole lesion volume. Patients pain was evaluated with Numerical Rating Scale (NRS), considering the upper tumor level at baseline MRIs. RESULTS 39 patients were studied (mean follow-up 18 months). Considering RECIST 1.1 there was not a significant reduction in tumor diameters (p = 0.19), instead there was a significant reduction in tumor volume (p

Purpose To generate virtual 4DCT from 4DMRI with field of view (FOV) extended to the entire involved patient anatomy, in order to evaluate its use in carbon ion radiation therapy (CIRT) of the abdominal site in a clinical scenario. Materials and methods The virtual 4DCT was generated by deforming a reference CT in order to (1) match the anatomy depicted in the 4DMRI within its FOV, by calculating deformation fields with deformable image registration to describe inter-fractional and breathing motion, and (2) obtain physically plausible deformation outside of the 4DMRI FOV, by propagating and modulating the previously obtained deformation fields. The implemented method was validated on a digital anthropomorphic phantom, for which a ground truth (GT) 4DCT was available. A CIRT treatment plan was optimized at the end-exhale reference CT and the RBE-weighted dose distribution was recalculated on both the virtual and GT 4DCTs. The method estimation error was quantified by comparing the virtual and GT 4DCTs and the corresponding recomputed doses. The method was then evaluated on 8 patients with pancreas or liver tumors treated with CIRT using respiratory gating at end-exhale. The clinical treatment plans adopted at the National Center for Oncological Hadrontherapy (CNAO, Pavia, Italy) were considered and the dose distribution was recomputed on all respiratory phases of the planning and virtual 4DCTs. By comparing the two datasets and the corresponding dose distributions, the geometrical and dosimetric impact of organ motion was assessed. Results For the phantom, the error outside of the 4DMRI FOV was up to 4.5 mm, but it remained sub-millimetric in correspondence to the target within the 4DMRI FOV. Although the impact of motion on the target D95% resulted in variations ranging from 22% to 90% between the planned dose and the doses recomputed on the GT 4DCT phases, the corresponding estimation error was ≤2.2%. In the patient cases, the variation of the baseline tumor position between the planning and the virtual end-exhale CTs presented a median (interquartile range) value of 6.0 (4.9) mm. For baseline variations larger than 5 mm, the tumor D95% variation between the plan and the dose recomputed on the end-exhale virtual CT resulted larger than 10%. Median variations higher than 10% in the target D95% and gastro-intestinal OARs D2% were quantified at the end-inhale, whereas close to the end-exhale phase, limited variations of relevant dose metrics were found for both tumor and OARs. Conclusions The negligible impact of the geometrical inaccuracy in the estimated anatomy outside of the 4DMRI FOV on the overall dosimetric accuracy suggests the feasibility of virtual 4DCT with extended FOV in CIRT of the abdominal site. In the analyzed patient group, inter-fractional variations such as baseline variation and breathing variability were quantified, demonstrating the method capability to support treatment planning in gated CIRT of the abdominal site.

Purpose To evaluate if baseline ADC from DWI sequences could predict response to treatment in patients with sacral chordoma not suitable for surgery treated with carbon ion radiotherapy (CIRT) alone compared with volume changes. Methods Fifty-nine patients with sacral chordoma not suitable for surgery underwent one cycle of CIRT alone and a minimum of 12-months follow-up. All patients underwent MRI before treatment (baseline), every three months in the first two years after treatment, and every six months afterwards. For each MRI, lesion volume was obtained and median, kurtosis, and skewness ADC were analyzed within the whole lesion volume. Volume changes between baseline and the last available follow-up were used to divide patients with partial response, progression of disease and stable disease (PR, PD, and SD). Results Ten patients were excluded since DWI sequences from baseline MRI were not available. ADC maps obtained from baseline DWI examinations of 50 lesions in the remaining 49 patients were considered. Seven lesions were categorized as PD, 30 PR, and 13 SD. PD showed significantly higher median ADC values at baseline (p = 0.003) compared with both PR and SD (1665vs1253vs1263 *10−6 mm²/s), and more negative skewness values (-0.26vs0.26vs0.08), although not significantly different (p = 0.16). Conclusions Preliminary results suggest that baseline ADC could predict response to treatment with CIRT, particularly to detect potential non-responder patients.

