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Background and Purpose: To report the factors predictive of radio-induced complications (i.e. radiation retinopathy [RR], radiation papillopathy [RP] and neovascular glaucoma [NVG]) in uveal melanoma (UM) patients undergoing gamma knife radiosurgery (GKR)., Materials and Methods: Longitudinal cohort study on patients with UM treated at the Ocular Oncology Service, San Raffaele Scientific Institute, Milan, between June 1994 and November 2018. Data were retrospectively reviewed. Rates of GKR-related complications were reported. Variables associated with each complication were investigated using multivariable Cox models and confirmed by logistic regression analysis. Hazard ratio (HR) and 95% confidence intervals (CI) were reported for significant associations., Results: One hundred ninety-four patients (99 males, 51%) were included, and 184 tumours were primarily located in the choroid (95%). Median follow-up was 57 months (range 6-286). Local control was achieved in 182 eyes (94%), and 152 eyes (78%) experienced at least one radiation-induced complication. Radiation retinopathy was documented in 67 eyes (35%) after a median of 23 months. Older age (HR = 0.97, 95% CI = 0.95-0.99, p = 0.02) had a protective effect for RR. Radiation papillopathy was diagnosed in 35 eyes (18%) after a median of 14 months after GKR. Macular or peripapillary location (HR = 3.06, 95% CI = 1.52-6.16, p = 0.002) was associated with increased risk of RP, while older age was protective (HR = 0.95, 95% CI = 0.93-0.98, p = 0.001). New-onset NVG was found in 53 eyes (27%), and median onset was 28 months. Tumour thickness (HR = 4.41, 95% CI = 2.23-8.72, p < 0.001) and peripapillary location (HR = 2.78, 95% CI = 1.46-5.27, p = 0.002) were the main risk factors associated with NVG., Conclusion: Understanding factors predictive for radiation-related complications in patients undergoing GKR might help for better counselling and treatment planning., (© 2021 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Gamma Knife radiosurgery (GKRS) is a well-established safe and effective treatment for trigeminal neuralgia (TN) with high initial success rate (80-90%). Why the pain relief is progressively decreased with time is a matter of considerable debate. To investigate factors related to long-lasting pain relief, the authors conducted a retrospective analysis focusing on anatomical and radiosurgical related parameters, chosen according to literature review. One hundred and twelve patients with classical trigeminal neuralgia and follow-up longer than 12 months were selected from our institutional consecutive series of patients treated by GKRS. Patients were followed for a mean period of 61.5 ± 3.5 months (range, 12-126 months) to evaluate, as endpoints, long-term pain relief and hypoesthesia onset. The median maximum radiation dose was 80 Gy (range 70-90 Gy). Factors related to poor long-term pain relief were prescription dose < 80 Gy (p = 0.038), calibration dose rate < 2.5 Gy/min (p = 0.018), and distance between isocenter and trigeminal nerve emergence > 8 mm (p < 0.001). When analyzing patients who received 80 Gy as maximum dose without any sector blocking, we notice that ID 50 < 2.7 mJ was predictive for longer period of pain control (p = 0.043). It was experienced also among patients in which a small volume of the nerve (< 35%) received more than 80% of the maximal dose, compared to those in which a larger volume of the nerve was irradiated with maximal dose (p 0.034). This last result was significant if the shot was 8 mm or less from the pons. Several single-patient anatomical and radiosurgical parameters should be considered to improve GKRS effectiveness., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Objective: Gamma Knife radiosurgery (GKRS) is a well-defined treatment for trigeminal neuralgia. The aim of this study was to determine how the GKRS planning might change on the basis of the patient's own anatomy and