A motion model-guided 4D dose reconstruction for pencil beam scanned proton therapy.

Objective.4D dose reconstruction in proton therapy with pencil beam scanning (PBS) typically relies on a single pre-treatment 4DCT (p4DCT). However, breathing motion during the fractionated treatment can vary considerably in both amplitude and frequency. We present a novel 4D dose reconstruction method combining delivery log files with patient-specific motion models, to account for the dosimetric effect of intra- and inter-fractional breathing variability.Approach.Correlation between an external breathing surrogate and anatomical deformations of the p4DCT is established using principal component analysis. Using motion trajectories of a surface marker acquired during the dose delivery by an optical tracking system, deformable motion fields are retrospectively reconstructed and used to generate time-resolved synthetic 4DCTs ('5DCTs') by warping a reference CT. For three abdominal/thoracic patients, treated with respiratory gating and rescanning, example fraction doses were reconstructed using the resulting 5DCTs and delivery log files. The motion model was validated beforehand using leave-one-out cross-validation (LOOCV) with subsequent 4D dose evaluations. Moreover, besides fractional motion, fractional anatomical changes were incorporated as proof of concept.Main results.For motion model validation, the comparison of 4D dose distributions for the original 4DCT and predicted LOOCV resulted in 3%/3 mm gamma pass rates above 96.2%. Prospective gating simulations on the p4DCT can overestimate the target dose coverage V95%by up to 2.1% compared to 4D dose reconstruction based on observed surrogate trajectories. Nevertheless, for the studied clinical cases treated with respiratory-gating and rescanning, an acceptable target coverage was maintained with V95%remaining above 98.8% for all studied fractions. For these gated treatments, larger dosimetric differences occurred due to CT changes than due to breathing variations.Significance.To gain a better estimate of the delivered dose, a retrospective 4D dose reconstruction workflow based on motion data acquired during PBS proton treatments was implemented and validated, thus considering both intra- and inter-fractional motion and anatomy changes.

The dependence of interplay effects on the field scan direction in PBS proton therapy.

The literature is controversial about the scan direction dependency of interplay effects in pencil beam scanning (PBS) treatment of moving targets. A directional effect is supported by many simulation studies, whereas the experimental data are mostly limited to simple geometries, not reflecting realistically clinical treatment plans. We have compared increasingly complex treatment fields, from a homogeneous single energy layer to a more modulated lung plan, under identical experimental settings, seeking evidence for differences in motion mitigation due to the selection of primary scanning direction. In total, 120 experimental samples were taken, combining two primary scan directions and three rescanning regimes with different motion scenarios. 4D dose distributions were measured in water with a moving ionisation chamber array and compared to those of a stationary delivery using 2D gamma analysis. Each plan has been verified twice for the same rescanning regime and motion scenario, changing the meandering direction in between to scan perpendicularly to, or along, the target motion. Additionally, machine log files of the lung plan, together with 4DCT data, were used to calculate the dose distribution that such deliveries would have produced in the patient. The primary meandering direction has a clear influence on measured dose distributions when considering a single energy layer. Introducing spot weight modulation and multiple energy layers however, makes the dynamic of interplay more complex and difficult to predict. Overall, gamma (3%/3 mm) differences between scanning along or orthogonal to the target motion follow a normal distribution [Formula: see text] when considering multiple motion scenarios and rescanning regimes. Nevertheless, data spread [Formula: see text] is significant enough such that, for individual experiments and set-ups, a dependency may be observed even if this is not a general result. Patient reconstructed doses follow the same trend, the two primary scan directions producing statistically insignificant differences in dose distributions in terms of conformity or homogeneity. Except for extremely simplified cases of mono-energetic and homogeneous treatment fields, the interplay effect has been found to be only marginally influenced by the choice of the primary scanning direction.

The impact of pencil beam scanning techniques on the effectiveness and efficiency of rescanning moving targets.

Therapeutic pencil beams are typically scanned using one of the following three techniques: spot scanning, raster scanning or line scanning. While providing similar dose distributions to the target, these three techniques can differ significantly in their delivery time sequence. Thus, we can expect differences in effectiveness and time efficiency when trying to mitigate interplay effects using rescanning. At the Paul Scherrer Institute, we are able to irradiate treatment plans using either of the three delivery techniques. Hence, we can compare them directly with identical underlying machine parameters such as energy switching time or minimum/maximum beam current. For this purpose, we selected three different liver targets, optimized plans for spots, and converted them to equivalent raster and line scanning plans. In addition to the scanning technique, we varied the underlying motion curve, starting phase, prescription dose and rescanning strategy, which resulted in a total of 1584 4D dose calculations and 49 measurements. They indicate that rescanning becomes effective when achieving a high number of rescans for every dose element. Fixed minimum spot weights for spot and raster scanning machines often hamper this. By introducing adaptive scaling of the beam current within iso-energy layers for line scanning, we can flexibly lower the minimum weight whenever required and achieve higher rescanning capability. Averaged over all scenarios studied, volumetric rescanning is significantly more effective than layered provided the same number of rescans are applied. Fast lateral scanning contributes to the efficiency of rescanning. We observed that in any given time window, we can always perform more rescans using raster or line scanning compared to spot scanning irradiations. Thus, we conclude that line scanning represents a promising technique for rescanning by combining both effectiveness and efficiency.

