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INTRODUCTION Ocular biometry in Ocular Proton Therapy (OPT) currently relies on a generic geometrical eye model built by referencing surgically implanted markers. An alternative approach based on image fusion of volumetric Magnetic Resonance Imaging (MRI) and panoramic fundus photography was investigated. MATERIALS AND METHODS Eighteen non-consecutive uveal melanoma (UM) patients, who consented for an MRI and had their tumour base visible on panoramic fundus photography, were included in this comparative analysis. Through generating digitally-reconstructed projections from MRI images using the Lambert azimuthal equal-area projection, 2D-3D image fusion between fundus photography and an eye model delineated on MRI scans was achieved and allowed for a novel definition of the target base (MRI + FCTV). MRI + FCTV was compared with MRI-only delineation (MRIGTV) and the conventional (EyePlan) target definition (EPCTV). RESULTS The combined use of fundus photography and MRI to define tumour volumes reduced the average discrepancies by almost 65% with respect to the MRI only tumour definitions when comparing with the conventionally planned EPCTV. With the proposed method, shallow sub-retinal tumour infiltration, otherwise invisible on MRI, can be included in the target volume definition. Moreover, a novel definition of the fovea location improves the accuracy and personalisation of the 3D eye model. CONCLUSION MRI and fundus image fusion overcomes some of the limitations of ophthalmological MRI for tumour volume definition in OPT. This novel eye tumour modelling method might improve treatment planning personalisation, allowing to better anticipate which patients could benefit from prophylactic treatment protocols for radiation induced maculopathy.

AIMS Sacral chordomas are locally aggressive, radio-resistant tumours. Proton therapy has the potential to deliver high radiation doses, which may improve the therapeutic ratio when compared with conventional radiotherapy. We assessed tumour control and radiation-induced toxicity in a cohort of sacral chordoma patients treated with definitive or postoperative pencil beam scanning proton therapy. METHODS AND MATERIALS Sixty patients with histologically proven sacral chordoma treated between November 1997 and October 2018 at the Paul Scherrer Institute with postoperative (n = 50) or definitive proton therapy (n = 10) were retrospectively analysed. Only 10 (17%) patients received combined photon radiotherapy and proton therapy. Survival rates were calculated using the Kaplan-Meier actuarial method. The Log-rank test was used to compare different functions for local control, freedom from distant recurrence and overall survival. Acute and late toxicity were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. RESULTS The median follow-up was 48 months (range 4-186). Local recurrence occurred in 20 (33%) patients. The 4-year local control, freedom from distant recurrence and overall survival rates were 77%, 89% and 85%, respectively. On univariate analysis, subtotal resection/biopsy (P = 0.02), tumour extension restricted to bone (P = 0.01) and gross tumour volume >130 ml (P = 0.04) were significant predictors for local recurrence. On multivariate analysis, tumour extension restricted to bone (P = 0.004) and gross total resection (P = 0.02) remained independent favourable prognostic factors for local recurrence. Twenty-four (40%), 28 (47%) and eight (11%) patients experienced acute grade 1, 2 and 3 toxicities, respectively. The 4-year late toxicity-free survival was 91%. Two patients developed secondary malignancies to the bladder 3-7 years after proton therapy. CONCLUSIONS Our data indicate that pencil beam scanning proton therapy for sacral chordomas is both safe and effective. Gross total resection, tumour volume

Central nervous system (CNS) tumors are the most common solid malignancies in children and adolescents and young adults (C-AYAs). Craniospinal irradiation (CSI) is an essential treatment component for some malignancies, but it can also lead to important toxicity. Pencil beam scanning proton therapy (PBSPT) allows for a minimization of dose delivered to organs at risk and, thus, potentially reduced acute and late toxicity. This study aims to report the clinical outcomes and toxicity rates after CSI for C-AYAs treated with PBSPT. Seventy-one C-AYAs (median age: 7.4 years) with CNS tumors were treated with CSI between 2004 and 2021. Medulloblastoma (n = 42: 59%) and ependymoma (n = 8; 11%) were the most common histologies. Median prescribed total PBSPT dose was 54 GyRBE (range: 18-60.4), and median prescribed craniospinal dose was 24 GyRBE (range: 18-36.8). Acute and late toxicities were coded according to Common Terminology Criteria for Adverse Events. After a median follow-up of 24.5 months, the estimated 2-year local control, distant control, and overall survival were 86.3%, 80.5%, and 84.7%, respectively. Late grade ≥3 toxicity-free rate was 92.6% at 2 years. Recurrent and metastatic tumors were associated with worse outcome. In conclusion, excellent tumor control with low toxicity rates was observed in C-AYAs with brain tumors treated with CSI using PBSPT.

