Non-lesional white matter in relapsing-remitting multiple sclerosis assessed by multicomponent T2 relaxation.

INTRODUCTION: The purpose of the study is to investigate, by T2 relaxation, non-lesional white matter (WM) in relapsing-remitting (RR) multiple sclerosis (MS). METHODS: Twenty stable RR MS patients underwent 1.5T Magnetic Resonance Imaging (MRI) with 3D Fluid-Attenuated Inversion-Recovery (FLAIR), 3D-T1-weighted, and T2-relaxation multi-echo sequences. The Lesion Segmentation Tool processed FLAIR images to identify focal lesions (FLs), whereas T1 images were segmented to identify WM and FL sub-volumes with T1 hypo-intensity. Non-lesional WM was obtained as the segmented WM, excluding FL volumes. The multi-echo sequence allowed decomposition into myelin water, intra-extracellular water, and free water (Fw), which were evaluated on the segmented non-lesional WM. Correlation analysis was performed between the non-lesional WM relaxation parameters and Expanded Disability Status Scale (EDSS), disease duration, patient age, and T1 hypo-intense FL volumes. RESULTS: The T1 hypo-intense FL volumes correlated with EDSS. On the non-lesional WM, the median Fw correlated with EDSS, disease duration, age, and T1 hypo-intense FL volumes. Bivariate EDSS correlation of FL volumes and WM T2-relaxation parameters did not improve significance. CONCLUSION: T2 relaxation allowed identifying subtle WM alterations, which significantly correlated with EDSS, disease duration, and age but do not seem to be EDSS-predictors independent from FL sub-volumes in stable RR patients. Particularly, the increase in the Fw component is suggestive of an uninvestigated prodromal phenomenon in brain degeneration.

The INFN proton computed tomography system for relative stopping power measurements: calibration and verification.

Objective. This paper describes the procedure to calibrate the three-dimensional (3D) proton stopping power relative to water (SPR) maps measured by the proton computed tomography (pCT) apparatus of the Istituto Nazionale di Fisica Nucleare (INFN, Italy). Measurements performed on water phantoms are used to validate the method. The calibration allowed for achieving measurement accuracy and reproducibility to levels below 1%.Approach. The INFN pCT system is made of a silicon tracker for proton trajectory determination followed by a YAG:Ce calorimeter for energy measurement. To perform the calibration, the apparatus has been exposed to protons of energies ranging from 83 to 210 MeV. Using the tracker, a position-dependent calibration has been implemented to keep the energy response uniform across the calorimeter. Moreover, correction algorithms have been developed to reconstruct the proton energy when this is shared in more than one crystal and to consider the energy loss in the non-uniform apparatus material. To verify the calibration and its reproducibility, water phantoms have been imaged with the pCT system during two data-taking sessions.Main results. The energy resolution of the pCT calorimeter resulted to beσEE≅0.9%at 196.5 MeV. The average values of the water SPR in fiducial volumes of the control phantoms have been calculated to be 0.995±0.002. The image non-uniformities were below 1%. No appreciable variation of the SPR and uniformity values between the two data-taking sessions could be identified.Significance. This work demonstrates the accuracy and reproducibility of the calibration of the INFN pCT system at a level below 1%. Moreover, the uniformity of the energy response keeps the image artifacts at a low level even in the presence of calorimeter segmentation and tracker material non-uniformities. The implemented calibration technique allows the INFN-pCT system to face applications where the precision of the SPR 3D maps is of paramount importance.

Characterization of the INFN proton CT scanner for cross-calibration of x-ray CT.