how to best choose the target location., Methods: Trigeminal cisternal length, pontotrigeminal angle, and distance between middle of the shot and emergence were evaluated in 112 consecutive GKRS plans for trigeminal neuralgia. Correlations with pain outcomes and facial hypoesthesia were analyzed., Results: The mean angle was 29° ± 4.4° and 37° ± 0.9°, respectively, in patients developing and not developing severe hypoesthesia (P = 0.045), despite no significant difference on brainstem dose (11.9 ± 0.8 and 10.5 ± 0.3 Gy; P = 0.22). The length of the nerve was not relevant on clinical outcomes but the shot-emergence distance (mean 8.1 ± 0.2 mm) depended on both trigeminal length and angle (P = 0.01). At constant prescription dose, 6-month cumulative rates of pain relief and control without therapy were 52.9% when the shot-emergence distance was ≤8 mm, whereas 25% when this distance was >8 mm (P = 0.017). The maintenance of good pain control was more long lasting in the first group (49.5 ± 6.6 vs. 25.4 ± 5 months; P = 0.006) with a 5-year cumulative rate of 70% and 26%, respectively (P < 0.001)., Conclusions: The pontotrigeminal angle and the shot-emergence distance should be considered during GKRS planning: the first as a potential risk factor for hypoesthesia, and the second should not exceed 8 mm., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Few studies have evaluated the relationship between brain arteriovenous malformations (bAVMs) angioarchitecture and the response to Gamma Knife Stereotactic Radiosurgery (GKSR)., Methods: A prospectively enrolled single-center cohort of patients with bAVMs treated by GKSR has been studied to define independent predictors of obliteration with particular attention to angioarchitectural variables. Only patients older than 18 years old (y.o.), who underwent baseline digital subtraction angiography (DSA) and clinico-radiological follow-up of at least 36 months, were included in the study., Results: Data of 191 patients were evaluated. After a mean follow-up of 80 months (range 37-173), total obliteration rate after first GKSR treatment was 66%. Mean dose higher than 22 Gy (P = .019, OR = 2.39, 95% CI 1.15-4.97) and flow rate dichotomized into high vs non-high (P < .001, OR = 0.23, 95% CI 0.11-0.51) resulted to be independent predictors of obliteration. Flow-surrogate angioarchitectural features did not emerge as independent outcome predictors., Conclusions: Flow rate seems to be associated in predicting outcome after GKSR conferring high-flow AVM a lower occlusion rate. Its role should be considered when planning radiosurgical treatment of bAVM, and it could be added to other parameters used in GKRS outcome predicting scales.

Altered macrophage infiltration upon tissue damage results in inadequate healing due to inappropriate remodeling and stem cell recruitment and differentiation. We investigated in vivo whether cells of endothelial origin phenotypically change upon heterotopic ossification induction and whether infiltration of innate immunity cells influences their commitment and alters the ectopic bone formation. Liposome-encapsulated clodronate was used to assess macrophage impact on endothelial cells in the skeletal muscle upon acute damage in the ECs specific lineage-tracing Cdh5CreER T2 :R26REYFP/dtTomato transgenic mice. Macrophage depletion in the injured skeletal muscle partially shifts the fate of ECs toward endochondral differentiation. Upon ectopic stimulation of BMP signaling, monocyte depletion leads to an enhanced contribution of ECs chondrogenesis and to ectopic bone formation, with increased bone volume and density, that is reversed by ACVR1/SMAD pathway inhibitor dipyridamole. This suggests that macrophages contribute to preserve endothelial fate and to limit the bone lesion in a BMP/injury-induced mouse model of heterotopic ossification. Therefore, alterations of the macrophage-endothelial axis may represent a novel target for molecular intervention in heterotopic ossification.