To assess the incidence and severity of changes in hearing threshold in patients undergoing high-dose pencil-beam-scanning proton therapy (PBS-PT). This retrospective cohort study included fifty-one patients (median 50 years (range, 13–68)) treated with PBS-PT for skull base tumors. No chemotherapy was delivered. Pure tone averages (PTAs)were determined before (baseline) and after PBS-PT as the average hearing thresholds at frequencies of 0.5, 1, 2, and 4 kHz. Hearing changes were calculated as PTA differences between pre-and post-PBS-PT. A linear mixed-effects model was used to assess the relationship between the PTA at the follow-up and the baseline, the cochlea radiation dose intensity, the increased age, and the years after PBS-PT. Included patients were treated for chordoma (n = 24), chondrosarcoma (n = 9), head and neck tumors (n = 9), or meningioma (n = 3), with a mean tumor dose of 71.1 Gy (RBE) (range, 52.0–77.8), and a mean dose of 37 Gy (RBE) (range, 0.0–72.7) was delivered to the cochleas. The median time to the first follow-up was 11 months (IQR, 5.5–33.7). The PTA increased from a median of 15 dB (IQR 10.0–25) at the baseline to 23.8 (IQR 11.3–46.3) at the first follow-up. In the linear mixed-effect model, the baseline PTA (estimate 0.80, 95%CI 0.64 to 0.96, p ≤ 0.001), patient’s age (0.30, 0.03 to 0.57, p = 0.029), follow-up time (2.07, 0.92 to 3.23, p ≤ 0.001), and mean cochlear dose in Gy (RBE) (0.34, 0.21 to 0.46, p ≤ 0.001) were all significantly associated with an increase in PTA at follow-up. The applied cochlear dose and baseline PTA, age, and time after treatment were significantly associated with hearing loss after proton therapy.

To assess the incidence and severity of changes in hearing threshold in patients undergoing high-dose pencil-beam-scanning proton therapy (PBS-PT). This retrospective cohort study included fifty-one patients (median 50 years (range, 13-68)) treated with PBS-PT for skull base tumors. No chemotherapy was delivered. Pure tone averages (PTAs)were determined before (baseline) and after PBS-PT as the average hearing thresholds at frequencies of 0.5, 1, 2, and 4 kHz. Hearing changes were calculated as PTA differences between pre-and post-PBS-PT. A linear mixed-effects model was used to assess the relationship between the PTA at the follow-up and the baseline, the cochlea radiation dose intensity, the increased age, and the years after PBS-PT. Included patients were treated for chordoma (n = 24), chondrosarcoma (n = 9), head and neck tumors (n = 9), or meningioma (n = 3), with a mean tumor dose of 71.1 Gy (RBE) (range, 52.0-77.8), and a mean dose of 37 Gy (RBE) (range, 0.0-72.7) was delivered to the cochleas. The median time to the first follow-up was 11 months (IQR, 5.5-33.7). The PTA increased from a median of 15 dB (IQR 10.0-25) at the baseline to 23.8 (IQR 11.3-46.3) at the first follow-up. In the linear mixed-effect model, the baseline PTA (estimate 0.80, 95%CI 0.64 to 0.96

According to the definition of the ‘‘Rome ecosystem’’ first proposed by Giacomini (ref. in Blasi et al., 2008), more than 10 years ago a Rome Biosphere Reserve was imagined in the context of an interdisciplinary project, involving landscape ecologists, geologists, plant ecologists, zoologists, geographers, city planners and environmental psychologists. The project was a pilot experience, afterward it evolved deepening the knowledge of land use changes over time, the floristic, vegetational, and ecological territorial analyses, and the planning of green infrastructures based on biodiversity and ecosystem services.Geodiversity studies were since the beginning supporting ecological land classification for biodiversity monitoring and conservation purposes. Land units are fundamental for the assessment of the natural heterogeneity of an area, defined by climatic, abiotic and biotic parameters, which allows the assessment of potential natural biodiversity (in the sense of ecosystem diversity). Subsequently, the comparison with the real heterogeneity and the real biodiversity, allows the planning of conservation actions and restoration interventions.In particular land units’ hierarchical divisive classification (top-down) uses lithology to define land systems (inside bioclimatic regions) and geomorphology to define land facets (inside systems). Moreover, morphometric parameters affect the ecosystems composition and distribution and therefore their functionality at different scales of analysis.The Geodiversity indexing and mapping methods available in literature use a variety of criteria. The most used criteria are the same supporting ecological land classification: lithology, landforms, land use.The converging objectives of assessing urban geodiversity and mapping Rome land units, opened the interdisciplinary dialogue among the authors and led to the study presented here, aiming at evaluating the heavier morphology influence on the potential biodiversity heterogeneity at a detailed scale.For this purpose, the most used geodiversity indexes have been taken into account, in order to choose the best ones fitting our study case. We focused on methods including geomorphodiversity parameters, such as the Geomorphodiversity index by Melelli et al. (2017) modified for introducing the automatic classification of geomorphological features and tested on a multiscale analysis.In an urban context, the morphometric analysis of topography changes, anthropogenic features and natural landforms modified by humans in time, make geomorphological mapping fundamental to calibrate the geodiversity models in a truly multidisciplinary approach to urban biodiversity investigation.In particular, the peculiarities of the urban environment and the relative difficulties in evaluating geodiversity with methods built up and tested in natural areas, requests to consider:the thickness of landfill deposits characterizing anthropogenic layering in historical cities, which alters the original morphology and the local pedogenesis the need to define the boundaries between urban and peri-urban areas. Besides the consolidated application in natural systems, such as protected areas, the role of geodiversity indexing and mapping is therefore promoted also in urban systems, where it can foster a truly holistic and integrated ecosystem / geosystem approach. Actually, geodiversity assessment, joined to the biodiversity one, can effectively contribute to urban green infrastructure planning by sustaining and enhancing important regulating and cultural ecosystem services.

