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The goal of this article is to identify and understand the fundamental role of spatial symmetries in the emergence of undulatory swimming using an anguilliform robot. Here, the local torque at the joints of the robot is controlled by a chain of oscillators forming a central pattern generator (CPG). By implementing a symmetric CPG with respect to the transverse plane, motor activation waves are inhibited, preventing the emergence of undulatory swimming and resulting in an oscillatory gait. We show experimentally that the swimmer can recover from the traveling wave inhibition by using distributed fluid force feedback to modulate the phase dynamics of each oscillator. This transition from oscillatory to undulating swimming is characterized by a symmetry breaking in the CPG and the body dynamics. By studying the stability of the oscillator chain, we show that the sensory feedback produces a frequency detuning gradient along the CPG chain while preserving its stability. To explain the origin of the instability, we introduce a toy model where the couplings between the dynamics of the oscillators and the body deformation reinforce the symmetry breaking.

Objective. Determining and verifying the number of monitor units is crucial to achieving the desired dose distribution in radiotherapy and maintaining treatment efficacy. However, current commercial treatment planning system(s) dedicated to ocular passive eyelines in proton therapy do not provide the number of monitor units for patient-specific plan delivery. Performing specific pre-treatment field measurements, which is time and resource consuming, is usually gold-standard practice. This proof-of-concept study reports on the development of a multi-institutional-based generalized model for monitor units determination in proton therapy for eye melanoma treatments. Approach. To cope with the small number of patients being treated in proton centers, three European institutes participated in this study. Measurements data were collected to address output factor differences across the institutes, especially as function of field size, spread-out Bragg peak modulation width, residual range, and air gap. A generic model for monitor units prediction using a large number of 3748 patients and broad diversity in tumor patterns, was evaluated using six popular machine learning algorithms: (i) decision tree; (ii) random forest, (iii) extra trees, (iv) K-nearest neighbors, (v) gradient boosting, and (vi) the support vector regression. Features used as inputs into each machine learning pipeline were: Spread-out Bragg peak width, range, air gap, fraction and calibration doses. Performance measure was scored using the mean absolute error, which was the difference between predicted and real monitor units, as collected from institutional gold-standard methods. Main results. Predictions across algorithms were accurate within 3% uncertainty for up to 85.2% of the plans and within 10% uncertainty for up to 98.6% of the plans with the extra trees algorithm. Significance. A proof-of-concept of using machine learning-based generic monitor units determination in ocular proton therapy has been demonstrated. This could trigger the development of an independent monitor units calculation tool for clinical use., (Creative Commons Attribution license.)

Purpose: Patients with large uveal melanomas are at major risk of liver metastases. Some patients are reluctant to undergo the standard treatment (ie, immediate enucleation). Proton therapy yields 5-year local control rates and eyeball retention of >85% and ≈20% in large uveal melanomas. Patients with T3/T4 uveal melanomas refusing enucleation were randomized between standard 4 to 13 Gy-fraction or moderately hypofractionated 8 to 6.5 Gy-fraction proton therapy. The main endpoint was the 2-year local recurrence-free survival without enucleation., Methods and Materials: A single-masked 1:2 randomized phase 2 trial was conducted between 2015 and 2017 with planned endoresection and distance to the posterior pole as strata. Local events were defined as local relapse, or enucleation due to complications or relapse., Results: The 32 patients, with a mean age of 64 years, had T3/4 (N = 17/15), M1 (N = 2) uveal melanomas, of mean tumor diameter and thickness of 16.5 mm and 9.1 mm, and of posterior location in 56.5%. Median follow-up was 56.7 months. The 2-year local recurrence-free survival rate without enucleation was 79% (95% confidence interval, 65%-96%), similar in both arms. There were 9 enucleations, 3 at relapse and 6 for toxicities. Twelve patients had distant metastases. The 2-year-overall survival was 72% (95% confidence interval, 58%-89%). At baseline, visual acuity by average logarithm value of the minimum angle of resolution was 0.68 and 0.70 in the standard and experimental arms, and at last follow-up 2 and 1.7, with mean differences of 1.44 and 1.01, respectively (P = .39)., Conclusion: An 8-times 6.5 Gy scheme is feasible without deteriorating local control and with similar toxicity rates in patients with large uveal melanomas. Larger studies incorporating adjuvant treatments are warranted., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: During their initial management, some macular melanocytic lesions can be closely monitored to wait for a documented growth before advocating a treatment by irradiation. However, the visual outcomes of this strategy have not yet been assessed. This study compares the visual outcomes of macular melanocytic lesions that underwent delayed proton beam therapy (PBT) after an initial observation to those treated early., Methods: A total of 162 patients with suspicious melanocytic lesions whose margins were located within 3 mm of the fovea were recruited from two French ocular oncology centers., Results: Overall, 82 patients treated with PBT within 4 months after the initial visit (early PBT group) were compared to 24 patients treated with delayed PBT (delayed PBT group) and 56 patients not treated with PBT (observation group). Visual acuity was not significantly different between baseline and last visit in the observation group (p = 0.325). Between baseline and last visit, the median [IQR] loss in visual acuity was significant in both the early (0.7 [0.2; 1.8], p < 0.001) and the delayed (0.5 [0.2; 1.5], p < 0.001) PBT groups. After irradiation, there was no significant difference between the early and delayed PBT groups for visual loss (p = 0.575), diameter reduction (p = 0.190), and thickness lowering (p = 0.892). In multivariate analysis, history of diabetes mellitus and Bruch's membrane rupture remained significantly associated with greater visual loss (p = 0.036 and p = 0.002, respectively)., Conclusion: For small lesions in which there is no clear diagnosis of malignant melanoma, an initial close monitoring to document tumor growth does not impact visual prognosis, despite the potential complications associated with the untreated tumor. However, the survival should remain the main outcome of the treatment of these lesions., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective. The range uncertainty in proton radiotherapy is a limiting factor to achieve optimum dose conformity to the tumour volume. Ionoacoustics is a promising approach for in situ range verification, which would allow to reduce the size of the irradiated volume relative to the tumour volume. The energy deposition of a pulsed proton beam leads to an acoustic pressure wave (ionoacoustics), the detection of which allows conclusion about the distance between the Bragg peak and the acoustic detector. This information can be transferred into a co-registered ultrasound image, marking the Bragg peak position relative to the surrounding anatomy. Approach. A CIRS 3D abdominal phantom was irradiated with 126 MeV protons at a clinical proton therapy centre. Acoustic signals were recorded on the beam axis distal to the Bragg peak with a Cetacean C305X hydrophone. The ionoacoustic measurements were processed with a correlation filter using simulated filter templates. The hydrophone was rigidly attached to an ultrasound device (Interson GP-C01) recording ultrasound images of the irradiated region. Main results. The time of flight obtained from ionoacoustic measurements were transferred to an ultrasound image by means of an optoacoustic calibration measurement. The Bragg peak position was marked in the ultrasound image with a statistical uncertainty of σ = 0.5 mm of 24 individual measurements depositing 1.2 Gy at the Bragg peak. The difference between the evaluated Bragg peak position and the one obtained from irradiation planning (1.0 mm) is smaller than the typical range uncertainty (≈4 mm) at the given penetration depth (10 cm). Significance. The measurements show that it is possible to determine the Bragg peak position of a clinical proton beam with submillimetre precision and transfer the information to an ultrasound image of the irradiated region. The dose required for this is smaller than that used for a typical irradiation fraction., (Creative Commons Attribution license.)

