MRI-guidance for motion management in external beam radiotherapy: current status and future challenges.

High precision conformal radiotherapy requires sophisticated imaging techniques to aid in target localisation for planning and treatment, particularly when organ motion due to respiration is involved. X-ray based imaging is a well-established standard for radiotherapy treatments. Over the last few years, the ability of magnetic resonance imaging (MRI) to provide radiation-free images with high-resolution and superb soft tissue contrast has highlighted the potential of this imaging modality for radiotherapy treatment planning and motion management. In addition, these advantageous properties motivated several recent developments towards combined MRI radiation therapy treatment units, enabling in-room MRI-guidance and treatment adaptation. The aim of this review is to provide an overview of the state-of-the-art in MRI-based image guidance for organ motion management in external beam radiotherapy. Methodological aspects of MRI for organ motion management are reviewed and their application in treatment planning, in-room guidance and adaptive radiotherapy described. Finally, a roadmap for an optimal use of MRI-guidance is highlighted and future challenges are discussed.

An anthropomorphic breathing phantom of the thorax for testing new motion mitigation techniques for pencil beam scanning proton therapy.

Motion-induced range changes and incorrectly placed dose spots strongly affect the quality of pencil-beam-scanned (PBS) proton therapy, especially in thoracic tumour sites, where density changes are large. Thus motion-mitigation techniques are necessary, which must be validated in a realistic patient-like geometry. We report on the development and characterisation of a dynamic, anthropomorphic, thorax phantom that can realistically mimic thoracic motions and anatomical features for verifications of proton and photon 4D treatments. The presented phantom is of an average thorax size, and consists of inflatable, deformable lungs surrounded by a skeleton and skin. A mobile 'tumour' is embedded in the lungs in which dosimetry devices (such as radiochromic films) can be inserted. Motion of the tumour and deformation of the thorax is controlled via a custom made pump system driving air into and out of the lungs. Comprehensive commissioning tests have been performed to evaluate the mechanical performance of the phantom, its visibility on CT and MR imaging and its feasibility for dosimetric validation of 4D proton treatments. The phantom performed well on both regular and irregular pre-programmed breathing curves, reaching peak-to-peak amplitudes in the tumour of <20 mm. Some hysteresis in the inflation versus deflation phases was seen. All materials were clearly visualised in CT scans, and all, except the bone and lung components, were MRI visible. Radiochromic film measurements in the phantom showed that imaging for repositioning was required (as for a patient treatment). Dosimetry was feasible with Gamma Index agreements (4%/4 mm) between film dose and planned dose >90% in the central planes of the target. The results of this study demonstrate that this anthropomorphic thorax phantom is suitable for imaging and dosimetric studies in a thoracic geometry closely-matched to lung cancer patients under realistic motion conditions.

Stopping Criteria for Log-Domain Diffeomorphic Demons Registration: An Experimental Survey for Radiotherapy Application.

A crucial issue in deformable image registration is achieving a robust registration algorithm at a reasonable computational cost. Given the iterative nature of the optimization procedure an algorithm must automatically detect convergence, and stop the iterative process when most appropriate. This paper ranks the performances of three stopping criteria and six stopping value computation strategies for a Log-Domain Demons Deformable registration method simulating both a coarse and a fine registration. The analyzed stopping criteria are: (a) velocity field update magnitude, (b) mean squared error, and (c) harmonic energy. Each stoping condition is formulated so that the user defines a threshold ∊, which quantifies the residual error that is acceptable for the particular problem and calculation strategy. In this work, we did not aim at assigning a value to e, but to give insights in how to evaluate and to set the threshold on a given exit strategy in a very popular registration scheme. Experiments on phantom and patient data demonstrate that comparing the optimization metric minimum over the most recent three iterations with the minimum over the fourth to sixth most recent iterations can be an appropriate algorithm stopping strategy. The harmonic energy was found to provide best trade-off between robustness and speed of convergence for the analyzed registration method at coarse registration, but was outperformed by mean squared error when all the original pixel information is used. This suggests the need of developing mathematically sound new convergence criteria in which both image and vector field information could be used to detect the actual convergence, which could be especially useful when considering multi-resolution registrations. Further work should be also dedicated to study same strategies performances in other deformable registration methods and body districts.

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.

Regularization in deformable registration of biomedical images based on divergence and curl operators.