The scientific literature on urban geomorphology focuses on city case studies with a centuries-old historical settlement and analyze mainly the downtown areas.In this framework, the well-known multitemporal and multidisciplinary research procedures, including ancient maps and documents, are widely available for the recognition of the original morphological arrangement and for identifying the spatial and temporal changes to the landscape due to the human presence.This approach has inevitably centered the research on case studies which, for the most part, are on the European territory. The main European cities in fact arose many centuries ago when the choice of the site was conditioned also, and above all, by morphological and more generally geological conditions (availability of underground water resources, proximity to rivers, lakes and seas, mineral resources, etc.).The current trend towards urbanization (it is expected that in 2030 more than 60% of the world population will live in urban areas) affects Africa and Asia in particular, with a city model greatly different from what we are used to conceiving in the "old continent". These metropolises or in some cases megalopolises, are a little known but very interesting school field to understand the differences in terms of hazard and resources for such large areas.In the same time the European cities are growing too, with evident problems in contrast to the idea of a sustainable development. Even if the social and economic differences between European cities and the African and Asian ones are well evident, comparing these urban models for the geomorphological investigation could reveal interesting food for thought.Our opened questions are: in a holistic model of sustainable urban development what can be the role of geomorphology for large cities? Does it make sense talking about transformations of natural morphology in areas where urbanization has reached such a high level of impact, does it represent a lesson to be learned? Above all, can research on urban geomorphology be a useful approach for a sustainable model of urbanization?This contribution proposes a guideline for the study of urban geomorphology in these new metropolises, identifying the differences in terms of boundary conditions, related issues and the role of geomorphology as a parameter for reaching the sustainability.

The geomorphological map of Rome city centre, first published in 2016, is one of the most representative case studies for urban geomorphology, due to the widespread anthropogenic changes to landscape caused by human activities over the city’s millenarian history.The today topographical and hydrographic setting is therefore the result of both natural and anthropogenic processes, which have occurred and intertwined over time. In particular, the most relevant human interventions affect the hydrographic network in the eastern area of the city, where it firstly arose and developed and where resource abundance and at the same time water management and supply needs were more relevant.Before significant land-use changes had started since the roman time, this area was drained by the most important left tributaries of the Tiber River, such as the Aniene River, the main watercourses of the city, the Nodicus-Aqua Mariana stream, the Almone River, the Grotta Perfetta and the Vallerano streams. Their courses became culverted or were diverted. Emblematic is the example of the Nodicus valley, standing between Aventino and Palatino historical hills, and the Rivo Aqua Mariana artificially streaming into the Nodicus drainage basin since the 1122 a.D. diversion, which probably restored the original Nodicus hydrographic system.This work aims at presenting the first relevant results towards the reconstruction of the main topographic transformations on the Tevere River hydrographic left area by analysing the current drainage network and its anthropogenic modifications. The methodological approach consists of multidisciplinary bibliographic research supported by multitemporal geomorphological and topographical analyses. The results of this work are summarized in the map of the changes to the hydrographic network.

Zusammenfassung Klinisches/methodisches Problem Mundhöhlenmalignome stellen weltweit die häufigsten Tumoren im Bereich der Hals-Nasen-Ohrenheilkunde bzw. Otorhinolaryngologie dar. Es handelt sich um eine heterogene Gruppe an Tumoren, deren Kenntnis erforderlich ist, um den unterschiedlichen Anforderungen an Diagnostik und Therapie gerecht zu werden. Radiologische Standardverfahren Computertomographie (CT), Magnetresonanztomographie (MRT), Sonographie, nuklearmedizinische Verfahren (NUK). Leistungsfähigkeit Die o. g. Diagnostika werden komplementär eingesetzt. Bewertung Eine frühzeitigere Diagnose des Tumors verbessert das Staging und somit die Therapie und Prognose des Patienten. Schlussfolgerung Dem Radiologen kommt bei der interdisziplinären Behandlung von Malignomen der Mundhöhle eine bedeutende Rolle zu. Trotz großer Fortschritte in der Radiotherapie, Onkologie und Immuntherapie spielt die Chirurgie weiterhin eine wichtige Rolle in der Behandlung maligner Erkrankungen der Mundhöhle.