Purpose: The Bragg peak located at the end of the ion beam range is one of the main advantages of ion beam therapy compared to X-Ray radiotherapy. However, verifying the exact position of the Bragg peak within the patient online is a major challenge. The goal of this work was to achieve submillimeter proton beam range verification for pulsed proton beams of an energy of up to 220 MeV using ionoacoustics for a clinically relevant dose deposition of typically 2 Gy per fraction by i) using optimal proton beam characteristics for ionoacoustic signal generation and ii) improved signal detection by correlating the signal with simulated filter templates., Methods: A water tank was irradiated with a preclinical 20 MeV proton beam using different pulse durations ranging from 50 ns up to 1 μs in order to maximise the signal-to-noise ratio (SNR) of ionoacoustic signals. The ionoacoustic signals were measured using a piezo-electric ultrasound transducer in the MHz frequency range. The signals were filtered using a cross correlation-based signal processing algorithm utilizing simulated templates, which enhances the SNR of the recorded signals. The range of the protons is evaluated by extracting the time of flight (ToF) of the ionoacoustic signals and compared to simulations from a Monte Carlo dose engine (FLUKA)., Results: Optimised SNR of 28.0 ± 10.6 is obtained at a beam current of 4.5 μA and a pulse duration of 130 ns at a total peak dose deposition of 0.5 Gy. Evaluated ranges coincide with Monte Carlo simulations better than 0.1 mm at an absolute range of 4.21 mm. Higher beam energies require longer proton pulse durations for optimised signal generation. Using the correlation-based post-processing filter a SNR of 17.8 ± 5.5 is obtained for 220 MeV protons at a total peak dose deposition of 1.3 Gy. For this clinically relevant dose deposition and proton beam energy, submillimeter range verification was achieved at an absolute range of 303 mm in water., Conclusion: Optimal proton pulse durations ensure an ideal trade-off between maximising the ionoacoustic amplitude and minimising dose deposition. In combination with a correlation-based post-processing evaluation algorithm, a reasonable SNR can be achieved at low dose levels putting clinical applications for online proton or ion beam range verification into reach., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schauer, Wieser, Huang, Ruser, Lascaud, Würl, Chmyrov, Vidal, Herault, Ntziachristos, Assmann, Parodi and Dollinger.)

Purpose: In radiotherapy, the dose and volumes of the irradiated normal tissues is correlated to the complication rate. We assessed the performances of low-energy proton therapy (ocular PT) with eye-dedicated equipment, high energy PT with pencil-beam scanning (PBS) or CyberKnife R   -based stereotactic irradiation (SBRT)., Material and Methods: CT-based comparative dose distribution between external beam radiotherapy techniques was assessed using an anthropomorphic head phantom. The prescribed dose was 60Gy&#95;RBE in 4 fractions to a typical posterior pole uveal melanoma. Clinically relevant structures were delineated, and doses were calculated using radiotherapy treatment planning softwares and measured using Gafchromic dosimetry films inserted at the ocular level., Results: Precision was significantly better with ocular PT than both PBS or SBRT in terms of beam penumbra (80%-20%: laterally 1.4 vs. ≥10mm, distally 0.8 vs. ≥2.5mm). Ocular PT duration was shorter, allowing eye gating and lid sparing more easily. Tumor was excellent with all modalities, but ocular PT resulted in more homogenous and conformal dose compared to PBS or SBRT. The maximal dose to ocular/orbital structures at risk was smaller and often null with ocular PT compared to other modalities. Mean dose to ocular/orbital structures was also lower with ocular PT. Structures like the lids and lacrimal punctum could be preserved with ocular PT using gaze orientation and lid retractors, which is easier to implement clinically than with the other modalities. The dose to distant organs was null with ocular PT and PBS, in contrast to SBRT., Conclusions: ocular PT showed significantly improved beam penumbra, shorter treatment delivery time, better dose homogeneity, and reduced maximal/mean doses to critical ocular structures compared with other current external beam radiation modalities. Similar comparisons may be warranted for other tumor presentations., (Copyright © 2022 Société française de radiothérapie oncologique (SFRO). All rights reserved.)

Introduction: Despite reduction of xerostomia with intensity-modulated compared to conformal X-ray radiotherapy, radiation-induced dental complications continue to occur. Proton therapy is promising in head and neck cancers to further reduce radiation-induced side-effects, but the optimal dental management has not been defined., Material and Methods: Dental management before proton therapy was assessed compared to intensity-modulated radiotherapy based on a bicentric experience, a literature review and illustrative cases., Results: Preserved teeth frequently contain metallic dental restorations (amalgams, crowns, implants). Metals blur CT images, introducing errors in tumour and organ contour during radiotherapy planning. Due to their physical interactions with matter, protons are more sensitive than photons to tissue composition. The composition of restorative materials is rarely documented during radiotherapy planning, introducing dose errors. Manual artefact recontouring, metal artefact-reduction CT algorithms, dual or multi-energy CT and appropriate dose calculation algorithms insufficiently compensate for contour and dose errors during proton therapy. Physical uncertainties may be associated with lower tumour control probability and more side-effects after proton therapy. Metal-induced errors should be quantified and removal of metal restorations discussed on a case by case basis between dental care specialists, radiation oncologists and physicists. Metallic amalgams can be replaced with water-equivalent materials and crowns temporarily removed depending on rehabilitation potential, dental condition and cost. Implants might contraindicate proton therapy if they are in the proton beam path., Conclusion: Metallic restorations may more severely affect proton than photon radiotherapy quality. Personalized dental care prior to proton therapy requires multidisciplinary assessment of metal-induced errors before choice of conservation/removal of dental metals and optimal radiotherapy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To evaluate choriocapillaris alterations following proton beam therapy irradiation using swept-source optical coherence tomography-angiography, and to assess their correlation with the grade of radiation retinopathy (RR)., Methods: Eyes with uveal melanoma evaluated before and after irradiation with proton beam therapy were included, as well as the healthy fellow eye. The gradation of RR was based on a previously published classification. Choriocapillaris flow voids area was analyzed using Phansalkar thresholding. Retinal vascularization was described by foveal avascular zone (FAZ) perimeter, FAZ area, FAZ circularity index, and percentage of nonperfusion area (PAN) in the superficial capillary plexus (SCP) or deep capillary plexus., Results: A total of 157 eyes of 83 patients were analyzed. Overall, there was a significant difference between the control group, the uveal melanoma before proton beam therapy group, and the grades of RR in the uveal melanoma after proton beam therapy group for FAZ perimeter ( P < 0.001), FAZ area ( P < 0.001), FAZ-circularity index ( P < 0.001), PAN-SCP ( P < 0.001), PAN-deep capillary plexus ( P < 0.001), and choriocapillaris flow voids area ( P < 0.001). Moreover, choriocapillaris flow voids area was significantly increased in the early stages of RR ( P = 0.003) and was further significantly correlated with FAZ perimeter ( P < 0.001), FAZ area ( P < 0.001), FAZ-circularity index ( P = 0.010), PAN-SCP ( P < 0.001), and PAN-deep capillary plexus ( P < 0.001)., Conclusion: Quantitative optical coherence tomography-angiography alterations in the choriocapillaris microvascularization are an early biomarker of RR and are correlated to the severity of the disease.

The eye is an exemplarily challenging organ to treat when considering ocular tumors. It is at the crossroads of several major aims in oncology: tumor control, organ preservation, and functional outcomes including vision and quality of life. The proximity between the tumor and organs that are susceptible to radiation damage explain these challenges. Given a high enough dose of radiation, virtually any cancer will be destroyed with radiotherapy. Yet, the doses inevitably absorbed by normal tissues may lead to complications, the likelihood of which increases with the radiation dose and volume of normal tissues irradiated. Precision radiotherapy allows personalized decision-making algorithms based on patient and tumor characteristics by exploiting the full knowledge of the physics, radiobiology, and the modifications made to the radiotherapy equipment to adapt to the various ocular tumors. Anticipation of the spectrum and severity of radiation-induced complications is crucial to the decision of which technique to use for a given tumor. Radiation can damage the lacrimal gland, eyelashes/eyelids, cornea, lens, macula/retina, optic nerves and chiasma, each having specific dose-response characteristics. The present review is a report of non-cancer effects that may occur following ionizing irradiation involving the eye and orbit and their specific patterns of toxicity for a given radiotherapy modality.