Objective. The goal of this study was to assess the imaging performances of the pCT system developed in the framework of INFN-funded (Italian National Institute of Nuclear Physics) research projects. The spatial resolution, noise power spectrum (NPS) and RSP accuracy has been investigated, as a preliminary step to implement a new cross-calibration method for x-ray CT (xCT).Approach. The INFN pCT apparatus, made of four planes of silicon micro-strip detectors and a YAG:Ce scintillating calorimeter, reconstructs 3D RSP maps by a filtered-back projection algorithm. The imaging performances (i.e. spatial resolution, NPS and RSP accuracy) of the pCT system were assessed on a custom-made phantom, made of plastic materials with different densities ((0.66, 2.18) g cm-3). For comparison, the same phantom was acquired with a clinical xCT system.Main results. The spatial resolution analysis revealed the nonlinearity of the imaging system, showing different imaging responses in air or water phantom background. Applying the Hann filter in the pCT reconstruction, it was possible to investigate the imaging potential of the system. Matching the spatial resolution value of the xCT (0.54 lp mm-1) and acquiring both with the same dose level (11.6 mGy), the pCT appeared to be less noisy than xCT, with an RSP standard deviation of 0.0063. Concerning the RSP accuracy, the measured mean absolute percentage errors were (0.23+-0.09)% in air and (0.21+-0.07)% in water.Significance. The obtained performances confirm that the INFN pCT system provides a very accurate RSP estimation, appearing to be a feasible clinical tool for verification and correction of xCT calibration in proton treatment planning.

Does variable RBE affect toxicity risks for mediastinal lymphoma patients? NTCP-based evaluation after proton therapy treatment.

INTRODUCTION: Mediastinal lymphoma (ML) is a solid malignancy affecting young patients. Modern combined treatments allow obtaining good survival probability, together with a long life expectancy, and therefore with the need to minimize treatment-related toxicities. We quantified the expected toxicity risk for different organs and endpoints in ML patients treated with intensity-modulated proton therapy (IMPT) at our centre, accounting also for uncertainties related to variable RBE. METHODS: Treatment plans for ten ML patients were recalculated with a TOPAS-based Monte Carlo code, thus retrieving information on LET and allowing the estimation of variable RBE. Published NTCP models were adopted to calculate the toxicity risk for hypothyroidism, heart valve defects, coronary heart disease and lung fibrosis. NTCP was calculated assuming both constant (i.e. 1.1) and variable RBE. The uncertainty associated with individual radiosensitivity was estimated by random sampling α/ß values before RBE evaluation. RESULTS: Variable RBE had a minor impact on hypothyroidism risk for 7 patients, while it led to significant increase for the remaining three (+24% risk maximum increase). Lung fibrosis was slightly affected by variable RBE, with a maximum increase of â‰… 1%. This was similar for heart valve dysfunction, with the exception of one patient showing an about 10% risk increase, which could be explained by means of large heart volume and D1 increase. DISCUSSION: The use of NTCP models allows for identifying those patients associated with a higher toxicity risk. For those patients, it might be worth including variable RBE in plan evaluation.

Toxicity and Clinical Results after Proton Therapy for Pediatric Medulloblastoma: A Multi-Centric Retrospective Study.

Medulloblastoma is the most common malignant brain tumor in children. Even if current treatment dramatically improves the prognosis, survivors often develop long-term treatment-related sequelae. The current radiotherapy standard for medulloblastoma is craniospinal irradiation with a boost to the primary tumor site and to any metastatic sites. Proton therapy (PT) has similar efficacy compared to traditional photon-based radiotherapy but might achieve lower toxicity rates. We report on our multi-centric experience with 43 children with medulloblastoma (median age at diagnosis 8.7 years, IQR 6.6, M/F 23/20; 26 high-risk, 14 standard-risk, 3 ex-infant), who received active scanning PT between 2015 and 2021, with a focus on PT-related acute-subacute toxicity, as well as some preliminary data on late toxicity. Most acute toxicities were mild and manageable with supportive therapy. Hematological toxicity was limited, even among HR patients who underwent hematopoietic stem-cell transplantation before PT. Preliminary data on late sequelae were also encouraging, although a longer follow-up is needed.

Technical challenges in the treatment of mediastinal lymphomas by proton pencil beam scanning and deep inspiration breath-hold.