Background: Changes after reimplantation of the autologous bone have been largely described. However, the rate and the extent of resorption in cranial grafts have not been clearly defined. Aim of our study is to evaluate the bone flap resorption (BFR) after cryopreservation., Methods: We retrospectively reviewed 27 patients, aged 18 years or older, subjected to cranioplasty (CP) adopting autologous cryopreserved flap. The BFR was derived from the percentage of decrease in flap volume (BFR%), comparing the first post-operative computed tomography (CT) and the last one available (performed at least 1 year after surgery). We also proposed a semiquantitative scoring system, based on CT, to define a clinically workable BFR classification., Results: After a mean ± SE follow-up of 32.5 ± 2.4 months, the bone flap volume decreased significantly (p < 0.0001). The mean BFR% was 31.7 ± 3.8% and correlated with CT-score (p < 0.001). Three BFR classes were described: mild (14.8% of cases) consisting in minimal bone remodelling, CT-score ≤ 6, mean BFR% = 3.5 ± 0.7%; moderate (51.9% of cases) corresponding to satisfactory cerebral protection, CT-score < 13, mean BFR% = 25.6 ± 2.2%; severe (33.3% of cases) consisting in loss of cerebral protection, CT-score ≥ 13, mean BFR% = 54.2 ± 3.9%. Females had higher BFR% than males (p = 0.022). BFR classes and new reconstructive surgery were not related (p = 0.58)., Conclusions: BFR was moderate or severe in 85.2% of re-implanted cryopreserved flaps. The proposed CT-score is an easy and reproducible tool to define resorption extent.

Purpose: Arteriovenous malformations' (AVMs) obliteration depends on several factors; among the many factors that must be considered to obtain a high rate of obliteration and a low rate of complications, Flickinger-Pollock Score (FPS) seems to have an important role but still have to be validated in the pediatric population while Paddick-Conformity Index (PCI) still has no demonstration of its utility on the outcome and is considered only as a treatment quality marker., Methods: We retrospectively analyzed 33 consecutive children (2-18 years) with an AVM, treated with stereotactic radiosurgery Gamma Knife (SRS-GK) from 2001 to 2014 in our institution. We assess angiographic (DSA) Obliteration Rate (OR) as well FPS and PCI to draw conclusions., Results: DSA-OR was 60.6% with a rate of hemorrhage of 0%. median target volume (TV) was 3.60 cc (mean 4.32 ± 3.63; range 0.15-14.2), median PD was 22 Gy (mean 21.4 ± 2.6; range 16.5-25). Median percentage of coverage was 98% (mean 97 ± 3; range 84-100). The median modified FPS was 0.78 (mean 0.89 ± 0.52; range 0.21-2.1) and highly correlate with OR (p = 0.01). The median PCI was 0.65 (mean 0.65 ± 0.14; range 0.34-0.95) A PCI lower than 0.57 highly correlates with final OR (p = 0.02)., Conclusion: SRS-GK was safe and gradually effective in children. A prescription dose-like that used in adult population (i.e. > 18 and between 20 and 25 Gy) is essential to achieve obliteration. A PD of 23 Gy and 22 Gy did impact OR, respectively (p = 0.02) and (p = 0.05). FPS and PCI are valuable scores that seem to correlate with the OR also in the pediatric population although further prospective studies are needed to confirm these observations.

Aims: The aim of the present work is to assess the main predictors of the most clinically relevant radio-induced effects after Gamma Knife stereotactic radiosurgery (GKRS) for uveal melanoma (UM)., Materials and Methods: Medical records and three-dimensional dosimetry data of critical structures of 66 patients were retrospectively reviewed. Cox's proportional hazard model was used to identify clinical and dosimetric variables as independent risk factor for GKRS-related complications., Results: The fraction of the posterior segment receiving more than 20Gy (V20), Bruch's membrane rupture and tumour thickness were significant prognostic factors for neovascular glaucoma. A clear relationship with the dose received by 1% of the optic nerve (D1%) was found for radiation retinopathy and papillopathy. Multivariables models resulted for visual acuity (VA) reduction >20% of the basal value and for complete VA loss, both including largest tumour diameter and D1% to the optic nerve. The predictive model for complete VA loss includes also Bruch's membrane rupture. An alternative model for complete visual acuity loss, including the optic nerve-prescription isodose minimum distance, was also suggested., Conclusions: We found clinical and dosimetric variables to clearly predict the risk of the main side effects after GKRS for UM. These results may provide dose constraints to critical structures, potentially able to reduce side effects. Constraining D1% to the optic nerve below 12-13Gy may result in a dramatic reduction of blindness risk, while reducing V20 of the