Undulatory swimming represents an ideal behavior to investigate locomotion control and the role of the underlying central and peripheral components in the spinal cord. Many vertebrate swimmers have central pattern generators and local pressure-sensitive receptors that provide information about the surrounding fluid. However, it remains difficult to study experimentally how these sensors influence motor commands in these animals. Here, using a specifically designed robot that captures the essential components of the animal neuromechanical system and using simulations, we tested the hypothesis that sensed hydrodynamic pressure forces can entrain body actuation through local feedback loops. We found evidence that this peripheral mechanism leads to self-organized undulatory swimming by providing intersegmental coordination and body oscillations. Swimming can be redundantly induced by central mechanisms, and we show that, therefore, a combination of both central and peripheral mechanisms offers a higher robustness against neural disruptions than any of them alone, which potentially explains how some vertebrates retain locomotor capabilities after spinal cord lesions. These results broaden our understanding of animal locomotion and expand our knowledge for the design of robust and modular robots that physically interact with the environment., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Purpose: Eye-dedicated proton therapy (PT) facilities are used to treat malignant intraocular lesions, especially uveal melanoma (UM). The first commercial ocular PT beamline from Varian was installed in the Netherlands. In this work, the conceptual design of the new eyeline is presented. In addition, a comprehensive comparison against five PT centers with dedicated ocular beamlines is performed, and the clinical impact of the identified differences is analyzed., Material/methods: The HollandPTC eyeline was characterized. Four centers in Europe and one in the United States joined the study. All centers use a cyclotron for proton beam generation and an eye-dedicated nozzle. Differences among the chosen ocular beamlines were in the design of the nozzle, nominal energy, and energy spectrum. The following parameters were collected for all centers: technical characteristics and a set of distal, proximal, and lateral region measurements. The measurements were performed with detectors available in-house at each institution. The institutions followed the International Atomic Energy Agency (IAEA) Technical Report Series (TRS)-398 Code of Practice for absolute dose measurement, and the IAEA TRS-398 Code of Practice, its modified version or International Commission on Radiation Units and Measurements Report No. 78 for spread-out Bragg peak normalization. Energy spreads of the pristine Bragg peaks were obtained with Monte Carlo simulations using Geant4. Seven tumor-specific case scenarios were simulated to evaluate the clinical impact among centers: small, medium, and large UM, located either anteriorly, at the equator, or posteriorly within the eye. Differences in the depth dose distributions were calculated., Results: A pristine Bragg peak of HollandPTC eyeline corresponded to the constant energy of 75 MeV (maximal range 3.97 g/cm 2 in water) with an energy spread of 1.10 MeV. The pristine Bragg peaks for the five participating centers varied from 62.50 to 104.50 MeV with an energy spread variation between 0.10 and 0.70 MeV. Differences in the average distal fall-offs and lateral penumbrae (LPs) (over the complete set of clinically available beam modulations) among all centers were up to 0.25 g/cm 2 , and 0.80 mm, respectively. Average distal fall-offs of the HollandPTC eyeline were 0.20 g/cm 2 , and LPs were between 1.50 and 2.15 mm from proximal to distal regions, respectively. Treatment time, around 60 s, was comparable among all centers. The virtual source-to-axis distance of 120 cm at HollandPTC was shorter than for the five participating centers (range: 165-350 cm). Simulated depth dose distributions demonstrated the impact of the different beamline characteristics among institutions. The largest difference was observed for a small UM located at the posterior pole, where a proximal dose between two extreme centers was up to 20%., Conclusions: HollandPTC eyeline specifications are in accordance with five other ocular PT beamlines. Similar clinical concepts can be applied to expect the same high local tumor control. Dosimetrical properties among the six institutions induce most likely differences in ocular radiation-related toxicities. This interinstitutional comparison could support further research on ocular post-PT complications. Finally, the findings reported in this study could be used to define dosimetrical guidelines for ocular PT to unify the concepts among institutions., (© 2021 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Purpose: To develop a high-resolution three-dimensional (3D) magnetic resonance imaging (MRI)-based treatment planning approach for uveal melanomas (UM) in proton therapy., Materials/methods: For eight patients with UM, a segmentation of the gross tumor volume (GTV) and organs-at-risk (OARs) was performed on T1- and T2-weighted 7 Tesla MRI image data to reconstruct the patient MR-eye. An extended contour was defined with a 2.5-mm isotropic margin derived from the GTV. A broad beam algorithm, which we have called πDose, was implemented to calculate relative proton absorbed doses to the ipsilateral OARs. Clinically favorable gazing angles of the treated eye were assessed by calculating a global weighted-sum objective function, which set penalties for OARs and extreme gazing angles. An optimizer, which we have named OPT'im-Eye-Tool, was developed to tune the parameters of the functions for sparing critical-OARs., Results: In total, 441 gazing angles were simulated for every patient. Target coverage including margins was achieved in all the cases (V 95%  > 95%). Over the whole gazing angles solutions space, maximum dose (D max ) to the optic nerve and the macula, and mean doses (D mean ) to the lens, the ciliary body and the sclera were calculated. A forward optimization was applied by OPT'im-Eye-Tool in three different prioritizations: iso-weighted, optic nerve prioritized, and macula prioritized. In each, the function values were depicted in a selection tool to select the optimal gazing angle(s). For example, patient 4 had a T2 equatorial tumor. The optimization applied for the straight gazing angle resulted in objective function values of 0.46 (iso-weighted situation), 0.90 (optic nerve prioritization) and 0.08 (macula prioritization) demonstrating the impact of that angle in different clinical approaches., Conclusions: The feasibility and suitability of a 3D MRI-based treatment planning approach have been successfully tested on a cohort of eight patients diagnosed with UM. Moreover, a gaze-angle trade-off dose optimization with respect to OARs sparing has been developed. Further validation of the whole treatment process is the next step in the goal to achieve both a non-invasive and a personalized proton therapy treatment., (© 2020 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Purpose: The aim of this study was to compare the functional and anatomical effectiveness of photodynamic therapy (PDT) versus proton beam therapy (PBT) in a real-life setting for the treatment of circumscribed choroidal hemangioma., Methods: A total of 191 patients with a diagnosis of circumscribed choroidal hemangioma and treated by PBT or PDT were included for analyses., Results: The 119 patients (62.3%) treated by PDT were compared with the 72 patients treated by PBT. The final best-corrected visual acuity did not differ significantly between the two groups (P = 0.932) and final thickness was lower in the PBT compared with the PDT group (P = 0.001). None of the patients treated by PBT needed second-line therapy. In comparison, 53 patients (44.5%) initially treated by PDT required at least one other therapy and were associated with worse final best-corrected visual acuity (P = 0.037). In multivariate analysis, only an initial thickness greater than 3 mm remained significant (P = 0.01) to predict PDT failure with an estimated odds ratio of 2.72, 95% confidence interval (1.25-5.89)., Conclusion: Photodynamic therapy and PBT provide similar anatomical and functional outcomes for circumscribed choroidal hemangioma ≤3 mm, although multiple sessions are sometimes required for PDT. For tumors >3 mm, PBT seems preferable because it can treat the tumor in only 1 session with better functional and anatomical outcomes.

Purpose: Normal tissue complication probability (NTCP) models could aid the understanding of dose dependence of radiation-induced toxicities after eye-preserving radiotherapy of choroidal melanomas. We performed NTCP-modeling and established dose-response relationships for visual acuity (VA) deterioration and common late complications after treatments with proton therapy (PT)., Design: Retrospective study from single, large referral center., Participants: We considered patients from Nice, France, diagnosed with choroidal melanoma and treated primarily with hypofractionated PT (52 Gy physical dose in 4 fractions). Complete VA deterioration information was available for 1020 patients, and complete information on late complications was available for 991 patients., Methods: Treatment details, dose-volume histograms (DVHs) for relevant anatomic structures, and patient and tumor characteristics were available from a dedicated ocular database. Least absolute shrinkage and selection operator (LASSO) variable selection was used to identify variables with the strongest impact on each end point, followed by multivariate Cox regressions and logistic regressions to analyze the relationships among dose, clinical characteristics, and clinical outcomes., Main Outcome Measures: Dose-response relationship for VA deterioration and late complications., Results: Dose metrics for several structures (i.e., optic disc, macula, retina, globe, lens, ciliary body) correlated with clinical outcome. The near-maximum dose to the macula showed the strongest correlation with VA deterioration. The near-maximum dose to the retina was the only variable with clear impact on the risk of maculopathy, the dose to 20% of the optic disc had the largest impact on optic neuropathy, dose to 20% of cornea had the largest impact on neovascular glaucoma, and dose to 20% of the ciliary body had the largest impact on ocular hypertension. The volume of the ciliary body receiving 26 Gy was the only variable associated with the risk of cataract, and the volume of retina receiving 52 Gy was associated with the risk of retinal detachment. Optic disc-to-tumor distance was the only variable associated with dry eye syndrome in the absence of DVH for the lachrymal gland., Conclusions: VA deterioration and specific late complications demonstrated dependence on dose delivered to normal structures in the eye after PT for choroidal melanoma. VA deterioration depended on dose to a range of structures, whereas more specific complications were related to dose metrics for specific structures., (Copyright © 2020 American Academy of Ophthalmology. All rights reserved.)