Purpose In image-guided particle radiotherapy of abdominal lesions, respiratory motion hinders treatment accuracy. In this study, 2D cineMRI data were used to quantify the tumor (GTV) motion and to evaluate the clinical approach based on deriving an internal target volume (ITV) from a planning 4DCT for gating treatments. Methods Seven patients with abdominal lesions were treated with carbon-ion therapy at the National Centre of Oncological Hadron-therapy (Italy). The MR scan was performed on the same day of the 4DCT acquisition. For four patients, an additional MR was acquired approximately after 1 week. The cineMRI combined with deformable image registration algorithm was used to quantify tumor motion. Afterwards, two ITVs were defined considering (1) all phases (ITVFB) and (2) only phases within the gating window (ITVG), and then compared with the clinical (4DCT-derived) ITVs (ITVCG and ITVCFB). Results Tumor residual motion estimated by cineMRI data in the two MRI sessions resulted not significantly different from 4DCT, although cineMRI accounted for cycle-to-cycle variations. The ITV normalized for the GTV median values were higher for ITVFB with respect to ITVG, ITVCFB and ITVCG. The Hausdorff distances with respect to the GTV were up to 10.55 mm, 3.13 mm, 5.56 mm and 2.51 mm, for ITVFB, ITVG, ITVCFB and ITVCG, respectively. According to both metrics, ITVCG and ITVG were not found significantly different. Conclusions CineMRI acquisitions allowed to quantify organ motion without delivering additional dose to the patient and to verify treatment margins in gated carbon-ion therapy of abdominal lesions.

Objective: Accurate patient positioning is crucial in particle therapy due to the geometrical selectivity of particles. We report and discuss the National Center for Oncological Hadrontherapy (CNAO) experience in positioning accuracy and stability achieved with solid thermoplastic masks fixed on index base plates and assessed by daily orthogonal X-ray imaging. Methods: Positioning data were retrospectively collected (between 2012 and 2018) and grouped according to the treated anatomical site. 19696 fractions of 1325 patients were evaluated. The study was designed to assess: (i) the number of fractions in which a single correction vector was applied(SCV); (ii) the number of fractions in which further setup verification was performed (SV); (iii) the number of fractions in which SV lead to an additional correction within (MCV5min) 5 minutes from the first setup correction; (iv) the systematic (Σ) and random (σ) error components of the correction vectors applied. Results: A SCV was applied in 71.5% of fractions, otherwise SV was required. In 30.6% of fractions with SV, patient position was not further revised. In the remaining fractions, MCV5min were applied mainly in extracranial and cranial sites respectively. Interfraction Σ was ≤ 1.7 mm/0.7° and σ was ≤ 1.2 mm/0.6° in cranial sites while in extracranial sites Σ was ≤ 5.5 mm/0.9° and σ was ≤4.4 mm/0.9°. Setup residuals were submillimetric in all sites. In cranial patients, maximum intrafractional Σ was 0.8 mm/0.4°. Conclusion: This report extensively quantifies inter- and intrafraction setup accuracy on an institutional basis and confirms the need of image guidance to fully benefit from the geometrical selectivity of particles. Advances in knowledge: The reported analysis provides a board institutional data set on the evaluation of patient immobilization and bony anatomy alignment for several particle therapy clinical indications.

Particle therapy (PT) has shown positive therapeutic results in local control of locally advanced pancreatic lesions. PT effectiveness is highly influenced by target localization accuracy both in space, since the pancreas is located in proximity to radiosensitive vital organs, and in time as it is subject to substantial breathing‐related motion. The purpose of this preliminary study was to quantify pancreas range of motion under typical PT treatment conditions. Three common immobilization devices (vacuum cushion, thermoplastic mask, and compressor belt) were evaluated on five male patients in prone and supine positions. Retrospective four‐dimensional magnetic resonance imaging data were reconstructed for each condition and the pancreas was manually segmented on each of six breathing phases. A k‐means algorithm was then applied on the manually segmented map in order to obtain clusters representative of the three pancreas segments: head, body, and tail. Centers of mass (COM) for the pancreas and its segments were computed, as well as their displacements with respect to a reference breathing phase (beginning exhalation). The median three‐dimensional COM displacements were in the range of 3 mm. Latero–lateral and superior–inferior directions had a higher range of motion than the anterior–posterior direction. Motion analysis of the pancreas segments showed slightly lower COM displacements for the head cluster compared to the tail cluster, especially in prone position. Statistically significant differences were found within patients among the investigated setups. Hence a patient‐specific approach, rather than a general strategy, is suggested to define the optimal treatment setup in the frame of a millimeter positioning accuracy. PACS number(s): 87.55.‐x, 87.57.nm, 87.61