PURPOSE: To comprehensively describe the treatment of mediastinal lymphoma by pencil beam scanning (PBS) proton therapy. METHODS: Fourteen patients underwent PBS proton treatment in a supine position in deep inspiration breath-hold (DIBH). Three DIBH computed tomography (CT) scans were acquired for each patient to delineate the Internal Target Volume (ITV). Intensity-modulated proton therapy (IMPT) was planned by min-max robust optimization on the ITV, with a 6 mm setup and 3.5% range uncertainties. Robustness analysis was performed and dose coverage was visually inspected on the corresponding voxel-wise minimum map. Layer repainting was set equal to 5 to compensate for cardiac motion. Intra-fraction reproducibility during treatment was assessed by repeated daily DIBH X-ray imaging. Finally, an additional CT was acquired at half treatment to estimate the impact of inter-fraction dosimetric reproducibility. RESULTS: IMPT guaranteed robust mediastinal target coverage and organs-at-risk sparing. However, visual voxel-wise robustness evaluation showed that in five patients a second optimization with focused objectives in the cost-function was necessary to achieve a robust coverage of the target regions at the interface between lungs and soft tissue. In six patients, repainting was not used due to excessive treatment time length and poor patient compliance. Intra-fraction average reproducibility was within 1 mm/1degree. On repeated CT scans, inter-fraction setup errors and/or anatomical changes showed minimal dosimetric differences in CTV coverage. CONCLUSION: IMPT in DIBH is effective and reproducible to treat mediastinal lymphomas. Caution is recommended to guarantee robust dose delivery to high-risk regions at the interface between lungs and soft tissue.

Is it beneficial to use apertures in proton radiosurgery with a scanning beam? A dosimetric comparison in neurinoma and meningioma patients.

PURPOSE: To assess the dosimetric advantages of apertures in intracranial single fraction proton radiosurgery. MATERIALS AND METHODS: Six neuroma and 10 meningioma patients were investigated. For each patient, six plans were computed, with two spot spacing and three aperture settings (no apertures, 5 and 8 mm margin between aperture and clinical target volume [CTV]). All plans were optimized on the CTV with the same beam arrangement and the same single-field robust optimization (2 mm setup errors, 3.5% range uncertainties). Robustness analysis was performed with 0.5 and 1.0 mm systematic setup errors and 3.5% range uncertainties. CTV coverage in the perturbed scenarios and healthy brain tissue sparing in the surrounding of the CTV were compared. RESULTS: Meningiomas were larger and at a shallow depth than neuromas. In neuromas, spot spacing did not affect OAR doses or the robustness of CTV coverage and the apertures reduced brain dose without any significant impact on CTV robustness. In meningiomas, smaller spot spacing produced a reduction in brain V5Gy and improved robustness of CTV coverage; in addition, an 8 mm margin aperture reduced low and medium brain tissue doses without affecting robustness in the 0.5 mm perturbed scenario. A 5 mm margin aperture caused a reduction of plan robustness. CONCLUSION: The optimal use of apertures is a trade-off between sparing of low and medium dose to the healthy brain and robustness of target coverage, also depending on size and depth of the lesion.

Combining Low-Dose Radiation Therapy and Magnetic Resonance Guided Focused Ultrasound to Reduce Amyloid-ß Deposition in Alzheimer's Disease.

Amyloid-ß deposition is one of the neuropathological hallmarks of Alzheimer's disease (AD), but pharmacological strategies toward its reduction are poorly effective.Preclinical studies indicate that low-dose radiation therapy (LD-RT) may reduce brain amyloid-ß. Animal models and proof-of-concept preliminary data in humans have shown that magnetic resonance guided focused ultrasound (MRgFUS) can reversibly open the blood-brain-barrier and facilitate the delivery of targeted therapeutics to the hippocampus, to reduce amyloid-ß and promote neurogenesis in AD. Ongoing clinical trials on AD are exploring whole-brain LD-RT, which may damage radio-sensitive structures, i.e., hippocampus and white matter, thus contributing to reduced neurogenesis and radiation-induced cognitive decline. However, selective irradiation of cortical amyloid-ß plaques through advanced LD-RT techniques might spare the hippocampus and white matter. We propose combined use of advanced LD-RT and targeted drug delivery through MRgFUS for future clinical trials to reduce amyloid-ß deposition in AD since its preclinical stages.