Purpose To evaluate why small- and certain medium-sized parapapillary choroidal melanoma (pcM) patients treated with hypo-fractionated proton therapy (PT) retain excellent long-term visual acuity (VA) and assess the negative predictive factors for retaining good vision (≤ 0.2 logMAR (≥ 0.6 decimal) after 5 years. Methods This single-center, retrospective, comparative study recruited consecutive pcM patients that were treated with PT. Between 1984 and 2005, 609 patients received a total of 60 CGE, of whom 310 met the following inclusion criteria: posterior tumor border ≤ 2.5 mm from the optic disc, largest tumor diameter ≤ 17.9 mm, tumor thickness ≤ 5.2 mm and available follow-up data for at least 5 years. Results Mean follow-up was 120.8 ± 48.8 months (54.0–295.0). Out of 310 patients, 64 (21%) maintained a VA ≤ 0.2 logMAR (≥ 0.6 decimal) for at least 5 years following PT and were allocated to the “good visual outcome” (GVO) group, while the remaining 246 (79%) constituted the “poor visual outcome” (PVO) group, subdivided into 70 (22%) with a VA of 0.3–1.0 logMAR (0.1–0.5 decimal) and 157 (57%) patients with a VA > 1.0 logMAR (P = 0.04), tumor localization ≤ 0.5 mm to the fovea (P P = 0.02 and P Conclusions Of 310 small- to medium-sized pcM patients successfully treated with PT, 21% retained a VA ≤ 0.2 logMAR (≥ 0.6 decimal) for at least 5 years. Strongest negative predictive factor for retaining good long-term vision was the volume of the macula irradiated with at least 30 Gy.

Background and purpose This study analyses the dosimetric and dose averaged Linear Energy transfer (LETd) correlation in paediatric craniopharyngioma (CP) patients with and without radiation-induced cerebral vasculopathies (RICVs) treated with pencil beam scanning (PBS) proton therapy (PT). Material and methods We reviewed a series of 16 CP patients treated with PT to a median dose of 54 Gy(RBE). Two (12.5%) index patients presented RICVs 14 and 24 months (median, 19) after PT. Organs at risks (OARs) as bilateral internal carotid arteries (ICAs) and circle of Willis were contoured based on CTs and MRIs pre- and post-PT. Dosimetry was reviewed and LETd distributions were calculated; LETd metric for PTVs and OARs were analysed. For a sub-cohort, dosimetric and LETd values robustness due to range uncertainties were computed. Results For the two index patients, no correlation was observed between RICVs and OARs doses. However for those patients mean(maximum) LETd values in the affected OARs were up to 4.0 ± 0.4 (7.8 ± 0.1)keV/μm; those LETd values were significantly higher (p = 0.02) than the mean(maximum) LETd values for the rest of the cohort (mean: 3.1 ± 0.3, maximum: 4.8 ± 1.0 keV/μm). This was due to asymmetric field arrangement, thus resulting in marked asymmetric LETd distributions. For such arrangement, maximum LETd values variations in vascular structures due to range uncertainties were up to 1.2 keV/μm, whilst for the symmetric one they were up to 0.7 keV/μm. Conclusions For children with and without RICVs, quantitative analysis showed a significant correlation with LETd average/maximum values in vascular structures, whilst no correlation was found on dosimetric parameters.

More efforts are required to minimise late radiation side-effects for paediatric patients. Pencil beam scanning proton beam therapy (PBS-PT) allows increased sparing of normal tissues while maintaining conformality, but is prone to dose degradation from interplay effects due to respiratory motion. We report our clinical experience of motion mitigation with volumetric rescanning (vRSC) and outcomes of children with neuroblastoma.Nineteen patients with high-risk (n = 16) and intermediate-risk (n = 3) neuroblastoma received PBS-PT. The median age at PBS-PT was 3.5 years (range 1.2-8.6) and the median PBS-PT dose was 21 Gy (relative biological effectiveness). Most children (89%) were treated under general anaesthesia. Seven patients (37%) underwent four-dimensional computed tomography for motion assessment and were treated with vRSC for motion mitigation.The mean result of maximum organ motion was 2.7 mm (cranial-caudal), 1.2 mm (left-right), 1.0 mm (anterior-posterior). Four anaesthetised children (21%) showing5 mm motion had four-dimensional dose calculations (4DDC) to guide the number of vRSC. The mean deterioration or improvement to the planning target volume covered by 95% of the prescribed dose compared with static three-dimensional plans were: 4DDC no vRSC, -0.6%; 2 vRSC, +0.3%; 4 vRSC, +0.3%; and 8 vRSC, +0.1%. With a median follow-up of 14.9 months (range 2.7-49.0) there were no local recurrences. The 2-year overall survival was 94% and distant progression-free survival was 76%. Acute grade 2-4 toxicity was 11%. During the limited follow-up time, no late toxicities were observed.The early outcomes of mainly high-risk patients with neuroblastoma treated with PBS-PT were excellent. With a subset of our cohort undergoing PBS-PT with vRSC we have shown that it is logistically feasible and safe. The clinical relevance of vRSC is debatable in anaesthetised children with small pre-PBS-PT motion of5 mm.

Purpose Ocular proton therapy is an effective therapeutic option for patients affected with uveal melanomas. An optical eye-tracking system (ETS) aiming at noninvasive motion monitoring was developed and tested in a clinical scenario. Materials and methods The ETS estimates eye position and orientation at 25 frames per second using the three-dimensional position of pupil and cornea curvature centers identified, in the treatment room, through stereoscopic optical imaging and infrared eye illumination. Its capabilities for automatic detection of eye motion were retrospectively evaluated on 60 treatment fractions. Then, the ETS performance was benchmarked against the clinical standard based on visual control and manual beam interruption. Results Eye-tracking system detected eye position successfully in 97% of all available frames. Eye-tracking system-based eye monitoring during therapy guarantees quicker response to involuntary eye motions than manual beam interruptions and avoids unnecessary beam interruptions. Conclusions Eye-tracking system shows promise for on-line monitoring of eye motion. Its introduction in the clinical workflow will guarantee a swifter treatment course for the patient and the clinical personnel.