A clinical trial named PROMETHEUS is currently ongoing for inoperable hepatocellular carcinoma (HCC) at the Heidelberg Ion Beam Therapy Center (HIT, Germany). In this framework, 4D PET-CT datasets are acquired shortly after the therapeutic treatment to compare the irradiation induced PET image with a Monte Carlo PET prediction resulting from the simulation of treatment delivery. The extremely low count statistics of this measured PET image represents a major limitation of this technique, especially in presence of target motion. The purpose of the study is to investigate two different 4D PET motion compensation strategies towards the recovery of the whole count statistics for improved image quality of the 4D PET-CT datasets for PET-based treatment verification. The well-known 4D-MLEM reconstruction algorithm, embedding the motion compensation in the reconstruction process of 4D PET sinograms, was compared to a recently proposed pre-reconstruction motion compensation strategy, which operates in sinogram domain by applying the motion compensation to the 4D PET sinograms. With reference to phantom and patient datasets, advantages and drawbacks of the two 4D PET motion compensation strategies were identified. The 4D-MLEM algorithm was strongly affected by inverse inconsistency of the motion model but demonstrated the capability to mitigate the noise-break-up effects. Conversely, the pre-reconstruction warping showed less sensitivity to inverse inconsistency but also more noise in the reconstructed images. The comparison was performed by relying on quantification of PET activity and ion range difference, typically yielding similar results. The study demonstrated that treatment verification of moving targets could be accomplished by relying on the whole count statistics image quality, as obtained from the application of 4D PET motion compensation strategies. In particular, the pre-reconstruction warping was shown to represent a promising choice when combined with intra-reconstruction smoothing.

Purpose To derive personalized tumour control probability (TCP) models, using diffusion-weighted (DW-) MRI for defining initial tumour cellular density in skull-base chordoma patients undergoing carbon-ion radiotherapy (CIRT). Materials and methods 67 patients affected by skull-base chordoma were enrolled for a standardized CIRT treatment (70.4 Gy (RBE) prescription dose). Local control information was clinically assessed. For 20 of them, apparent diffusion coefficient (ADC) maps were computed from DW-MRI and then converted into cellular density. Radiosensitivity parameters (α, β) were estimated from the available data through an optimization procedure, taking advantage of a relationship observed between local control and the dose received by at least the 98% of the gross tumour volume. These parameters were fed into two poissonian TCP models, based on the LQ model, being the first (TCPLIT) computed from literature parameters and the second (TCPADC) enriched by a personalized initial cellular density derived from ADC maps. Results The inclusion of the cellular density derived from ADC into TCPADC yielded slightly higher dose values at which TCP = 0.5 (D50 = 38.91 Gy (RBE)) with respect to TCPLIT (D5034.16 Gy (RBE)). This suggested a more conservative approach, even if the prognostic power of TCPADC and TCPLIT, tested with respect to local control, was equivalent in terms of sensitivity (0.867) and specificity (0.600). Conclusions Both TCPADC and TCPLIT exhibited good agreement with a clinically validated information of local control, the former providing more conservative predictions.

An increased life expectancy of people with Down syndrome (DS) and the occurrence of early aging are now recognized. However, few data exist on functioning and disability profile of early-aging people with DS, which takes into account how health conditions interact with environmental factors. Based on the World Health Organization's International Classification of Functioning, Disability and Health (ICF), the authors collected preliminary data describing functioning and disability about early aging from 31 adults with DS aged 45 and older residing in the greater Milan, Italy, area. ICF checklist was used to collect data. Of the 31, 18 were women (mean age = 51.1), all were unmarried, 21 lived with their family, and 23 never worked. Few problems in body functions (e.g., vision and hearing, cognitions) and body structures (e.g., ear and eye structures, cardiovascular, endocrine, and digestive systems, skin structures) were reported. ICF categories within Activity and Participation domain emphasized the facilitating effect of environmental factors on activities related to domestic life (e.g., doing housework, acquisition of goods and services, preparation of meals). Within the Environmental Factors domain there are few barriers, mainly with respect to labor services, and very strong facilitating factors, particularly related to product of technology (for personal indoor and outdoor mobility and transportation) and the support of family members. The authors note that the findings can set out premises for further study on aging people with DS and their caregivers at national and international levels.