Multicomponent T2 relaxometry reveals early myelin white matter changes induced by proton radiation treatment.

PURPOSE: To investigate MRI myelin water imaging (MWI) by multicomponent T2 relaxometry as a quantitative imaging biomarker for brain radiation-induced changes and to compare it with DTI. METHODS: Sixteen patients underwent fractionated proton therapy (PT) receiving dose to the healthy tissue because of direct or indirect (base skull tumors) irradiation. MWI was performed by a multi-echo sequence with 32 equally spaced echoes (10-320 ms). Decay data were processed to identify 3 T2 compartments: myelin water (Mw) below 40 ms, intra-extracellular water (IEw) between 40 and 250 ms, and free water (CSFw) above 250 ms. Both MWI and DTI scans were acquired pre (pre)-treatment and immediately at the end (end) of PT. After image registration, voxel-wise difference maps, obtained by subtracting MWI and DTI pre from those acquired at the end of PT, were compared with the corresponding biological equivalent dose (BED). RESULTS: Mw difference showed a positive correlation and IEw difference showed a negative correlation with BED considering end-pre changes (P < .01). The changes in CSFw were not significantly correlated with the delivered BED. The changes in DTI data, considering end-pre acquisitions, showed a positive correlation between fractional anisotropy and the delivered BED. CONCLUSION: MWI might detect early white matter radiation-induced alterations, providing additional information to DTI, which might improve the understanding of the pathogenesis of the radiation damage.

Clinical validation of a GPU-based Monte Carlo dose engine of a commercial treatment planning system for pencil beam scanning proton therapy.

PURPOSE: To perform the validation of the GPU-based (Graphical Processing Unit based) proton Monte Carlo (MC) dose engine implemented in a commercial TPS (RayStation 10B) and to report final dose calculation times for clinical cases. MATERIALS AND METHODS: 440 patients treated at the Proton Therapy Center of Trento, Italy, between 2018 and 2019 were selected for this study. 636 approved plans with 3361 beams computed with the clinically implemented CPU-MC dose engine (version 4.2 and 4.5), were used for the validation of the new algorithm. For each beam, the dose was recalculated using the new GPU-MC dose engine with the initial CPU computation settings and compared to the original CPU-MC dose. Beam dose difference distributions were studied to ensure that the two dose distributions were equal within the expected fluctuations of the MC statistical uncertainty (s) of each computation. Plan dose distributions were compared with respect to the dosimetric indices D98, D50 and D1 of all ROIs defined as targets. A complete assessment of the computation time as a function of s and dose grid voxel size was done. RESULTS: The median over all mean beam dose differences between CPU- and GPU-MC was -0.01% and the median of the corresponding standard deviations was close to (√2s) both for simulations with an s of 0.5% and 1.0% per beam. This shows that the two dose distributions can be considered equal. All the DVH indices showed an average difference below 0.04%. About half of the plans were computed with 1.0% statistical uncertainty on a 2 mm dose calculation grid, for which the median computation time was 5.2 s. The median computational speed for all plans in the study was 8.4 million protons/second. CONCLUSION: A validation of a clinical MC algorithm running on GPU was performed on a large pool of patients treated with pencil beam scanning proton therapy. We demonstrated that the differences with the previous CPU-based MC were only due to the intrinsic statistical fluctuations of the MC method, which translated to insignificant differences on plan dose level. The significant increase in dose calculation speed is expected to facilitate new clinical workflows.

Quantitative Multicomponent T2 Relaxation Showed Greater Sensitivity Than Flair Imaging to Detect Subtle Alterations at the Periphery of Lower Grade Gliomas.