Ecodiversity stems from the interaction between the biosphere and the geosphere, and it is one of the necessary conditions for achieving a sustainable planet. Thus, the relationship between geodiversity and biodiversity should be clearly defined. The relationship between climate and topography in roughened mountain areas at low-latitudes, as constrains for the high values of biodiversity, has already been established. As a consequence, topography is the first and most important input parameter for investigating the connections between abiotic and biotic variety. Spatial analysis in a GIS framework is the key approach to better understand the role of topographic and hydrographic variables in evaluating geodiversity (geomorphodiversity) .In this paper we focused on analyzing urban areas, where in 2030 60% of the world's population is expected to live. A science of cities is the future challenge for Earth Sciences: urban geomorphology could be the key to have a complete overview on the abiotic and biotic parameters in sustainable cities. To achieve this aim, the conservation of urban biodiversity is fundamental. Analysing the correlation between substantial geodiversity and biodiversity may be a guideline for science of cities and for designing and managing sustainable urban areas.These ideas, if transposed in an urban context, should go beyond morphometric analysis of topography and take into account anthropogenic features and natural landforms modified by humans in time. To this end, geomorphological mapping is fundamental to calibrate the quantitative models in a truly multidisciplinary approach to a science of cities and urban biodiversity. We consider our contribution as a new model for the analysis of geodiversity in urban areas.

BACKGROUND With improved survival rates for children with cancer, quality-of-life (QoL) issues have increasingly become the focus of attention. We report the QoL of children with Ewing sarcoma (EWS) treated with pencil-beam-scanning proton therapy (PT). METHODS A PEDQOL (QoL questionnaire for children 4-18 years) self/proxy questionnaire was used to prospectively assess the QoL of 23 children

Proton therapy (PT) is delivered to complex brain tumors to obtain an optimal curative treatment with limited toxicity. Value-based oncological medicine is increasingly important, particularly when long-term survival is to be expected. This study aims to evaluate health-related quality of life (HRQOL) and patient reported outcomes (PROs) in patients treated with PT for brain tumors. Adult patients with brain tumors treated with PT filled out the EORTC-QLQ-C30 and BN20 questionnaires up to three years following PT. Toxicity was scored using the CTCAE v4.03. QoL and PRO were correlated to clinical factors. Three-year overall survival, distant brain control and local control rates were 98%, 97% and 84%, respectively. No ≥G3 acute toxicity was observed. Late PT-related ≥G3 severe toxicity occurred in seven patients (5.7%). Lower global QoL scores after PT were significantly correlated to low Karnofsky performance status (KPS) before PT (p = 0.001), surgical complications before PT (p = 0.04) and progressive disease (p = 0.017). A low QLQ-30 summary score at one year follow-up was correlated to sex (p = 0.015), low KPS before PT (p &lt, 0.001), and central nervous system symptoms before PT (p = 0.018). Reported QLQ-BN20 neurological symptoms were correlated to lower KPS at baseline (p &lt, 0.001) and surgical complications before PT (p = 0.03). PT-related toxicity only influenced reported symptoms directly following PT, but not QoL. Although global QoL temporarily decreased after treatment, it improved again from one year onwards. Global QoL and reported symptoms over time were not correlated with the proton therapy and were more related to preexisting symptoms and progressive disease. This study assists in improving patient support in patients with brain tumors receiving PT.

BACKGROUND: Craniospinal irradiation (CSI) is an essential treatment component to achieve cure for some brain tumors in children and young adults/adolescents (C-AYAs). Multimodal treatment approaches are however associated with treatment-related late toxicities in these developing patients. Pencil beam scanning proton therapy (PBSPT) allows for a minimization of dose delivered to organs at risk and the brain integral dose and, thus, potentially also a reduction of radiation-induced adverse events. We report the clinical outcome and toxicity rates after CSI for C-AYAs treated with PBSPT. METHODS: We reviewed 71 C-AYAs with a median age of 7.4 years (1.7 – 21.3) who received CSI with PBSPT. Medullobastoma (n=42, 59%) and ependymoma (n=8, 11%) were the most common histologies. Thirty-four (48%) patients presented with metastatic disease at diagnosis. Sixteen (23%) patients were treated for tumor recurrence/progression and 9 (13%) patients underwent re-irradiation. Median prescribed total dose was 54 GyRBE (18 – 60.4) and median craniospinal dose 24 GyRBE (18 – 36.8). Toxicities were recorded according to CTCAE v5.0. RESULTS: With a median follow-up time of 24 months (2 – 195), 12 (17%) patients died due to progressive disease. Eight (11%) patients experienced local failure and 15 (21%) distant failure after PBSPT. Estimated 2-year OS, LC and DC was 86.9%, 86.0% and 80.4%, respectively. Grade 3 acute toxicity (thrombocytopenia, neutropenia, nausea) was observed in 5 (7%) patients. Late grade 3 toxicities (stroke, cataract and CNS necrosis) were observed in 3 (4%) patients, 8, 9 and 16 months after PBSPT, respectively. One (1%) patient developed grade 4 CNS necrosis 8 months after CSI. Late grade ≥3 toxicity free rate was 92.3% at 2 years. No radiation-induced secondary cancer was observed. CONCLUSION: Excellent tumor and brain/spinal distant control and a low late grade ≥3 toxicity rate after CSI were observed in our cohort of C-AYAs treated with PBSPT.