BACKGROUND: Similarity measures in medical images do not uniquely determine the correspondence between two voxels in deformable image registration. Uncertainties in the final computed deformation exist, questioning the actual physiological consistency of the deformation between the two images. OBJECTIVES: We developed a deformable image registration method that regularizes the deformation field in order to model a deformation with physiological properties, relying on vector calculus based operators as a regularization function. METHOD: We implemented a 3D multi-resolution parametric deformable image registration, containing divergence and curl of the deformation field as regularization terms. Exploiting a BSpline model, we fit the transformation to optimize histogram-based mutual information similarity measure. In order to account for compression/expansion, we extract sink/source/circulation components as irregularities in the warped image and compensate them. The registration performance was evaluated using Jacobian determinant of the deformation field, inverse-consistency, landmark errors and residual image difference along with displacement field errors. Finally, we compare our results to a robust combination of second derivative regularization, as well as to non-regularized methods. RESULTS: The implementation was tested on synthetic phantoms and clinical data, leading to increased image similarity and reduced inverse-consistency errors. The statistical analysis on clinical cases showed that regularized methods are able to achieve better image similarity than non regularized methods. Also, divergence/curl regularization improves anatomical landmark errors compared to second derivative regularization. CONCLUSION: The implemented divergence/curl regularization was successfully tested, leading to promising results in comparison with competitive regularization methods. Future work is required to establish parameter tuning and reduce the computational cost.

Validation of automatic contour propagation for 4D treatment planning using multiple metrics.

The aim of this work is to provide insights into multiple metrics clinical validation of deformable image registration and contour propagation methods in 4D lung radiotherapy planning. The following indices were analyzed and compared: Volume Difference (VD), Dice Similarity Coefficient (DSC), Positive Predictive Value (PPV) and Surface Distances (SD). The analysis was performed on three patient datasets, using as reference a ground-truth volume generated by means of Simultaneous Truth And Performance Level Estimation (STAPLE) algorithm from the outlines of five experts. Significant discrepancies in the quality assessment provided by the different metrics in all the examined cases were found. Metrics sensitivity was more evident in presence of image artifacts and particularly for tubular anatomical structures, such as esophagus or spinal cord. Volume Differences did not account for position and DSC exhibited criticalities due to its intrinsic symmetry (i.e. over- and under-estimation of the reference contours cannot be discriminated) and dependency on the total volume of the structure. PPV analysis showed more robust performance, as each voxel concurs to the classification of the propagation, but was not able to detect inclusion of propagated and ground-truth volumes. Mesh distances could interpret the actual shape of the structures, but might report higher mismatches in case of large local differences in the contour surfaces. According to our study, the combination of VD and SD for the validation of contour propagation algorithms in 4D could provide the necessary failure detection accuracy.

The role of regularization in deformable image registration for head and neck adaptive radiotherapy.

Deformable image registration provides a robust mathematical framework to quantify morphological changes that occur along the course of external beam radiotherapy treatments. As clinical reliability of deformable image registration is not always guaranteed, algorithm regularization is commonly introduced to prevent sharp discontinuities in the quantified deformation and achieve anatomically consistent results. In this work we analyzed the influence of regularization on two different registration methods, i.e. B-Splines and Log Domain Diffeomorphic Demons, implemented in an open-source platform. We retrospectively analyzed the simulation computed tomography (CTsim) and the corresponding re-planning computed tomography (CTrepl) scans in 30 head and neck cancer patients. First, we investigated the influence of regularization levels on hounsfield units (HU) information in 10 test patients for each considered method. Then, we compared the registration results of the open-source implementation at selected best performing regularization levels with a clinical commercial software on the remaining 20 patients in terms of mean volume overlap, surface and center of mass distances between manual outlines and propagated structures. The regularized B-Splines method was not statistically different from the commercial software. The tuning of the regularization parameters allowed open-source algorithms to achieve better results in deformable image registration for head and neck patients, with the additional benefit of a framework where regularization can be tuned on a patient specific basis.

WE-E-213CD-02: Gaussian Weighted Multi-Atlas Based Segmentation for Head and Neck Radiotherapy Planning.