PURPOSE: To demonstrate that quantitative multicomponent T2 relaxation can be more sensitive than conventional FLAIR imaging for detecting cerebral tissue abnormalities. METHODS: Six patients affected by lower-grade non-enhancing gliomas underwent T2 relaxation and FLAIR imaging before a radiation treatment by proton therapy (PT) and were examined at follow-up. The T2 decay signal obtained by a thirty-two-echo sequence was decomposed into three main components, attributing to each component a different T2 range: water trapped in the lipid bilayer membrane of myelin, intra/extracellular water and cerebrospinal fluid. The T2 quantitative map of the intra/extracellular water was compared with FLAIR images. RESULTS: Before PT, in five patients a mismatch was observed between the intra/extracellular water T2 map and FLAIR images, with peri-tumoral areas of high T2 that typically extended outside the area of abnormal FLAIR hyper-intensity. Such mismatch regions evolved into two different types of patterns. The first type, observed in three patients, was a reduced extension of the abnormal regions on T2 map with respect to FLAIR images (T2 decrease pattern). The second type, observed in two patients, was the appearance of new areas of abnormal hyper-intensity on FLAIR images matching the anomalous T2 map extension (FLAIR increase pattern), that was considered as asymptomatic radiation induced damage. CONCLUSION: Our preliminarily results suggest that quantitative T2 mapping of the intra/extracellular water component was more sensitive than conventional FLAIR imaging to subtle cerebral tissue abnormalities, deserving to be further investigated in future clinical studies.

Clinical implementation of pencil beam scanning proton therapy for liver cancer with forced deep expiration breath hold.

PURPOSE: To present our technique for liver cancer treatments with proton therapy in pencil beam scanning mode and to evaluate the impact of uncertainties on plan quality. MATERIALS AND METHODS: Seventeen patients affected by liver cancer were included in this study. Patients were imaged and treated in forced breath-hold using the Active Breathing Coordinator system and monitored with an optical tracking system. Three simulation CTs were acquired to estimate the anatomical variability between breath-holds and generate an internal target volume (ITV). The treatment plans were optimized with a Single Field Optimization technique aimed at minimizing the use of range shifter. Plan robustness was tested simulating systematic range and setup uncertainties, as well as the interplay effect between breath-holds. The appropriateness of margin was further verified based on the actual positioning data acquired during treatment. RESULTS: The dose distributions of the nominal plans achieved a satisfactory target coverage in 11 out of 17 patients, while in the remaining 6 D95 to the PTV was affected by the constraint on mean liver dose. The constraints for all other organs at risk were always within tolerances. The interplay effect had a limited impact on the dose distributions: the worst case scenario showed a D95 reduction in the ITV < 3.9 GyRBE and no OAR with D1 > 105% of the prescription dose. The robustness analysis showed that for 13 out of 17 patients the ITV coverage in terms of D95 was better than D95 of the PTV in the nominal plan. For the remaining 4 patients, the maximum difference between ITV D95 and PTV D95 was ≤0.7% even for the largest simulated setup error and it was deemed clinically acceptable. Hot spots in the OARs were always lower than 105% of the prescription dose. Positioning images confirmed that the breath hold technique and the PTV margin were adequate to compensate for inter- and intra-breath-hold variations in liver position. CONCLUSION: We designed and clinically applied a technique for the treatment of liver cancer with proton pencil beam scanning in forced deep expiration breath-hold. The initial data on plan robustness and patient positioning suggest that the choices in terms of planning technique and treatment margins are able to reach the desired balance between target coverage and organ at risk sparing.

Technical Note: CT calibration for proton treatment planning by cross-calibration with proton CT data.