Involvement of MAF/SPP1 axis in the development of bone marrow fibrosis in PMF patients.

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by hyperplastic megakaryopoiesis and myelofibrosis. We recently described the upregulation of MAF (v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog) in PMF CD34+ hematopoietic progenitor cells (HPCs) compared to healthy donor. Here we demonstrated that MAF is also upregulated in PMF compared with the essential thrombocytemia (ET) and polycytemia vera (PV) HPCs. MAF overexpression and knockdown experiments shed some light into the role of MAF in PMF pathogenesis, by demonstrating that MAF favors the megakaryocyte and monocyte/macrophage commitment of HPCs and leads to the increased expression of proinflammatory and profibrotic mediators. Among them, we focused our further studies on SPP1 and LGALS3. We assessed SPP1 and LGALS3 protein levels in 115 PMF, 47 ET and 24 PV patients plasma samples and we found that SPP1 plasma levels are significantly higher in PMF compared with ET and PV patients. Furthermore, in vitro assays demonstrated that SPP1 promotes fibroblasts and mesenchymal stromal cells proliferation and collagen production. Strikingly, clinical correlation analyses uncovered that higher SPP1 plasma levels in PMF patients correlate with a more severe fibrosis degree and a shorter overall survival. Collectively our data unveil that MAF overexpression contributes to PMF pathogenesis by driving the deranged production of the profibrotic mediator SPP1.

Image guided particle therapy in CNAO room 2: implementation and clinical validation.

In this contribution we describe the implementation of a novel solution for image guided particle therapy, designed to ensure the maximal accuracy in patient setup. The presented system is installed in the central treatment room at Centro Nazionale di Adroterapia Oncologica (CNAO, Italy), featuring two fixed beam lines (horizontal and vertical) for proton and carbon ion therapy. Treatment geometry verification is based on robotic in-room imaging acquisitions, allowing for 2D/3D registration from double planar kV-images or 3D/3D alignment from cone beam image reconstruction. The calculated six degrees-of-freedom correction vector is transferred to the robotic patient positioning system, thus yielding automated setup error compensation. Sub-millimetre scale residual errors were measured in absolute positioning of rigid phantoms, in agreement with optical- and laser-based assessment. Sub-millimetre and sub-degree positioning accuracy was achieved when simulating setup errors with anthropomorphic head, thorax and pelvis phantoms. The in-house design and development allowed a high level of system customization, capable of replicating the clinical performance of commercially available products, as reported with preliminary clinical results in 10 patients.

Commissioning and quality assurance of an integrated system for patient positioning and setup verification in particle therapy.

In an increasing number of clinical indications, radiotherapy with accelerated particles shows relevant advantages when compared with high energy X-ray irradiation. However, due to the finite range of ions, particle therapy can be severely compromised by setup errors and geometric uncertainties. The purpose of this work is to describe the commissioning and the design of the quality assurance procedures for patient positioning and setup verification systems at the Italian National Center for Oncological Hadrontherapy (CNAO). The accuracy of systems installed in CNAO and devoted to patient positioning and setup verification have been assessed using a laser tracking device. The accuracy in calibration and image based setup verification relying on in room X-ray imaging system was also quantified. Quality assurance tests to check the integration among all patient setup systems were designed, and records of daily QA tests since the start of clinical operation (2011) are presented. The overall accuracy of the patient positioning system and the patient verification system motion was proved to be below 0.5 mm under all the examined conditions, with median values below the 0.3 mm threshold. Image based registration in phantom studies exhibited sub-millimetric accuracy in setup verification at both cranial and extra-cranial sites. The calibration residuals of the OTS were found consistent with the expectations, with peak values below 0.3 mm. Quality assurance tests, daily performed before clinical operation, confirm adequate integration and sub-millimetric setup accuracy. Robotic patient positioning was successfully integrated with optical tracking and stereoscopic X-ray verification for patient setup in particle therapy. Sub-millimetric setup accuracy was achieved and consistently verified in daily clinical operation.

Commissioning of an integrated platform for time-resolved treatment delivery in scanned ion beam therapy by means of optical motion monitoring.