The quality of radiation therapy has been shown to significantly influence the outcomes for head and neck squamous cell carcinoma (HNSCC) patients. The results of dosimetric studies suggest that intensity-modulated proton therapy (IMPT) could be of added value for HNSCC by being more effective than intensity-modulated (photon) radiation therapy (IMRT) for reducing side effects of radiation therapy. However, the physical properties of protons make IMPT more sensitive than photons to planning uncertainties. This could potentially have a negative effect on the quality of IMPT planning and delivery. For this review, the three French proton therapy centers collaborated to evaluate the differences between IMRT and IMPT. The review explored the effects of these uncertainties and their management for developing a robust and optimized IMPT treatment delivery plan to achieve clinical outcomes that are superior to those for IMRT. We also provide practical suggestions for the management of HNSCC carcinoma with IMPT. Because metallic dental implants can increase range uncertainties (3-10%), patient preparation for IMPT may require more systematic removal of in-field alien material than is done for IMRT. Multi-energy CT may be an alternative to calculate more accurately the dose distribution. The practical aspects that we describe are essential to guarantee optimal quality in radiation therapy in both model-based and randomized clinical trials., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The aim of this study was to evaluate metastatic latency and survival after the occurrence of metastases in patients with choroidal/ciliary body melanoma treated with proton therapy. This was a retrospective cohort study. All consecutive patients with choroidal/ciliary body melanoma treated with proton therapy between 1991 and 2010 were included. Overall survival, specific survival (SS), local recurrence-free interval, and metastasis-free interval (MFI) were calculated. There were 508 patients. The mean follow-up was 239.4 months. Overall survival and SS rates were 57.2 and 67.6% at 10 years. Pre-equatorial tumor location, advanced tumor stage, and initial exudative retinal detachment were associated independently with SS. Thirty-three percent of the patients (n = 169) had metastases. Local recurrence-free interval and MFI were 91.3 and 65.7% at 10 years, respectively. MFI was shorter in pre-equatorial, large tumors, and/or tumors with exudative retinal detachment. After the occurrence of metastases, the median survival time was 1.25 years and survival probabilities were 62.1% at 1 year, 26.0% at 2 years, and 6.0% at 5 years. Except for age, none of the baseline clinical factors was associated with survival after metastasis occurrence. SS after metastasis occurrence was longer for metastasis occurring more than 10 years after tumor diagnosis (P =0.010). Death after metastasis is independent of initial tumor characteristics. Small tumors still have a risk for metastases after 10 years. Thus, lifelong follow-up is necessary for uveal melanoma patients. Larger series of metastatic patients are needed to evaluate aggressive multimodal treatments of metastases. Death after metastasis is independent of the initial tumor characteristics. Small tumors contraintuitively have a long-life risk of metastases. MFI is associated independently with pre-equatorial location, tumor stage, and retinal detachment.

The decision to irradiate during pregnancy is based on a risk benefit compromise of two kinds: maternal risk and fetal risk. The aim of this work is to determine the foetal risk, and uterine dose measurement in proton therapy. Foetal exposure during treatment is linked to two sources: the treatment phase, and the repositioning phase. An Alderson-Rando anthropomorphic ghost (170cm, 74kg) was positioned on the table in the treatment position. A tissue-equivalent proportional counter (TEPC), adapted to the analysis of complex radiation fields (neutron and photonics), was used to determine the irradiation related to the treatment phase. An AT1123 radiation survey meter was used to measure photons generated by X-ray radiation. I dosimetry was proposed using radio-photoluminescent dosimeters, allowing for a daily check of the dose received in the uterus. The treatment phase produces higher uterine doses than the positioning phase, but these remain very low. The equivalent dose received in the uterus for the entire treatment is estimated at 840 μSv. Using a methodology for measuring the out-of-field dose with pencil beam scanning proton therapy, the foetal dose in the first trimester was well below the acceptance dose of 100 mGy determined by the International Commission on Radiological Protection., (Copyright © 2020 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Purpose: The use of planar ultra-widefield fundus photography (UWF) may result in distortions and inaccurate measurement. The aim of the study was to evaluate the accuracy of UWF instead of the standard narrow field (SF) for the treatment planning phase of ocular tumours., Methods: Distortions between conformal SF and UWF were assessed in 43 patients with choroidal melanoma treated with either proton therapy or brachytherapy. imagej software was used to measure distortion., Results: The median interquartile range ([IQR]) distortion for all cases was 3.7% [1.7-10.8]. For cases with tumours within 6 mm of the optic disc, distortions appeared clinically nonsignificant. For peripheral and/or large tumours, significantly larger distortions were observed on UWF (median 4.4% [2.7-22.6] for tumours ≥6 mm from the optic disc versus 3.3% [1.6-9.9] for those <6 mm, p = 0.04). Images can be subdivided into three groups: minimal distortion (79.1% of eyes), similar level of major distortion for both measured distances (11.6%) and distortion with unequal level of distortion between the measured distances (9.3%)., Conclusion: Distortions with UWF appeared minimal in posterior regions of the fundus and increased with the distance from the posterior pole. UWF could therefore be used for treatment planning of ocular tumours as the planned radiation dose to the macula and optic disc are not impacted., (© 2019 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Introduction: conjunctival melanomas have high local relapse rates. Oncologic and visual outcomes can be improved with proton therapy and no-touch surgery., Material and Methods: a monocentric retrospective study of consecutive patients treated with surgery and proton therapy for conjunctival melanoma was conducted. Proton therapy was performed to a total dose of 45 Grays physical dose delivered in eight fractions over two weeks., Results: Ninety-two patients were included. The mean age was 63-year-old. 65.2% of patients had primary acquired melanosis. The mean tumor thickness and diameter was 2.5 mm and 7.0 mm respectively. The clinical stage was T1 in 71.6% of cases, with a quadrangular involvement of more than 90° in 69% of cases. Conjunctival melanomas were of epithelioid cell-type in 40% of cases. Mean follow-up was 4.7 years. Five-year local failure rate was 33.2%. Of 25 local recurrences, 14 were marginal/out-of-field, 4 in-field, others were undetermined. First surgery at expert center resulted in 24.3% of local failure at 5 years versus 38.7% if performed elsewhere (p = 0.41). Salvage exenteration was performed in 13 patients. Tumor stage and quadrangular involvement were significant factors for local failure. Five-year progression-free survival and cause-specific death rates were 61.5 and 3.6%. Stage and epithelioid type were associated with poorer progression-free survival. Trophic toxicity occurred in 22.9% of patients and was treated locally, with grafts in 7 patients. Glaucoma and cataract occurred in 13 and 22 patients respectively. Prognostic factors for visual deterioration were age, tumor extent (multifocality, quadrangular involvement > 180°) and cryotherapy., Conclusions: 5-year local failure rate after postoperative proton therapy for conjunctival melanoma was of 33.2%. Radiation-induced complications were overall manageable.