PURPOSE: This study explores the possibility of a new method for x-ray computed tomography (CT) calibration by means of cross-calibration with proton CT (pCT) data. The proposed method aims at a more accurate conversion of CT Hounsfield Units (HU) into proton stopping power ratio (SPR) relative to water to be used in proton-therapy treatment planning. METHODS: X-ray CT scan was acquired on a synthetic anthropomorphic phantom, composed of different tissue equivalent materials (TEMs). A pCT apparatus was instead adopted to obtain a reference three-dimensional distribution of the phantom's SPR values. After rigid registration, the x-ray CT was artificially blurred to the same resolution of pCT. Then a scatter plot showing voxel-by-voxel SPR values as a function of HU was employed to link the two measurements and thus obtaining a cross-calibrated x-ray CT calibration curve. The cross-calibration was tested at treatment planning system and then compared with a conventional calibration based on exactly the same TEMs constituting the anthropomorphic phantom. RESULTS: Cross-calibration provided an accurate SPR mapping, better than by conventional TEMs calibration. The dose distribution of single beams optimized on the reference SPR map was recomputed on cross-calibrated CT, showing, with respect to conventional calibration, minor deviation at the dose fall-off (lower than 1%). CONCLUSIONS: The presented data demonstrated that, by means of reference pCT data, a heterogeneous phantom can be used for CT calibration, paving the way to the use of biological samples, with their accurate description of patients' tissues. This overcomes the limitations of conventional CT calibration requiring homogenous samples, only available by synthetic TEMs, which fail in accurately mimicking the properties of biological tissues. Once a heterogeneous biological sample is provided with its corresponding reference SPR maps, a cross-calibration procedure could be adopted by other PT centers, even when not equipped with a pCT system.

Proton pencil beam scanning reduces secondary cancer risk in breast cancer patients with internal mammary chain involvement compared to photon radiotherapy.

PURPOSE: Proton pencil beam scanning (PBS) represents an interesting option for the treatment of breast cancer (BC) patients with nodal involvement. Here we compare tangential 3D-CRT and VMAT to PBS proton therapy (PT) in terms of secondary cancer risk (SCR) for the lungs and for contralateral breast. METHODS: Five BC patients including supraclavicular (SVC) nodes in the target (Group 1) and five including SVC plus internal-mammary-nodes (IMNs, Group 2) were considered. The Group 1 patients were planned by PT versus tangential 3D-CRT in free-breathing (FB). The Group 2 patients were planned by PT versus VMAT considering both FB and deep-inspiration breath hold (DIBH) irradiation. The prescription dose to the target volume was 50 Gy (2 Gy/fraction). A constant RBE = 1.1 was assumed for PT. The SCR was evaluated with the excess absolute risk (EAR) formalism, considering also the age dependence. A cumulative EAR was finally computed. RESULTS: According to the linear, linear-exponential and linear-plateau dose response model, the cumulative EAR for Group 1 patients after PT was equal to 45 ± 10, 17 ± 3 and 15 ± 3, respectively. The corresponding relative increase for tangential 3D-CRT was equal to a factor 2.1 ± 0.5, 2.1 ± 0.4 and 2.3 ± 0.4. Group 2 patients showed a cumulative EAR after PT in FB equal to 65 ± 3, 21 ± 1 and 20 ± 1, according to the different models; the relative risk obtained with VMAT increased by a factor 3.5 ± 0.2, 5.2 ± 0.3 and 5.1 ± 0.3. Similar values emerge from DIBH plans. Contrary to photon radiotherapy, PT appears to be not sensitive to the age dependence due to the very low delivered dose. CONCLUSIONS: PBS PT is associated to significant SCR reduction in BC patients compared to photon radiotherapy. The benefits are maximized for young patients with both SVC and IMNs involvement. When combined with the improved sparing of the heart, this might contribute to the establishment of effective patient-selection criteria for proton BC treatments.

An avoidance method to minimize dose perturbation effects in proton pencil beam scanning treatment of patients with small high-Z implants.