In the framework of geosite management, specific targeted symbols for geomorphological legends are still lacking. Concerning geosites of geomorphological interest, geomorphological mapping requires targeted symbols in relation to goals and applications, either concerning geomorphic hazards and risk detection or the enhancement of resources, in particular those related to cultural heritage and, hence, geoheritage. A new methodology for mapping geo(morpho)heritage on geomorphological maps is presented in this paper. Nine iconic examples from the Italian landscape, selected in different morphogenetic and morphoclimatic contexts, are proposed to test the methodology in relation to point, polyline and polygon features. Moreover, guidelines for mapping are suggested according to the importance of the site and to the complexity of processes characterizing each case study.

Background The use of proton therapy (PT) in adolescents and young adults (AYAs) is becoming increasingly popular. This study aims to assess the outcomes and late toxicity consequences in AYAs (15-39 years) with brain/skull base tumors treated with pencil beam scanning proton therapy. Methods One hundred seventy six AYAs treated curatively at the Paul Scherrer Institute (PSI) were identified. Median age was 30 years (range 15-39) and median prescribed dose was 70.0 Gy (relative biological effectiveness [RBE]) (range 50.4-76.0). The most common tumors treated were chordomas/chondrosarcomas (61.4%), followed by gliomas (15.3%), and meningiomas (14.2%). Results After a median follow up of 66 months (range 12-236), 24 (13.6%) local only failures and one (0.6%) central nervous system (CNS) distant only failure were observed. The 6-year local control, distant progression-free survival, and overall survival were 83.2%, 97.4%, and 90.2%, respectively. The 6-year high-grade (≥grade [G] 3) PT-related late toxicity-free survival was 88.5%. Crude late toxicity rates were 26.2% G1, 37.8% G2, 12.2% G3, 0.6% G4, and 0.6% G5. The one G4 toxicity was a retinopathy and one G5 toxicity was a brainstem hemorrhage. The 6-year cumulative incidences for any late PT-related pituitary, ototoxicity, and neurotoxicity were 36.3%, 18.3%, and 25.6%; whilst high-grade (≥G3) ototoxicity and neurotoxicity were 3.4% and 2.9%, respectively. No secondary malignancies were observed. The rate of unemployment was 9.5% pre-PT, increasing to 23.8% post-PT. Sixty-two percent of survivors were working whilst 12.7% were in education post-PT. Conclusions PT is an effective treatment for brain/skull base tumors in the AYA population with a reasonable late toxicity profile. Despite good clinical outcomes, around one in four AYA survivors are unemployed after treatment.

Purpose: We present a 3-dimensional patient-specific eye model from magnetic resonance imaging (MRI) for proton therapy treatment planning of uveal melanoma (UM). During MRI acquisition of UM patients, the point fixation can be difficult and, together with physiological blinking, can introduce motion artifacts in the images, thus challenging the model creation. Furthermore, the unclear boundary of the small objects (eg, lens, optic nerve) near the muscle or of the tumors with hemorrhage and tantalum clips can limit model accuracy., Methods and Materials: A dataset of 37 subjects, including 30 healthy eyes of volunteers and 7 eyes of UM patients, was investigated. In our previous work, active shape model was successfully applied to retinoblastoma eye segmentation in T1-weighted 3T MRI. Here, we evaluate this method in a more challenging setting, based on 1.5T MRI acquisition and different datasets of awake adult eyes with UM. The lens and cornea together with the sclera, vitreous humor, and optic nerve were automatically segmented and validated against manual delineations of a senior ocular radiation oncologist, in terms of the Dice similarity coefficient and Hausdorff distance., Results: Leave-one-out cross validation (mixing both volunteers and UM patients) yielded median Dice similarity coefficient values (respective of Hausdorff distance) of 94.5% (1.64 mm) for the sclera, 92.2% (1.73 mm) for the vitreous humor, 88.3% (1.09 mm) for the lens, and 81.9% (1.86 mm) for the optic nerve. The average computation time for an eye was 10 seconds., Conclusions: To our knowledge, our work is the first attempt to automatically segment adult eyes, including patients with UM. Our results show that automated active shape model segmentation can succeed in the presence of motion, tumors, and tantalum clips. These results are promising for inclusion in clinical practice. (C) 2018 Elsevier Inc. All rights reserved.