The integrated use of optical technologies for patient monitoring is addressed in the framework of time-resolved treatment delivery for scanned ion beam therapy. A software application has been designed to provide the therapy control system (TCS) with a continuous geometrical feedback by processing the external surrogates tridimensional data, detected in real-time via optical tracking. Conventional procedures for phase-based respiratory phase detection were implemented, as well as the interface to patient specific correlation models, in order to estimate internal tumor motion from surface markers. In this paper, particular attention is dedicated to the quantification of time delays resulting from system integration and its compensation by means of polynomial interpolation in the time domain. Dedicated tests to assess the separate delay contributions due to optical signal processing, digital data transfer to the TCS and passive beam energy modulation actuation have been performed. We report the system technological commissioning activities reporting dose distribution errors in a phantom study, where the treatment of a lung lesion was simulated, with both lateral and range beam position compensation. The zero-delay systems integration with a specific active scanning delivery machine was achieved by tuning the amount of time prediction applied to lateral (14.61 ± 0.98 ms) and depth (34.1 ± 6.29 ms) beam position correction signals, featuring sub-millimeter accuracy in forward estimation. Direct optical target observation and motion phase (MPh) based tumor motion discretization strategies were tested, resulting in 20.3(2.3)% and 21.2(9.3)% median (IQR) percentual relative dose difference with respect to static irradiation, respectively. Results confirm the technical feasibility of the implemented strategy towards 4D treatment delivery, with negligible percentual dose deviations with respect to static irradiation.

Tumor tracking based on correlation models in scanned ion beam therapy: an experimental study.

Accurate dose delivery to extra-cranial lesions requires tumor motion compensation. An effective compensation can be achieved by real-time tracking of the target position, either measured in fluoroscopy or estimated through correlation models as a function of external surrogate motion. In this work, we integrated two internal/external correlation models (a state space model and an artificial neural network-based model) into a custom infra-red optical tracking system (OTS). Dedicated experiments were designed and conducted at GSI (Helmholtzzentrum für Schwerionenforschung). A robotic breathing phantom was used to reproduce regular and irregular internal target motion as well as external thorax motion. The position of a set of markers placed on the phantom thorax was measured with the OTS and used by the correlation models to infer the internal target position in real-time. Finally, the estimated target position was provided as input for the dynamic steering of a carbon ion beam. Geometric results showed that the correlation models transversal (2D) targeting error was always lower than 1.3 mm (root mean square). A significant decrease of the dosimetric error with respect to the uncompensated irradiation was achieved in four out of six experiments, demonstrating that phase shifts are the most critical irregularity for external/internal correlation models.

Automated fiducial localization in CT images based on surface processing and geometrical prior knowledge for radiotherapy applications.

We propose a novel method for radio-opaque external marker localization in CT scans for infrared (IR) patient set-up in radiotherapy. Efforts were focused on the quantification of uncertainties in marker localization in the CT dataset as a function of algorithm performance. We implemented a 3-D approach to fiducial localization based on surface extraction and marker recognition according to geometrical prior knowledge. The algorithm parameters were optimized on a clinical CT dataset coming from 35 cranial and extra-cranial patients; the localization accuracy was benchmarked at variable image resolution versus laser tracker measurements. The applicability of conventional IR optical tracking systems for localizing external surrogates in daily patient set-up procedures was also investigated in 121 proton therapy treatment sessions. Our study shows that the implemented algorithm features surrogates localization with uncertainties lower than 0.3 mm and with a true positive rate of 90.1%, being this latter mainly influenced by fiducial homogeneity in the CT images. The reported clinical validation in proton therapy confirmed the submillimetric accuracy and the expected algorithm sensitivity. Geometrical prior knowledge allows judging the reliability of the extracted fiducial coordinates, ensuring the highest accuracy in patient set-up.

[Biomechanical overcharge of the upper limbs in hairdressers: from the task analysis to the job/exposition matrix]. / Il sovraccarico biomeccanico degli arti superiori nel comparto acconciatori: dall'analisi dei compiti alla matrice mansione-esposizione.

The analysis of professional diseases denounced from hairdressers in Italy and in Tuscany shows among these workers a reduction of some "typical" work related diseases, like dermatitis, asthma, etc. and a raise of upper limbs disorders. The upper limbs risk assessment process is very tough for the hairdresser's activity, because the working cycle includes different tasks (shampoo, cut, dyeing, etc.) and their combination in a working day is related to customers requests. The job illustrates the first results of a project started last year from the Tuscany Technical Advisory Department for Risk Assessment and. Prevention (CONTARP) of the Italian Workers' Compensation Authority (INAIL) and PISLL "G. Pieraccini" - ASL 10 of Florence. Through a study conducted with the OCRA Check List method on a sample constituted by 12 employees of five shops of the Florentine territory, we have arrived to a job-exposure matrix that allows to draw an index of exposure to the specific risk for every task, keeping in mind the contributions of the single repetitive assignment performed by the operator during the working day.

Change in major amputation rate in a center dedicated to diabetic foot care during the 1980s: prognostic determinants for major amputation.