To implement a multi-field-optimization (MFO) technique for treating patients with high-Z implants in pencil beam scanning proton-therapy and generate treatment plans that avoids small implants. Two main issues were addressed: (i) the assessment of the optimal CT acquisition and segmentation technique to define the dimension of the implant and (ii) the distance of pencil beams from the implant (avoidance margin) to assure that it does not affect dose distribution. Different CT reconstruction protocols (by O-MAR or standard reconstruction and by 12 bit or 16 bit dynamic range) followed by thresholding segmentation were tested on a phantom with lead spheres of different sizes. The proper avoidance margin was assessed on a dedicated phantoms of different materials (copper/tantalum and lead), shape (square slabs and spheres) and detectors (two-dimensional array chamber and radio-chromic films). The method was then demonstrated on a head-and-neck carcinoma patient, who underwent carotid artery embolization with a platinum coil close to the target. Regardless the application of O-MAR reconstruction, the CT protocol with a full 16 bit dynamic range allowed better estimation of the sphere volumes, with maximal error around -5% in the greater sphere only. Except the configuration with a shallow target (which required a pre-absorber), particularly with a retracted snout, an avoidance margin of around 0.9-1.3 cm allowed to keep the difference between planned and measured dose below 5-10%. The patient plan analysis showed adequate plan quality and confirmed effective implant avoidance. Potential target under-dosage can be produced by patient misalignment, which could be minimized by daily alignment on the implant, identifiable on orthogonal kilovolt images. By implant avoidance MFO it was possible to minimize potential dose perturbation effects produced by small high-Z implants. An advantage of such approach lies in its potential applicability for any type of implant, regardless the precise knowledge of its composition.

Accurate proton treatment planning for pencil beam crossing titanium fixation implants.

PURPOSE: To present a planning strategy for proton pencil-beam scanning when titanium implants need to be crossed by the beam. METHODS: We addressed three issues: the implementation of a CT calibration curve to assign to titanium the correct stopping power; the effect of artefacts on CT images and their reduction by a dedicated algorithm; the differences in dose computation depending on the dose engine, pencil-beam vs Monte-Carlo algorithms. We performed measurement tests on a simple cylinder phantom and on a real implant. These phantoms were irradiated with three geometries (single spots, uniform mono-energetic layer and uniform box), measuring the exit dose either by radio-chromic film or multi-layer ionization chamber. The procedure was then applied on two patients treated for chordoma. RESULTS: We had to set in the calibration curve a mass density equal to 4.37 g/cm3 to saturated Hounsfield Units, in order to have the correct stopping power assigned to titanium in TPS. CT artefact reduction algorithm allowed a better reconstruction of the shape and size of the implant. Monte-Carlo resulted accurate in computing the dose distribution whereas the pencil-beam algorithm failed due to sharp density interfaces between titanium and the surrounding material. Finally, the treatment plans obtained on two patients showed the impact of the dose engine algorithm, with 10-20% differences between pencil-beam and Monte-Carlo in small regions distally to the titanium screws. CONCLUSION: The described combination of CT calibration, artefacts reduction and Monte-Carlo computation provides a reliable methodology to compute dose in patients with titanium implants.

Sparse deconvolution of proton radiography data to estimate water equivalent thickness maps.

PURPOSE: In proton therapy, the conversion of the planning computed tomography (CT) into proton stopping powers is tainted by uncertainties which may jeopardize dose conformity. Proton radiography provides a direct information on the energy reduction of protons in the patient. However, it is currently limited by the degradation ("blurring") of the one-dimensional depth-dose deposition profiles which constitute the pixels. METHODS: An iterative algorithm is implemented to extract high-resolution water equivalent thickness (WET) maps from the measurements of depth-dose profiles acquired with a multilayer ionization chamber. The method relies on the assumption that those curves are a function of the WET, which can benefit from a sparse representation. RESULTS: When used without relying on any prior knowledge derived from the planning CT, the method already outperforms the published one in terms of accuracy. We also propose a variant which integrates the planning CT in a robust fashion to further improve the deconvolution result and reach an accuracy of 1.5 mm on the estimated WET. The methods are applied to both synthetic data and actual proton radiography acquisitions on phantoms. CONCLUSIONS: Besides the increase in accuracy achieved in the estimation of WET maps from proton radiography data, we demonstrate that the proposed deconvolution algorithm is also more robust with respect to confounding factors such as residual setup errors or changes in the anatomy. Therefore, proton radiography using a range probe provides both the required accuracy to assess and reduce range uncertainty in proton therapy and the simplicity of integrated-mode proton radiography.