In historical urban centres, the superimposition of excavation and deposition activities over time has resulted in an irregular spatial distribution of anthropogenic deposits, which may reach considerable thicknesses. The detection of those thicknesses requires extensive investigations. Broad borehole and geophysical campaigns cost time and money, consequently at the urban-planning level, it is usual to shift to an estimation of thicknesses, which may be performed through map-algebra operations, that is, by subtracting from the modelled ground surface the elevation of the anthropogenic-deposit basal surface. The latter is implemented through the interpolation of point elevation data, which are generally provided by borehole logs. Despite the development of advanced spatial interpolation methodologies, previous modelling results in the literature show that if the process is affected by insufficient input data, it produces imprecise interpolation outputs. This paper reports an interdisciplinary methodology aiming at enhancing elevation datasets, in order to obtain more accurate digital elevation models. The increase in number and spatial distribution of input points is achieved through past-landscape analyses mainly based on elevation data given by borehole logs, available archaeological reports and historical topographic maps, these being generally available for historical urban centres. The methodology was tested in an urban sector of Rome, where significant activities have been performed for millennia particularly during the Roman Age. A reliable model of the basal surface of the anthrostrata led to a better estimation of the spatial distribution of such deposits and, in addition, revealed the original topographic surface, as modified by human activities.

Purpose By precalculation of an entire set of planning solutions for protons, penalizing them and providing a graphical navigator tool (Automated Treatment Planning [ATP]), we aim to improve the efficiency of the planning procedure for uveal melanoma (UM) and make it independent of treatment planner experience. Methods and Materials A phase space of plans is evaluated by transforming the eye model in each gaze angle, calculating cumulative dose-volume histograms for each position, and defining a dose-volume constraint for each considered structure. The final result is a map of the plan phase space, displaying how many criteria are fulfilled for each gaze angle. Results To test its usability and performance, ATP was used retrospectively on 48 UM patients treated with protons. In 36 of 48 cases (75%), the planning result was either the same (13 of 48, 27%) or comparable (23 of 48, 48%). In 11 of 48 evaluated cases (23%), ATP plans showed improvements. In 1 case (2%) the patient's visual acuity had been impaired, and an optimization was not possible. Conclusions We have developed a dose calculation and planning engine that prepares a set of treatment plans covering a wide range of theoretical clinically feasible gaze angles for a given patient, by precalculating the dose distributions for each gaze angle. By considering different structures and adapting their constraints, the identification of the optimal gaze angle can be realized. With a better understanding of the dose-volume constraints and the development of strategies to react to the trade-offs between considered structures, ATP may lead to a complete automation of the planning process for UM treated with proton therapy.

PURPOSE Over the last four decades, Ocular Proton Therapy has been successfully used to treat patients affected by intraocular lesions. For this, treatment geometry verification is routinely performed using radiographic images to align a configuration of fiducial radiopaque markers implanted on the sclera outer surface. This paper describes the clinical application of an alternative approach based on optical eye tracking for three-dimensional non-invasive and automatic eye localization. An experimental protocol was designed to validate the optical-based eye referencing against both radiographic imaging system and the clinically used EYEPLAN treatment planning system. METHODS The eye tracking system (ETS) was installed in the OPTIS 2 treatment room at PSI to acquire eye motions during the treatment of nine patients. The pupil position and the cornea curvature centre were localized by segmenting the pupil contour and corneal light reflections on the images acquired by a pair of calibrated optical cameras. After calibration of the ETS, a direct comparison of radiopaque markers position, and consequentially eye position and orientation, provided by the ETS, radiographs and EYEPLAN was performed. RESULTS Nineteen out of thirty total monitored fractions were excluded from the study due to poor visibility of corneal reflection, resulting in a success rate of acquisition of 37%. For this data, overall median agreement between ETS-based and X-ray based markers position assessment were 0.29 mm and 0.94 degrees for translations and rotations respectively. Small discrepancies were also measured in the eye centre estimates of the ETS and EYEPLAN. Conversely, variations in measured eye orientation were higher, with inter-quartile range (IQR) between 4.39° and 7.58°. Nonetheless, dosimetric evaluation of the consequence of ETS uncertainties showed that the target volume would still be covered by more than 95% of the dose in all cases. CONCLUSION An ETS was successfully installed in a clinical ocular proton therapy treatment room and used to monitor eye position and orientation in a clinical scenario. First results show the potential of such a system as an eye localization device. However, the low success rate prevents straightforward clinical application and needs further improvements aimed at increasing corneal reflection visibility. This article is protected by copyright. All rights reserved.

Urbanization is a global phenomenon and currently more than half of the world’s population lives in urban areas. Studies on geomorphological heritage and the development of specific methods of investigation (assessment, inventories, cartography) are, however, relatively rare and limited. This paper first describes the relationships between urbanization and geomorphology. Secondly, it presents an overview of the main works on the urban geomorphological heritage. Then, the main methods of investigation are presented. Finally, we discuss the challenging issues concerning the protection and the promotion of the urban geomorphological heritage.