Purpose: To evaluate the use of the Lens Opacities Classification System III grading (LOCS III) for the characterization of radiation-induced cataract, and to correlate the proton beam projection onto the lens with cataract location and grade as defined by the LOCS III., Design: Prospective, interventional case series., Methods: Fifty-two consecutive patients with cataract following proton therapy were included. All cataracts were graded using LOCS III. Relationships between proton beam and cataract subtypes, as well as between dose, proportion of lens irradiated, and extent of cataracts, were assessed., Results: Tumor diameter, volume, stage, and equatorial tumor location were associated with extent of posterior subcapsular cataracts (PSC) that were diagnosed at a median (interquartile range) 36 months (22;83) after treatment. In multivariate analysis, the tumor volume (P < .01) and an equatorial tumor location (P = .01) were risk factors for extensive PSC. Lens irradiation was avoided in 10 patients. In the remaining 42 patients (81%), the extent of PSC significantly correlated with the dose to the lens receiving 10, 26, and 47 Gy (P = .03, P = .03, and P = .04, respectively), the dose to the lens periphery receiving 10 and 26 Gy (P = .02 and P = .02, respectively), and the dose to the ciliary body receiving 10 and 26 Gy (P = .03 and P = .02, respectively). Nuclear color significantly correlated with the dose to the ciliary body receiving 10 Gy (P = .03) and 26 Gy (P = .02). After adjustment of the results on tumor volume and tumor location, the volume of lens receiving 10 Gy (P = .04) and 26 Gy (P = .03) remained significantly associated with the extent of PSC., Conclusions: Proton dose correlated with the occurrence of PSC and nuclear color cataracts as defined by LOCS III grading. Better characterization of cataracts with the LOCS III after irradiation may help to further fill gaps in the current understanding of the mechanisms of radiation-induced cataracts., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Ocular surface squamous neoplasia includes a spectrum of diseases from dysplasia to invasive squamous cell carcinoma (SCC) of the conjunctiva. Whether the degree of invasion influences outcomes is debated. We evaluated the outcomes and management of conjunctival carcinomas defined as ≤0.2 mm invasion of the chorion (microinvasive; miSCC) or over (SCC)., Design: Retrospective case series., Methods: Clinical, tumor, and therapeutic characteristics and outcomes were collected for consecutive patients with histology-proven invasive conjunctival miSCC/SCC treated between 2002 and 2017., Results: Patients were 70% men, ≥70 years old (56%), with carcinomas of the bulbar conjunctiva (83.0%). Limbal, corneal, and/or scleral involvement were present in 70.4%, 42.6%, and 27.8%, respectively. Patient characteristics, tumor characteristics, and no-touch surgery rates were similar between the 39 SCC and 15 miSCC. However, mitomycin was performed in 93.3% and 20.5% of miSCC and SCC, respectively (P < .001). Proton therapy was performed in 0% and 92.0% of miSCC and SCC, respectively (P < .001). SCC received mitomycin in case of tumoral resection margins, respectively (P = .018). The 24-month incidence of local relapse was 14.8%, including 20% and 12% for miSCC and SCC, respectively (P = .079). Irradiation was the only prognostic factor associated with a lower risk for local relapse (hazard ratio [0.25]; P = .045). There were 2 cancer-related deaths (2%). Mild/moderate anterior segment complications occurred in one third of the patients., Conclusions: miSCC had slightly worse relapse rates compared with SCC. Postoperative proton therapy, performed in SCC only, was associated with a lower risk for relapse., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Uveal melanomas are the most frequent primary malignant eye tumor. Enucleation was historically the gold standard. Since then, several studies showed that conservative treatments did not increase the risk of metastasis or survival. Choroidal melanomas are both radioresistant and located close to visual structures (the optic nerve and macula) of the eye, which may be preserved in some settings without compromising tumor control, as this is the first priority. Different types of radiation therapy may be used for such tumors: brachytherapy and charged particles, including proton beam therapy. If visual prognosis is dependent to the local treatment, the vital prognosis is dependent on the metastatic risk, with a risk of liver involvement in 20 to 50% of patients, depending on tumor size and genomics. Median survival after the discovery of liver metastases is about 15 months. The management of these patients is often complex. Systemic therapies (chemotherapy, targeted therapies, immunotherapy, etc.) yield limited response rates and although local treatments of liver metastases are promising, they are only feasible in selected patients. The mission of the MELACHONAT national network is to improve the management of patients regardless of the stage of the disease. The patient association ANPACO is dedicated to help uveal melanoma patients in their health care path and to promote knowledge dissemination within the patient community. The aim of this review is to focus on the local treatments of uveal melanomas as well as the management of their metastatic evolution., (Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Purpose: To report on the clinical characteristics and outcomes for patients with iris melanoma using proton therapy., Design: Retrospective study., Participants: One hundred seven patients with iris melanoma from 3 regional ophthalmologic centers., Methods: A retrospective study was conducted for iris melanoma patients from 3 regional ophthalmologic centers referred to and treated at a single proton therapy facility between 1996 and 2015., Main Outcome Measures: At each follow-up visit, examinations included measurement of best-corrected VA, slit-lamp, examination, indirect ophthalmoscopy, and ultrasound biomicroscopy., Results: With a median follow-up of 49.5 months, 5 of 107 patients experienced a local relapse within a median of 36.3 months. The cumulative incidence of relapse was 7.5% at 5 years. All 5 patients showed involvement of the iridocorneal angle (P = 0.056). Diffuse iris melanoma showed a higher risk of relapse (P = 0.044). Four patients showed out-of-field relapse and 1 showed angular relapse. Three patients were retreated with proton therapy, whereas 2 other patients, one with T1b disease and another with diffuse T3 disease, underwent secondary enucleation. None of the patients experienced metastases nor died of iris melanoma. Vision improved in 59.4% of patients (n = 60/101). However, cataracts occurred in 57.4% of the 54 patients (n = 31) without cataract or implant at diagnosis. Secondary glaucoma was reported in 7.6% of the patients (n = 8), uveitis in 4.7% (n = 5), and hyphema in 3.7% (n = 4). All but 5 cases of complications were mild, transient, and not sight limiting after treatment. Five cases of glaucoma, including 1 with uveitis, were severe and associated with visual deterioration., Conclusions: Proton therapy showed efficacy and limited morbidity in iris melanomas., (Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

In this work, the synthesis of oleoyl-lysophosphatidylcholine by lipase-catalyzed esterification of glycerophosphocholine (GPC) and free oleic acid in a reaction medium without solvent is presented. The complete solubilisation of GPC, which is a crucial issue in non-polar liquids such as melted free fatty acids, was reached by heating the GPC/oleic acid mixture at high temperature during a short time. The immobilized lipase from Rhizomucor miehei (Lipozyme RM-IM) was shown to catalyze the reaction more efficiently than the immobilized lipases from Thermomyces lanuginosus (Lipozyme TL-IM) and Candida antarctica (Novozym 435). The condition reactions leading to the highest yield were as follows: substrate ratio: 1/20 (GPC/oleic acid); amount of catalyst: 10% (w/w of substrates); temperature: 50°C. Under these conditions, a yield of 75% of oleoyl-lysophosphatidylcholine was achieved in 24 h under stirring and almost no dioleoyl-lysophosphatidylcholine was produced. Unlike other studies dealing with the esterification of GPC with free fatty acids, the removal of the water produced while the reaction proceeds was not necessary to reach high yields.

Proton ranges in water between 145 MeV to 227 MeV initial energy have been measured at a clinical superconducting synchrocyclotron using the acoustic signal induced by the ion dose deposition (ionoacoustic effect). Detection of ultrasound waves was performed by a very sensitive hydrophone and signals were stored in a digital oscilloscope triggered by secondary prompt gammas. The ionoacoustic range measurements were compared to existing range data from a calibrated range detector setup on-site and agreement of better than 1 mm was found at a Bragg peak dose of about 10 Gy for 220 MeV initial proton energy, compatible with the experimental errors. Ionoacoustics has thus the potential to measure the Bragg peak position with submillimeter accuracy during proton therapy, possibly correlated with ultrasound tissue imaging.

Anomalous visual perceptions have been reported in various diseases of the retina and visual pathways or can be experienced under specific conditions in healthy individuals. Phosphenes are perceptions of light in the absence of ambient light, occurring independently of the physiological and classical photonic stimulation of the retina. They are a frequent symptom in patients irradiated in the region of the central nervous system (CNS), head and neck and the eyes. Phosphenes have historically been attributed to complex physical phenomena such as Cherenkov radiation. While phosphenes are related to Cherenkov radiation under high energy photon/electron irradiation conditions, physical phenomena are unlikely to be responsible for light flashes at energies used for ocular proton therapy. Phosphenes may involve a direct role for ocular photoreceptors and possible interactions between cones and rods. Other mechanisms involving the retinal ganglion cells or ultraweak biophoton emission and rhodopsin bleaching after exposure to free radicals are also likely to be involved. Despite their frequency as shown in our preliminary observations, phosphenes have been underreported probably because their mechanism and impact are poorly understood. Recently, phosphenes have been used to restore the vision and whether they might predict vision loss after therapeutic irradiation is a current field of investigation. We have reviewed and also investigated here the mechanisms related to the occurrence of phosphenes in irradiated patients and especially in patients irradiated by proton therapy for ocular tumors., Competing Interests: CONFLICTS OF INTEREST No conflicting relationship exists for any author.