Clinical implementation in proton therapy of multi-field optimization by a hybrid method combining conventional PTV with robust optimization.

To implement a robust multi-field optimization (MFO) technique compatible with the application of a Monte Carlo (MC) algorithm and to evaluate its robustness. Nine patients (three brain, five head-and-neck, one spine) underwent proton treatment generated by a novel robust MFO technique. A hybrid (hMFO) approach was implemented, planning dose coverage on isotropic PTV compensating for setup errors, whereas range calibration uncertainties are incorporated into PTV robust optimization process. hMFO was compared with single-field optimization (SFO) and full robust multi-field optimization (fMFO), both on the nominal plan and the worst-case scenarios assessed by robustness analysis. The SFO and the fMFO plans were normalized to hMFO on CTV to obtain iso-D95 coverage, and then the organs at risk (OARs) doses were compared. On the same OARs, in the normalized nominal plans the potential impact of variable relative biological effectiveness (RBE) was investigated. hMFO reduces the number of scenarios computed for robust optimization (from twenty-one in fMFO to three), making it practicable with the application of a MC algorithm. After normalizing on D95 CTV coverage, nominal hMFO plans were superior compared to SFO in terms of OARs sparing (p  < 0.01), without significant differences compared to fMFO. The improvement in OAR sparing with hMFO with respect to SFO was preserved in worst-case scenarios (p  < 0.01), confirming that hMFO is as robust as SFO to physical uncertainties, with no significant differences when compared to the worst case scenarios obtained by fMFO. The dose increase on OARs due to variable RBE was comparable to the increase due to physical uncertainties (i.e. 4-5 Gy(RBE)), but without significant differences between these techniques. hMFO allows improving plan quality with respect to SFO, with no significant differences with fMFO and without affecting robustness to setup, range and RBE uncertainties, making clinically feasible the application of MC-based robust optimization.

Heterogeneous Enhancement Pattern in DCE-MRI Reveals the Morphology of Normal Lymph Nodes: An Experimental Study.

Purpose: To investigate the heterogeneous enhancement pattern in normal lymph nodes of healthy mice by different albumin-binding contrast agents. Methods: The enhancement of normal lymph nodes was assessed in mice by dynamic contrast-enhanced MRI (DCE-MRI) after the administration of two contrast agents characterized by different albumin-binding properties: gadopentetate dimeglumine (Gd-DTPA) and gadobenate dimeglumine (Gd-BOPTA). To take into account potential heterogeneities of the contrast uptake in the lymph nodes, k-means cluster analysis was performed on DCE-MRI data. Cluster spatial distribution was visually assessed. Statistical comparison among clusters and contrast agents was performed on semiquantitative parameters (AUC, wash-in rate, and wash-out rate) and on the relative size of the segmented clusters. Results: Cluster analysis of DCE-MRI data revealed at least two main clusters, localized in the outer portion and in the inner portion of each lymph node. With both contrast agents, AUC (p < 0.01) and wash-in (p < 0.05) rates were greater in the inner cluster, which also showed a steeper wash-out rate than the outer cluster (Gd-BOPTA, p < 0.01; Gd-DTPA, p=0.056). The size of the outer cluster was greater than that of the inner cluster by Gd-DTPA (p < 0.05) and Gd-BOPTA (p < 0.01). The enhancement pattern of Gd-DTPA was not significantly different from the enhancement pattern of Gd-BOPTA. Conclusion: DCE-MRI in normal lymph nodes shows a characteristic heterogeneous pattern, discriminating the periphery and the central portion of the lymph nodes. Such a pattern deserves to be investigated as a diagnostic marker for lymph node staging.