PURPOSE: To develop a multi-atlas segmentation strategy for IMRT head and neck therapy planning. METHODS: The method was tested on thirty-one head and neck simulation CTs, without demographic or pathology pre-clustering. We compare Fixed Number (FN) and Thresholding (TH) selection (based on normalized mutual information ranking) of the atlases to be included for current patient segmentation. Next step is a pairwise demons Deformable Registration (DR) onto current patient CT. DR was extended to automatically compensate for patient different field of view. Propagated labels are combined according to a Gaussian Weighted (GW) fusion rule, adapted to poor soft tissues contrast. Agreement with manual segmentation was quantified in terms of Dice Similarity Coefficient (DSC). Selection methods, number of atlases used, as well as GW, average and majority voting fusion were discriminated by means of Friedman Test (a=5%). Experimental tuning of the algorithm parameters was performed on five patients, deriving an optimal configuration for each structure. RESULTS: DSC reduction was not significant when ten or more atlases are selected, whereas DSC for single most similar atlas selection is 10% lower in median. DSC of FN selection rule were significantly higher for most structures. Tubular structures may benefit from computing average contour rather than looking at the singular voxel contribution, whereas the best performing strategy for all other structures was GW. When half database is selected, final median DSC were 0.86, 0.80, 0.51, 0.81, 0.69 and 0.79 for mandible, spine, optical nerves, eyes, parotids and brainstem respectively. CONCLUSION: We developed an efficient algorithm for multiatlas based segmentation of planning CT volumes, based on DR and GW. FN selection of database atlases is foreseen to increase computational efficiency. The absence of clinical pre-clustering and specific imaging protocol on database subjects makes the results closer to real clinical application. "Progetto Roberto Rocca" funded by the Fondazione Fratelli Agostino and Enrico Rocca, Italy.

Scale Invariant Feature Transform as feature tracking method in 4D imaging: a feasibility study.

We propose the use of Scale Invariant Feature Transform (SIFT) as a method able to extract stable landmarks from 4D images and to quantify internal motion. We present a preliminary validation of the SIFT method relying on expert user identification of landmarks and then apply it to 4D lung CT and liver MRI data. Results demonstrate SIFT capabilities as an operator-independent feature tracking method.

Ranking of stopping criteria for log domain diffeomorphic demons application in clinical radiation therapy.

Deformable Image Registration is a complex optimization algorithm with the goal of modeling a non-rigid transformation between two images. A crucial issue in this field is guaranteeing the user a robust but computationally reasonable algorithm. We rank the performances of four stopping criteria and six stopping value computation strategies for a log domain deformable registration. The stopping criteria we test are: (a) velocity field update magnitude, (b) vector field Jacobian, (c) mean squared error, and (d) harmonic energy. Experiments demonstrate that comparing the metric value over the last three iterations with the metric minimum of between four and six previous iterations is a robust and appropriate strategy. The harmonic energy and vector field update magnitude metrics give the best results in terms of robustness and speed of convergence.

Thermodynamics of micelle formation in water, hydrophobic processes and surfactant self-assemblies.

The critical micelle concentration (c.m.c.) for four cationic surfactants, alkyl-trimethyl-ammonium bromides, was determined as a function of temperature by conductivity measurements. The values of the standard free energy of micellisation DeltaG degrees(mic) at different temperatures were calculated by using a pseudo-phase transition model. Then, from the diagram (-DeltaG degrees(mic)/T)=f(1/T), the thermodynamic functions DeltaH(app) and DeltaS(app) were calculated. From the plots DeltaH(app)=f(T) and DeltaS(app) = f(ln T) the slopes DeltaC(p) = n(w(H))C(p,w) and DeltaC(p)=n(w(S))C(p,w) were calculated, with the numbers n(w(H)) and n(w(S)) negative and equal and therefore defined simply as n(w). The number n(w)<0, indicating condensed water molecules, depends on the reduction of cavity that takes place as a consequence of the coalescence of the cavities previously surrounding the separate aliphatic or aromatic moieties. The analysis, based on a molecular model consisting of three forms of water, namely W(I), W(II), and W(III), respectively, was extended to several other types of surfactants for which c.m.c. data had been published by other authors. The results of this analysis form a coherent scheme consistent with the proposed molecular model. The enthalpy for all the types of surfactant is described by DeltaH(app)= -3.6 + 23.1xi(w)-xi(w)C(p,w)T and the entropy by DeltaS(app)= +10.2+428xi(w)-xi(w)C(p,w) ln T where xi(w)= |n(w)| represents the number of molecules W(III) involved in the reaction. The term Deltah(w)= +23.1 kJ mol(-1) xi(w)(-1) indicates an unfavourable endothermic contribution to enthalpy for reduction of the cavity whereas the term Deltas(w)= +428 J K(-1) mol(-1) xi(w)(-1) represents a positive entropy contribution for reduction of the cavity, what is the driving force of hydrophobic association. The processes of non polar gas dissolution in water and of micelle formation were found to be strictly related: they are, however, exactly the opposite of one another. In micelle formation no intermolecular electronic short bond is formed. We propose, therefore, to substitute the term "hydrophobic bond" with that of "hydrophobic association".