Purpose: To investigate whether proton therapy (PT) performs safely in superotemporal melanomas, in terms of risk of dry-eye syndrome (DES)., Methods and Materials: Tumor location, DES grade, and dose to ocular structures were analyzed in patients undergoing PT (2005-2015) with 52 Gy (prescribed dose, not accounting for biologic effectiveness correction of 1.1). Prognostic factors of DES and severe DES (sDES, grades 2-3) were determined with Cox proportional hazard models. Visual acuity deterioration and enucleation rates were compared by sDES and tumor locations., Results: Median follow-up was 44 months (interquartile range, 18-60 months). Of 853 patients (mean age, 64 years), 30.5% had temporal and 11.4% superotemporal tumors. Five-year incidence of DES and sDES was 23.0% (95% confidence interval [CI] 19.0%-27.7%) and 10.9% (95% CI 8.2%-14.4%), respectively. Multivariable analysis showed a higher risk for sDES in superotemporal (hazard ratio [HR] 5.82, 95% CI 2.72-12.45) and temporal tumors (HR 2.63, 95% CI 1.28-5.42), age ≥70 years (HR 1.90, 95% CI 1.09-3.32), distance to optic disk ≥5 mm (HR 2.71, 95% CI 1.52-4.84), ≥35% of retina receiving 12 Gy (HR 2.98, 95% CI 1.54-5.77), and eyelid rim irradiation (HR 2.68, 95% CI 1.49-4.80). The same risk factors were found for DES. Visual acuity deteriorated more in patients with sDES (0.86 ± 1.10 vs 0.64 ± 0.98 logMAR, P=.034) but not between superotemporal/temporal and other locations (P=.890). Enucleation rates were independent of sDES (P=.707) and tumor locations (P=.729)., Conclusions: Severe DES was more frequent in superotemporal/temporal melanomas. Incidence of vision deterioration and enucleation was no higher in patients with superotemporal melanoma than in patients with tumors in other locations. Tumor location should not contraindicate PT., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To assess the planning, treatment, and follow-up strategies worldwide in dedicated proton therapy ocular programs., Methods and Materials: Ten centers from 7 countries completed a questionnaire survey with 109 queries on the eye treatment planning system (TPS), hardware/software equipment, image acquisition/registration, patient positioning, eye surveillance, beam delivery, quality assurance (QA), clinical management, and workflow., Results: Worldwide, 28,891 eye patients were treated with protons at the 10 centers as of the end of 2014. Most centers treated a vast number of ocular patients (1729 to 6369). Three centers treated fewer than 200 ocular patients. Most commonly, the centers treated uveal melanoma (UM) and other primary ocular malignancies, benign ocular tumors, conjunctival lesions, choroidal metastases, and retinoblastomas. The UM dose fractionation was generally within a standard range, whereas dosing for other ocular conditions was not standardized. The majority (80%) of centers used in common a specific ocular TPS. Variability existed in imaging registration, with magnetic resonance imaging (MRI) rarely being used in routine planning (20%). Increased patient to full-time equivalent ratios were observed by higher accruing centers (P=.0161). Generally, ophthalmologists followed up the post-radiation therapy patients, though in 40% of centers radiation oncologists also followed up the patients. Seven centers had a prospective outcomes database. All centers used a cyclotron to accelerate protons with dedicated horizontal beam lines only. QA checks (range, modulation) varied substantially across centers., Conclusions: The first worldwide multi-institutional ophthalmic proton therapy survey of the clinical and technical approach shows areas of substantial overlap and areas of progress needed to achieve sustainable and systematic management. Future international efforts include research and development for imaging and planning software upgrades, increased use of MRI, development of clinical protocols, systematic patient-centered data acquisition, and publishing guidelines on QA, staffing, treatment, and follow-up parameters by dedicated ocular programs to ensure the highest level of care for ocular patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: Post-proton therapy surveillance of uveal melanomas relies on decreased thickness on repeat ultrasound B every 6 months for 2 years and yearly thereafter. Earlier pseudoprogression, a phenomenon described in other tumour types within the first months of irradiation, can also be observed in uveal melanomas and may lead to inappropriate enucleation. The Collaborative Ocular Melanoma Study (COMS) has defined ultrasound criteria to identify tumour progression after brachytherapy. We aimed to determine the reliability of ultrasound as a means to measure tumour height after proton therapy and predict local relapse., Materials and Methods: All 1992-2012 consecutive patients with at least three ultrasound B measurements during follow-up were included., Results: There were 55 local relapses of 886 patients (6.2%). Ultrasound B reliability was highest at 24 months, with specificity higher than 95% starting at 18 months., Conclusion: Before 18 months post-proton therapy, the risk of falsely concluding in favour of a relapse exceeds 5% and should prompt repeat measurements 3 and 6 months later but should not prompt enucleation without further clinical assessment., (Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

We present numerical simulations of the different two-dimensional flow regimes generated by a constant spatially periodic forcing balanced by viscous dissipation and large-scale drag with a dimensionless damping rate 1/Rh. The linear response to the forcing is a 6×6 square array of counterrotating vortices, which is stable when the Reynolds number Re or Rh are small. After identifying the sequence of bifurcations that lead to a spatially and temporally chaotic regime of the flow when Re and Rh are increased, we study the transitions between the different turbulent regimes observed for large Re by varying Rh. A large-scale circulation at the box size (the condensate state) is the dominant mode in the limit of vanishing large-scale drag (Rh large). When Rh is decreased, the condensate becomes unstable and a regime with random reversals between two large-scale circulations of opposite signs is generated. It involves a bimodal probability density function of the large-scale velocity that continuously bifurcates to a Gaussian distribution when Rh is decreased further.

Background: Choroidal metastases (CM) are the most common malignant intraocular lesion observed in up to 4-12% of necropsy series of patients with solid cancer. The spectrum of presentations varies from prevalent CM in disseminated cancer to isolated CM. CM are responsible for visual deterioration. Depending on the primary cancer, estimated life expectancy, overall cancer presentation and ocular symptoms, the management of CM varies widely. We address the multidisciplinary management of CM and technical aspects of radiotherapy., Material and Methods: A systematic review of literature was performed from 1974 to 2014., Results: Choroidal metastases occur preferentially in breast and lung carcinomas but are reported in all cancer types. The standard treatment remains external beam radiotherapy, applying 30Gy in 10 fractions or 40Gy in 20 fractions. The reported complete response and improved visual acuity rates are 80% and 57% to 89%, respectively. Some chemotherapy or new targeted therapy regimens yield promising CM response rates., Discussion: Radiation therapy consistently shows rapid symptom alleviation, yield excellent local control and functional outcomes. However, there are only few reports on late toxicities after 6months given the unfavorable prognostic of CM patients. Selected patients may live more than two years, underlying the need to better assess mean and long term outcomes. Some authors have favored exclusive systemic strategies with omission of irradiation. The current literature suffers from the scarcity of prospective trials. Duration of tumor response following systemic therapy is rarely reported but appears less favorable as compared to radiotherapy. Systemic treatments may be proposed for pauci-symptomatic CM in a polymetastatic context while radiation therapy remains necessary in symptomatic CM either upfront or as an alternating treatment. Focalized radiation like brachytherapy and proton therapy may be proposed for isolated CM with long disease-free interval between primary and CM, as these techniques have the potential to yield better tumor and functional outcomes in patients with long life expectancy., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: To report the clinical features and outcomes of iris melanomas treated by proton beam therapy., Materials and Methods: A retrospective study was conducted at the Croix-Rousse University Hospital of Lyon, Department of Ophthalmology, in 36 patients treated by proton beam therapy for presumed (n = 29) and confirmed (n = 7) iris melanomas between July 1997 and October 2010. Ciliary body melanomas with iris involvement were excluded. The patients' mean age was 54.4 years (range, 22-82 years). The average tumor diameter was 3.8 mm (range, 2.5-8.0). The iridocorneal angle was invaded by the tumor in 47% of cases (n = 17), the ciliary body in 17% of cases (n = 6), and the sclera in 3% (n = 1). Raised intraocular pressure was present before treatment in 11.1 % of cases (n = 4). Tumor biopsy was performed in 19% of cases (n = 7). Four patients had undergone an initial incomplete surgical excision of tumor before radiotherapy. Surgical preparation of the eye with tantalum ring positioning had been performed in all cases 3-4 weeks before irradiation. The prescribed dose was 60 Cobalt Gray Equivalent (CGE) of proton beam radiotherapy delivered in four fractions on four consecutive days., Results: The median follow-up was 50 months (mean 60.5, range 15-136). One patient (2.7%) was lost to follow-up. None of the patients showed tumor progression, local recurrence, or metastasis. None of the patients required secondary enucleation. Cataract was developed in 62% of patients, glaucoma in two cases (6%) after irradiation, and hyphema with the aggravation of pre-existing glaucoma in one patient. No patients developed neovascular glaucoma., Conclusions: Proton beam therapy appears to be the treatment of choice for the conservative treatment of iris melanomas with excellent tumor control and an acceptable rate of complications. Longer follow-up studies on a larger series is necessary to consolidate these results.