From 1990 to 1993, 115 diabetic patients were consecutively hospitalized in our diabetologic unit for foot ulcer and 27 (23.5%) major amputations were carried out. The major amputation rate of this series of cases was compared with that occurring in diabetic subjects taken into our hospital for foot ulcer in two previous periods: 1979-1981 (17 major amputations in 42 inpatients or 40.5%) and 1986-1989 (26 major amputations in 78 inpatients or 33.3%). The comparison shows a progressive reduction in major amputation rate [Odds ratio 0.66, 95% confidence interval (CI) 0.46-0.96]. Univariate and multivariate analysis, carried out in the population of the 1990-1993 period, in order to detect the independent factors associated with major amputation show the following prognostic determinants of major amputation: Wagner grade (odds ratio 7.69, CI 1.58-37.53), prior stroke (odds ratio 35.05, CI 3.14-390.53), prior major amputation (odds ratio 3.49, CI 1.26-9.38), transcutaneous oxygen level (odds ratio 1.06, CI 1.01-1.12), and ankle-brachial blood pressure index (odds ratio 4.35, CI 1.58-12.05), while an independent protective role was attributed to hyperbaric oxygen treatment (odds ratio 0.15, CI 0.03-0.64). In accordance with other studies, we, therefore, conclude that a comprehensive protocol as well as a multidisciplinary approach in a dedicated center can assure a decrease in major amputation rate. The parameters of limb perfusion were the modifiable prognostic determinants most strongly predictive for amputation.

[Analysis of the routine control colposcopic findings, of the preventive gynecological oncology service]. / Analisi dei quadri colposcopici di comune riscontro, del servizio di oncologia ginecologica preventiva.

Ten-thousand-fifty-one colposcopic examinations recorded using uniform and standardized criteria from 1983 to 1988 are analysed. The results confirm the validity of the protocol used. It is emphasized that the main problem concerning the prevention of cervical cancer still lies in putting high-risk patients in touch with the health services.

Early alteration of bioprosthetic cardiac valves in sheep: influence of the immunological status.

Ten Pericarbon valve bioprostheses were examined after being implanted in tricuspid position in two different groups of animals: group I sheep with increased immunoglobulins, plasma levels, and eosinophilis count of more than 10%, due to parasitic infection, and group II sheep without any parasitic infection, i.e. with normal blood data. The explanted valve follow up was between 60-95 hours in both groups. Microscopic observation of group I valves revealed a massive blood cell (lymphocytes, eosinophilis and large mononuclear cells) infiltration especially around the natural pericardial blood vessels in the region of flexion and attachment. The epipericardial surface was covered by fibrin sheath, and immunofluorescence studies showed a strongly positive reaction for immunoglobulins (IgG and IgE) on leaflet surfaces and lamellar stratification into the fibrosa. Microcalcifications were detected around pericardial blood vessels in the same zones where infiltrated blood cells were found. In group II valves cell infiltration was absent with no signs of calcification and immunofluorescence was negative. Our data suggest that immunoglobulins adherence followed by blood cell infiltration may be one of the early causes of tissue leaflet degeneration and there is a parallel trend between plasma immunoglobulin levels and the early tissue alteration. Our data show that the experimental model for testing bioprostheses in sheep is influenced by the pre-immunological status and it is important to control it before surgery.

Experimental right ventricular outflow tract reconstruction with a composite Mitrathane monocusp patch: preliminary results.

Twenty large white pigs underwent normothermic right ventricular bypass, pulmonary artery valve excision and right ventricular outflow tract (RVOT) reconstruction using a synthetic material (Mitrathane). The animals were divided in two groups (ten for each group) for the RVOT reconstruction model: Group I with a composite monocusp patch (with a new design geometrically related to pulmonary artery circumference) and Group II without a valve mechanism. Four early postoperative deaths occurred in Group I (unrelated to monocusp patch function) and seven in Group II (due to acute right ventricular failure). Follow up of the six animals of Group I was 600-630 (average 617.5) days and of the three Group II animals was 95-110 (average 101.6) days. In Group I haemodynamic studies showed no significant difference from preoperative values at 5 months while at 20 months there was a moderate valve insufficiency in all animals. In Group II severe right ventricular insufficiency was present in all animals and spontaneous death occurred after about 3 months. In Group I angiographic studies disclosed no evidence of graft calcification or stenosis while in Group II there was a moderate pulmonary trunk dilatation. Post mortem examination showed no signs of degeneration in any graft. Microscopic studies of both groups revealed an acellular layer of fibrin on the external surface and fibrous deposit on the inner part of the suture with the right ventricle. In Group I there were leukocyte and histocyte infiltration of the grafts. In these experiments our synthetic monocusp model showed good function and durability in comparison to a RVOT reconstruction without a valve mechanism.