Cervicovaginal shedding of TT virus in HIV-infected women.

OBJECTIVE: TT virus (TTV) is frequently detected in the serum and in other body fluids of humans. Recently TTV-specific deoxyribonucleic acid has been detected in cervical specimens from apparently healthy women and in seminal fluid, suggesting that sexual transmission may be common. STUDY DESIGN/METHODS: TT virus-deoxyribonucleic acid prevalence was assessed in paired samples of blood and cervical smears from 110 human immunodeficiency virus-positive women. Detection and typing of human papillomavirus (HPV) present in cervical smears was also performed. RESULTS: The prevalence of TTV-deoxyribonucleic acid in cervical smears was 16.4%, without significant difference (p = 0.81) between HPV-positive (18.6%) and -negative (14.9%) samples. The distribution of high/middle and low-risk HPV types was similar in TTV-positive and -negative samples. On the contrary, women with multiple HPV infections had a significantly higher TTV-deoxyribonucleic acid prevalence (60.0%) than HPV-negative women (p = 0.04). CONCLUSIONS: TT virus excretion in the female genital tract of human immunodeficiency virus-infected women is common, further supporting sexual transmission of this virus.

Evaluation of the readability of information sheets for healthy volunteers in phase-I trials.

OBJECTIVE: The aim of the present study was to assess whether information sheets/consent forms submitted to the healthy volunteers of the Clinical Pharmacology Unit (C.P.U.) panel at Glaxo-Wellcome (Verona, Italy) could be considered understandable and to verify the readability and comprehensibility of these documents. Since a volunteer bases his/her decision to take part in a study on the information sheet provided, it is of paramount ethical importance to know whether the sheet conveys all relevant information. In addition, a thorough awareness by the volunteer of the reasons and procedures of the study would increase compliance. METHODS: Four indices were used: Flesh-Vacca, Kincaid, Gunning's Fog and Gulpease. All indices rate the degree of difficulty of a text, in the light of the level of schooling of the target population. The documents evaluated were information sheets presented to volunteers. The level of schooling of the population that participated in at least one study was determined: 61.7% of volunteers finished high school and 22.6% had a University degree or diploma; the remaining 15.7% did not finish high school or the datum was not available. RESULTS: The results showed that, when the present study began, all information sheets were "readable" by all volunteers who had at least finished high school. After these preliminary results, some additional linguistic and graphic refinements were adopted in drawing up information sheets. Readability improved to such a degree that all information sheets could be understood by virtually all volunteers. CONCLUSION: A number of suggestions were identified, which are set out in this paper to assist in the preparation of improved information sheets and a recommendation to value the readability of consent sheets before giving them to the volunteers. The suggestions were split into three categories: communications to the volunteer, text format and text organisation.

Discriminating ability of composite indices for measuring disease activity in rheumatoid arthritis: a comparison of the Chronic Arthritis Systemic Index, Disease Activity Score and Thompson's articular index.

OBJECTIVE: To compare the discriminating ability of the chronic arthritis systemic index (CASI), an index that uses the Health Assessment Questionnaire (HAQ) as the main variable, with the disease activity score (DAS) and Thompson's articular index (TAI) to detect high and low disease activity in rheumatoid arthritis (RA). METHODS: Two hundred and two RA patients were examined. According to criteria proposed previously, they were divided into two subgroups: those with active disease and those with low activity. The areas under receiver operating characteristic (ROC) curves were employed to assess the diagnostic accuracy of the CASI in comparison with the DAS and TAI for the discrimination of disease activity. RESULTS: The difference between areas under the ROC curves of the CASI and TAI (0. 897+/-0.023 vs 0.780+/-0.032) and between the DAS and TAI (0.933+/-0. 018 vs 0.780+/-0.032) was highly significant (P=0.0001), thus reflecting the accuracy of the diagnostic assessment. No difference arose between areas under the ROC curves of the CASI and the DAS (difference between areas=0.036+/-0.022; P=0.103). CONCLUSION: The CASI discriminates just as well between high and low disease activity as does the DAS. Either index consisting of more than one variable performs better than TAI. We conclude that even including the HAQ, a severity parameter in the long term, it is possible to construct an index that, at any time point, evaluates disease activity as well.