We consider a fluid dynamo model generated by the flow on both sides of a moving layer. The magnetic permeability of the layer is larger than that of the flow. We show that there exists an optimum value of magnetic permeability for which the critical magnetic Reynolds number for dynamo onset is smaller than for a nonmagnetic material and also smaller than for a layer of infinite magnetic permeability. We present a mechanism that provides an explanation for recent experimental results. A similar effect occurs when the electrical conductivity of the layer is large.

Hydrodynamic and magnetic behaviors in a modified experimental setup of the von Kármán sodium flow-where one disk has been replaced by a propeller-are investigated. When the rotation frequencies of the disk and the propeller are different, we show that the fully turbulent hydrodynamic flow undergoes a global bifurcation between two configurations. The bistability of these flow configurations is associated with the dynamics of the central shear layer. The bistable flows are shown to have different dynamo efficiencies; thus for a given rotation rate of the soft-iron disk, two distinct magnetic behaviors are observed depending on the flow configuration. The hydrodynamic transition controls the magnetic field behavior, and bifurcations between high and low magnetic field branches are investigated.

We measure the decay rates of magnetic field modes in a turbulent flow of liquid sodium below the dynamo threshold. We observe that turbulent fluctuations induce energy transfers between modes with different symmetries (dipolar and quadrupolar). Using symmetry properties, we show how to measure the decay rate of each mode without being restricted to the one with the smallest damping rate. We observe that the respective values of the decay rates of these modes depend on the shape of the propellers driving the flow. Dynamical regimes, including field reversals, are observed only when the modes are both nearly marginal. This is in line with a recently proposed model.

Purpose: To study the prognosis of the different types of uveal melanoma recurrences treated by proton beam therapy (PBT)., Methods and Materials: This retrospective study analyzed 61 cases of uveal melanoma local recurrences on a total of 1102 patients treated by PBT between June 1991 and December 2010. Survival rates have been determined by using Kaplan-Meier curves. Prognostic factors have been evaluated by using log-rank test or Cox model., Results: Our local recurrence rate was 6.1% at 5 years. These recurrences were divided into 25 patients with marginal recurrences, 18 global recurrences, 12 distant recurrences, and 6 extrascleral extensions. Five factors have been identified as statistically significant risk factors of local recurrence in the univariate analysis: large tumoral diameter, small tumoral volume, low ratio of tumoral volume over eyeball volume, iris root involvement, and safety margin inferior to 1 mm. In the local recurrence-free population, the overall survival rate was 68.7% at 10 years and the specific survival rate was 83.6% at 10 years. In the local recurrence population, the overall survival rate was 43.1% at 10 years and the specific survival rate was 55% at 10 years. The multivariate analysis of death risk factors has shown a better prognosis for marginal recurrences., Conclusion: Survival rate of marginal recurrences is superior to that of the other recurrences. The type of recurrence is a clinical prognostic value to take into account. The influence of local recurrence retreatment by proton beam therapy should be evaluated by novel studies., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: In protontherapy, accessories are used in order to adapt the beam to the surface and to the depth of the target. They are positioned close to the patient in order to avoid perturbation effects related to proton scattering. The level of contamination of the beam caused by these accessories may be assessed by examining the dose maps in parallel planes to the beam incidence. The EBT2 radiochromic film is a suitable tool for this task, as it can be cut into small pieces and immersed in water. Prior to use the EBT2 film for dose measurements, its response when exposed to a proton beam must be analysed., Methods: The measurements were performed at the Centre Antoine Lacassagne, using the hospital-based MEDICYC isochronous cyclotron which provides 65 MeV protons. Monoenergetic as well as polyenergetic beams were used. Small pieces of EBT2 films were irradiated with proton beams in a small water phantom. Films were exposed at various angles close to the beam incidence and received doses ranging from 0.25 to 500 Gy. The optical density (OD) was studied as a function of angle, dose and linear energy transfer (LET)., Results: The effective atomic number of the active layer of the film is close to that of water which prevents disturbances of the measurement. However, the high density and the significant thickness of the Mylar substrate surrounding the active layer affect the use of the film in a parallel orientation to the beam. Therefore, the substrate layer may totally or partially slow down the protons. The measurement is then no longer representative to what happens in water. The measurement errors can be corrected by applying a tilt angle of at least 5° between the film and the beam. The dose analysis reveals that the green channel is the most sensitive in the dose range from 1 to 100 Gy. The OD is accurately described by a Weibull function of the dose with four free parameters. The Weibull function is valid for both monoenergetic and polyenergetic beams if the LET is limited to values below 15 MeV g(- 1) cm(2). When using a film orientation close to the beam incidence angle, increasing LET values are encountered throughout the film axis gradually with the protons slowing down in water. The EBT2 films show an underestimated response for higher LET values. The comparison of data from the present study to data obtained by other authors for EBT films allows modelling the underestimated response as a function of the LET. The definition improvement of the link between OD and LET requires to integrate more closely the beam energy characteristics., Conclusions: The EBT2 film is a suitable dosimeter for analysing dose plans in planes nearly parallel to the beam orientation by compensating the underestimated dose response due to LET.

The nature of dynamo action in shear flows prone to magnetohydrodynamc instabilities is investigated using the magnetorotational dynamo in Keplerian shear flow as a prototype problem. Using direct numerical simulations and Newton's method, we compute an exact time-periodic magnetorotational dynamo solution to three-dimensional dissipative incompressible magnetohydrodynamic equations with rotation and shear. We discuss the physical mechanism behind the cycle and show that it results from a combination of linear and nonlinear interactions between a large-scale axisymmetric toroidal magnetic field and nonaxisymmetric perturbations amplified by the magnetorotational instability. We demonstrate that this large-scale dynamo mechanism is overall intrinsically nonlinear and not reducible to the standard mean-field dynamo formalism. Our results therefore provide clear evidence for a generic nonlinear generation mechanism of time-dependent coherent large-scale magnetic fields in shear flows and call for new theoretical dynamo models. These findings may offer important clues to understanding the transitional and statistical properties of subcritical magnetorotational turbulence.

Using protons for the treatment of ocular melanoma (especially of posterior pole tumours), the radiation quality of the beam must be precisely assessed to preserve the vision and to minimise the damage to healthy tissue. The radiation quality of a therapeutic proton beam at the Centre Antoine Lacassagne in Nice (France) was measured using microdosimetric techniques, i.e. a miniaturised version of a tissue-equivalent proportional counter. Measurements were performed in a 1-µm site at different depths in a Lucite phantom. Experimental data showed a significant increase in the beam quality at the distal edge of the spread-out Bragg peak (SOBP). In this paper, the numerical simulation of the experimental setup is done with the FLUKA Monte Carlo radiation transport code. The calculated microdosimetric spectra are compared with the measured ones at different depths in tissue for a monoenergetic proton beam (E=62 MeV) and for a modulated SOBP. Numerically and experimentally predicted relative biological effectiveness values are in good agreement. The calculated frequency-averaged and dose-averaged lineal energy mean values are consistent with measured data.