posterior segment of the bulb could limit the neovascular glaucoma onset., Competing Interests: Competing interests: The corresponding author AdV has a contract as starter-up with Elekta Instrument AB. No other conflict of interests to declare for the other authors., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose: The goal of this work is to evaluate organ doses and lifetime attributable risk of cancer incidence and mortality in scoliosis examinations of adolescent patients performed with EOS imaging system, in order to optimize patient dose and protocols., Methods: An anthropomorphic phantom of a normal patient, with thermoluminescent dosimeters in correspondence with the main organs at risk, was imaged with both EOS and computed radiography (CR). For each modality, effective dose was calculated from the measured organ doses. Lifetime attributable risk was computed accordingly to the Committee on the Biological Effects of Ionizing Radiation (BEIR VII) and Public Health England (HPA) publications., Results: Except for testes and eyes, which were excluded from the scan in CR protocol, for all the other organs the doses delivered with CR examination were higher than these delivered by EOS system. The effective dose in EOS examination (0.43 ± 0.04 mSv) is about two times less than the dose in computed radiography with anti-scatter grid examination (0.87 ± 0.09 mSv), and, consequently, also the cancer probability is lower (5.4 vs 9.7 number of any cancers induction cases per 100,000 person examined, for a 20-year-old male patient)., Conclusions: The EOS system is efficient in limiting patient dose. The shielding of testes and the exclusion of eyes from the scan could allow to further reduce the dose.

OBJECTIVE There are few reported series regarding volume-staged Gamma Knife radiosurgery (GKRS) for the treatment of large, complex, cerebral arteriovenous malformations (AVMs). The object of this study was to report the results of using volume-staged Gamma Knife radiosurgery for patients affected by large and complex AVMs. METHODS Data from 20 patients with large AVMs were prospectively included in the authors' AVM database between 2004 and 2012. A staging strategy was used when treating lesion volumes larger than 10 cm 3 . Hemorrhage and seizures were the presenting clinical feature for 6 (30%) and 8 (40%) patients, respectively. The median AVM volume was 15.9 cm 3 (range 10.1-34.3 cm 3 ). The mean interval between stages (± standard deviation) was 15 months (± 9 months). The median margin dose for each stage was 20 Gy (range 18-25 Gy). RESULTS Obliteration was confirmed in 8 (42%) patients after a mean follow-up of 45 months (range 19-87 months). A significant reduction (> 75%) of the original nidal volume was achieved in 4 (20%) patients. Engel Class I-II seizure status was reported by 75% of patients presenting with seizures (50% Engel Class I and 25% Engel Class II) after radiosurgery. After radiosurgery, 71.5% (5/7) of patients who had presented with a worsening neurological deficit reported a complete resolution or amelioration. None of the patients who presented acutely because of hemorrhage experienced a new bleeding episode during follow-up. One (5%) patient developed radionecrosis that caused sensorimotor hemisyndrome. Two (10%) patients sustained a bleeding episode after GKRS, although only 1 (5%) was symptomatic. High nidal flow rate and a time interval between stages of less than 11.7 months were factors significantly associated with AVM obliteration (p = 0.021 and p = 0.041, respectively). Patient age younger than 44 years was significantly associated with a greater than 75% reduction in AVM volume but not with AVM obliteration (p = 0.024). CONCLUSIONS According to the results of this study, volume-staged GKRS is an effective and safe treatment strategy for large, complex, cerebral AVMs for which microsurgery or endovascular approaches could carry substantially higher risks to the patient. Radiation doses up to 20 Gy can be safely administered. The time interval between stages should be shorter than 11.7 months to increase the chance of obliteration. High nidal flow and a patient age younger than 44 years were factors associated with nidus obliteration and significant nidus reduction, respectively.

The goal of this work is to demonstrate that a CCD-based system can be used as a unified device which allows visible, β, X and γ rays imaging. A system composed of a CCD coupled with lens mounted on a black light-tight box and a high resolution intensifying screen for the radiations conversion were used. In order to investigate the detection of different type of radiations in vitro and in vivo experiments were performed. The comparison of the results obtained with our prototype and those obtained with dedicated commercial devices showed a good agreement.