[Colposcopy in human papilloma virus infections of the distal uro-ano-genital tract]. / Colposcopia nelle infezioni da Human Papova virus del tratto uro-ano-genitale distale.

HPV infections fall within the STDs and certain high-risk types have a significant role in the cancer genesis of the distal genital tract. The infection results can be clinically evident or be subclinical and in this latter case they are revealed by a highly-sensitive colposcopic examination after acetic acid application at 3% followed by Schiller's test with Lugol solution in weak iodine concentration. Indeed, the distal districts of male and female uroano-genital tracts takes advantage of the colposcopic diagnostics although complementary analysis like histology or DNA tests for HPV typing have sometimes to be performed to confirm the results or to evaluate the prognosis. HPV subclinical lesions, above all at cervical and vaginal level, are those mostly involved with the cancer genesis: the bright-white acidophilia often combined with irregular surface, atypical vascularization and discrete iodine caption represents a colposcopic indication to complementary diagnostic analysis aiming at choosing the most suitable therapy for which colposcopy can show the lesion topography and its frequent plurilocalizations.

Do chemokines play a role in HIV-1 heterosexual transmission? Susceptibility to HIV infection.

The probability of HIV transmission depends on the infectiousness of the infected partner, the susceptibility of the healthy partner, and the biological characteristics of HIV strains. A substantial role is attributable to the individual HIV susceptibility, which is affected by immunological and genetic factors. Among genetic factors, the chemokine receptor CCR5 has been thoroughly studied. CCR5 is a co-receptor for fusion and entry of macrophage-tropic variants of HIV-1, which are involved in sexual transmission. Consistent evidence shows that the absence of cell-surface expression of the HIV co-receptor CCR5, due to a homozygous 32 base pair deletion, renders individuals highly resistant to infection by macrophage-tropic HIV strains. Therefore, knowledge of this and of other genetic and immunologic factors that affect HIV-1 transmission is essential in understanding HIV-1 entry into cells, developing strategies for combating HIV-1 transmission and spread, and implementing new models for HIV-1 therapies and, hopefully, vaccines.

Progression of erosion and joint space narrowing scores in rheumatoid arthritis assessed by nonlinear models.

OBJECTIVE: To determine whether the first order kinetics model or the function proportional to the square root of disease duration better represents the progression of radiographic damage according to the disease duration than a linear model in rheumatoid patients. METHODS: Two hundred twenty-eight patients assessed at a single time point were studied by using 2 nonlinear models of radiographic damage. In 44 patients a second radiographic analysis was taken within a 3-year period. RESULTS: In this data set, both models reveal the highest rate of progression in the first 3 years of the disease. The square root of the disease duration seems to better depict the whole disease course. CONCLUSION: Nonlinear models should be compulsory in the assessment of radiographic damage, especially when slow acting antirheumatic drug effects after 5 years of disease duration are studied.

Polymorphonuclear leukocytes activation: in vitro modulation by 6-methoxy-2-naphthylacetic acid, the major active metabolite of nabumetone.

Reported here are the results of a study carried out in order to assess the possible influence of the major circulating active metabolite of nabumetone, 6-methoxy-2-naphthylacetic acid, on some aspects of polymorphonuclear leukocytes activation. The action of 6-methoxy-2-naphthylacetic acid was tested on the following features of polymorphonuclear leukocytes activation: reactive oxygen species production in polymorphonuclear leukocytes stimulated with different agonists, reactive oxygen species production in polymorphonuclear leukocytes treated with pertussis toxin, NADPH-oxidase activity. The findings showed that 6-methoxy-2-naphthylacetic acid decreased reactive oxygen species production in polymorphonuclear leukocytes stimulated with N-formyl-methionyl-leucyl-phenylalanine, phorbol myristate acetate, and opsonized zymosan, but failed to provoke a decrease of reactive oxygen species production when the cells were stimulated with calcium ionophore A23187. Moreover, 6-methoxy-2-naphthylacetic acid did not influence the transduction of the signal following the binding of stimuli to membrane receptors, and NADPH-oxidase activity. Finally, our findings showed that 6-methoxy-2-naphthyl acetic acid had no scavenger effect on reactive oxygen species production.