Purpose: To present the results of uveal melanomas treated at Nice Teaching Hospital., Methods and Materials: This retrospective study included 886 consecutive patients referred to our clinic for the treatment of uveal melanomas by proton beam radiotherapy from June 1991 to December 2007. Survival rates were determined by using Kaplan-Meier estimates, and prognostic factors were evaluated using the log-rank test or Cox model., Results: The number (percent total) of subjects staged according to the TNM classification system (6th edition) of malignant tumors included 39 stage T1 (4.4%), 420 stage T2 (47.40%), 409 stage T3 (46.16%), and 18 stage T4 (2.03%) patients. The median follow-up was 63.7 months. The Kaplan-Meier overall survival rate at 5 years according to the sixth edition TNM classification was 92% for T1, 89% for T2, 67% for T3, and 62% for T4; and at 10 years, 86% for T1, 78% for T2, 43% for T3, and 41% for T4. Five factors were found to be associated with an increased death rate: advanced age, tumor thickness, largest tumor basal diameter, tumor volume, and tumor volume-to-eyeball volume ratio. The metastasis-free survival rates were 88.3 % at 5 years and 76.4 % at 10 years. The local control rates were 93.9% at 5 years and 92.1% at 10 years. The ocular conservation rates were 91.1% at 5 years and 87.3% at 10 years., Conclusions: We report the results of a large series of patients treated for uveal melanomas with a very long follow-up. Despite the large tumor volume treated, our results were similar to previously published findings relating to proton beam therapy., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Background: Interventional radiology (IR) procedures in very low birth-weight (VLBW) infants (<1.5 kg) are challenging due to size, immaturity, comorbidities and lack of devices of suitable size. Infants are moved from the neonatal intensive care unit to the IR suite, further exposing them to risk. Our purpose was to review our experience of interventional procedures in VLBW infants, specifically complications and potential risks., Materials and Methods: VLBW infants referred for image-guided therapy between 1998 and 2005 were identified and medical records reviewed. "Complications" were divided into: major or minor, periprocedural or postprocedural, and intervention-/device-related, patient-related or equipment-related. Transport risk index of physiological stability (TRIPS) scores were calculated., Results: A total of 116 infants (68 male, 48 female) underwent 176 procedures (159 vascular access-related and 17 nonvascular). Of 158 complications identified, 116 were major and 42 were minor. Major complications included hypothermia (n=33), line manipulations/removals (n=25), bleeding (n=12), thrombosis (n=4), cardiac arrest (n=3), tamponade (n=2), and multiorgan failure (n=1). Of the complications, 119 were categorized as intervention-/device-related, 32 patient-related and 7 equipment-related. There were no significant differences between pre- and postprocedural TRIPS scores., Conclusion: Successful completion of IR procedures in the VLBW infant is possible, but complications still occur in these fragile infants.

In 2006, 3 sites have been selected by the Institut national of cancer (Lille, Nancy et Nice) to evaluate a radiotherapy robot, the CyberKnife. This machine, able to track mobile tumours in real time, gives new possibilities in the field of extra cranial stereotactic radiotherapy. Functionalities and medico economical issues of the machine will be evaluated during 2 years on the 3 sites.

The application of diamond to dosimetry is desirable because of its tissue equivalence, chemical inertness and small size, but this has not been commercially viable owing to the non-reproducible response of natural diamond. The chemical vapour deposition (CVD) of diamond permits controlled, reproducible and large-scale production of this material at potentially low cost. An investigation of some clinically relevant features like the depth-dose distribution as well as the absorbed dose profile, obtained using thermoluminescence (TL), is reported for several CVD diamond films. The TL characterisation presented here shows that CVD diamond films should be excellent TL-mode detectors in instances of radiotherapy and in vivo radiation dosimetry.

To investigate familial effects of neuropsychological deficits associated with seizure disorders, we studied 65 families, in which 1 member had epilepsy. The disorders included childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME) and temporal lobe epilepsy (TLE). Age-appropriate tests were administered to assess sustained attention, encoding and verbal memory, executive and focused attention and attentional flexibility/impulsivity. CAE probands attained lower scores than other probands in visual sustained attention and the ability to focus on and execute a visual-motor task. Scores of the unaffected relatives tended to fall between those of the probands and the controls. JME relatives had lower scores than other relatives in tests of visual and auditory sustained attention and attentional flexibility, and showed greater variability in response time. Behavioral information of this type may aid in the specification and differentiation of genetic linkages in affected families.

The minor component analysis (MCA) deals with the recovery of the eigenvector associated to the smallest eigenvalue of the autocorrelation matrix of the input data and is a very important tool for signal processing and data analysis. It is almost exclusively solved by linear neurons. This paper presents a linear neuron endowed with a novel learning law, called MCA EXINn and analyzes its features. The neural literature about MCA is very poor, in the sense that both a little theoretical basis is given (almost always focusing on the ODE asymptotic approximation) and only experiments on toy problems (at most four-dimensional problems) are presented, without any numerical analysis. This work addresses these problems and lays sound theoretical foundations for the neural MCA theory. In particular, it classifies the MCA neurons according to the Riemannian metric and justifies, from the analysis of the degeneracy of the error cost; the different behavior in approaching convergence. The cost landscape is studied and used as a basis for the analysis of the asymptotic behavior. All the phases of the dynamics of the MCA algorithms are investigated in detail and, together with the numerical analysis, lead to the identification of three possible kinds of divergence, here called sudden, dynamic, and numerical. The importance of the choice of low initial conditions is also explained. A lot of importance is given to the experimental part, where simulations on high-dimensional problems are,presented and analyzed. The orthogonal regression or total least squares (TLS) technique is also presented, together with a real-world application on the identification of the parameters of an electrical machine. It can be concluded that MCA EXIN is the best MCA neuron in terms of stability (no finite time divergence), speed, and accuracy.

The purpose of this study was to determine the effectiveness of a thermal mattress in stabilizing and maintaining body temperature during the transport of newborns who weigh less than 1,500 g. We compared 91 infants who were transported without a thermal mattress from April 1995 to March 1996 with 100 infants who were transported with the use of a transport thermal mattress (TTM) from April 1998 to October 1999. Temperature data were collected on arrival to the referring hospital, on departure from the referring hospital, and on arrival to the tertiary neonatal intensive care unit. The findings support that, over time, infants who were transported on a TTM had a greater increase or greater stability in body temperature, in comparison with infants who were not transported on a TTM (t = 5.1, p <.001). The data also supported that infants on a TTM maintained body temperature during stabilization and transport (F = 12.33, p =.001) better than the no mattress group did (F = 3.6, p =.061). Use of the TTM in the prevention of hypothermia in unstable environmental conditions can be extended to other areas within the hospital when thermoregulation of the premature infant is a concern, especially that of very low-birth weight infants. However, hyperthermia may also be a concern; body temperature should be monitored to watch for it., (Copyright 2001 by W.B. Saunders Company)

The binding of 125I-factor Xa to human aortic smooth muscle cell (SMC) monolayers was studied. At 4 degreesC, 125I-factor Xa bound to a single class of binding sites with a dissociation constant value of 3.6+/-0.7 nM and a binding site density of 11,720+/-1,240 sites/cell (n = 9). 125I-factor Xa binding was not affected by factor X, thrombin, or by DX9065, a direct inhibitor of factor Xa, but was inhibited by factor Xa (IC50 = 5.4+/-0.2 nM; n = 9) and by antibodies specific for the effector cell protease receptor 1 (EPR-1), a well-known receptor of factor Xa on various cell types. A factor X peptide duplicating the inter-EGF sequence Leu83-Leu88-(Gly) blocked the binding of 125I-factor Xa to these cells in a dose-dependent manner (IC50 = 110+/-21 nM). Factor Xa increased phosphoinositide turnover in SMCs and when added to SMCs in culture was a potent mitogen. These effects were inhibited by DX9065 and by antibodies directed against EPR-1 and PDGF. Increased expression of EPR-1 was identified immunohistochemically on SMCs growing in culture and in SMCs from the rabbit carotid artery after vascular injury. When applied locally to air-injured rabbit carotid arteries, antibodies directed against EPR-1 (100 mug/ artery) strongly reduced myointimal proliferation 14 d after vascular injury (65-71% inhibition, P < 0.01). DX9065 (10 mg/kg, subcutaneous) inhibited myointimal proliferation significantly (43% inhibition, P < 0.05). These findings indicate that SMCs express functional high affinity receptors for factor Xa related to EPR-1, which may be of importance in the regulation of homeostasis of the vascular wall and after vascular injury.