Objective The aim of this study was to evaluate the outcome of patients with head and neck adenoid cystic carcinoma (ACC) treated using pencil beam scanning proton therapy (PBS PT) at our institution. Materials and methods Thirty-five patients who underwent treatment with PBS PT for ACC between 2001 and 2017 were included. Local control (LC), distant control (DC), progression-free survival (PFS), overall survival (OS) and their prognostic factors were evaluated. Adverse effects were prospectively assessed. Results The median patient follow-up was 30 months. Prior to PT, 26 patients (74.3%) underwent surgery with R0/R1/R2 outcome in 5, 13 and 8 cases, respectively. Nine patients (25.7%) presented with inoperable disease. The 2-year LC, DC, PFS and OS was 92.2%, 77.8%, 74.3% and 88.8%, respectively. LC was influenced by patient age (p = 0.002) with a significant difference between local and distant failure (median 61.3 vs. 42.3 years, p = 0.005). Tumor T stage was a significant risk factor for PFS (p = 0.045) and tumor prognostic group affected OS (p = 0.049). No significant survival advantage for operable vs. inoperable disease could be identified. The acute and late grade 3 toxicity rates were 14.3% and 6.1%, respectively. No acute or late grade 4/5 toxicities were observed. Conclusions PBS PT is an effective and safe treatment for patients with head & neck ACC in both definitive and adjuvant setting. Distant metastases are the main pattern of failure. Age, tumor stage and clinical stage had a significant negative impact on LC, OS and PFS.

Background Skull base chordomas are rare and heterogeneously behaving tumors. Though still classified as benign they can grow rapidly, are locally aggressive, and have the potential to metastasize. To adapt the treatment to the specific needs of patients at higher risk of recurrence, a pre-proton therapy prognostic grading system would be useful. The aim of this retrospective analysis is to assess prognostic factors and the “Sekhar Grading System for Cranial Chordomas” (SGSCC) by evaluating the larger cohort of patients treated at our institution as to determine its reproducibility and ultimately to ensure more risk adapted local treatments for these challenging tumors. Methods We analyzed 142 patients treated for skull base chordomas between 2004 and 2016. We focused the analysis on the 5 criteria proposed for the SGSCC (tumor size, number of anatomic regions and vessels involved, intradural invasion, as well as recurrence after prior treatment) and classified our patients according to their score (based on the above mentioned criteria) into three prognostic groups, low-risk, intermediate-risk and high-risk. The three groups were then analyzed in regards of local control, local recurrence-free survival and overall survival. Results The median follow up was 52 months (range, 3–152). We observed 34 (24%) patients with a local recurrence, resulting in a local control of 75% at 5 years. Overall survival was 83% at 5 years, 12 (9%) patients had died due to local progression. When split into the three prognostic groups according to the SGSCC the observed local control was 90, 72 and 64% (p = 0.07) in the low-, intermediate- and high-risk group, respectively. A similar correlation was observed for local recurrence-free survival with 93, 89 and 66% (p = 0.05) and for overall survival with 89, 83 and 76% (p = 0.65) for the same prognostic groups. Conclusions After splitting our patient cohort into the three SGSCC risk groups, we found a trend towards better outcome for those patients with lower as opposed to higher scores. These results suggest that this prognostic grading system published by Sekhar et al. could be integrated in the management decision-tree for patients with skull base chordoma., Radiation Oncology, 15 (1)

Human cancers exhibit phenotypic diversity that medical imaging can precisely and non-invasively detect. Multiple factors underlying innovations and progresses in the medical imaging field exert diagnostic and therapeutic impacts. The emerging field of radiomics has shown unprecedented ability to use imaging information in guiding clinical decisions. To achieve clinical assessment that exploits radiomic knowledge sources, integration between diverse data types is required. A current gap is the accuracy with which radiomics aligns with clinical endpoints. We propose a novel methodological approach that synergizes data volumes (images), tissue-contextualized information breadth, and network-driven resolution depth. Following the Precision Medicine paradigm, disease monitoring and prognostic assessment are tackled at the individual level by examining medical images acquired from two patients affected by intracranial ependymoma (with and without relapse). The challenge of spatially characterizing intratumor heterogeneity is tackled by a network approach that presents two main advantages: (a) Increased detection in the image domain power from high spatial resolution, (b) Superior accuracy in generating hypotheses underlying clinical decisions.

Aims The outcome of chordoma patients with local or distant failure after proton therapy is not well established. We assessed the disease-specific (DSS) and overall survival of patients recurring after proton therapy and evaluated the prognostic factors affecting DSS. Materials and methods A retrospective analysis was carried out of 71 recurring skull base (n = 36) and extracranial (n = 35) chordoma patients who received adjuvant proton therapy at initial presentation (n = 42; 59%) or after post-surgical recurrence (n = 29; 41%). The median proton therapy dose delivered was 74 GyRBE (range 62–76). The mean age was 55 ± 14.2 years and the male/female ratio was about one. Results The median time to first failure after proton therapy was 30.8 months (range 3–152). Most patients (n = 59; 83%) presented with locoregional failure only. There were only 12 (17%) distant failures, either with (n = 5) or without (n = 7) synchronous local failure. Eight patients (11%) received no salvage therapy for their treatment failure after proton therapy. Salvage treatments after proton therapy failure included surgery, systemic therapy and additional radiotherapy in 45 (63%), 20 (28%) and eight (11%) patients, respectively. Fifty-three patients (75%) died, most often from disease progression (47 of 53 patients; 89%). The median DSS and overall survival after failure was 3.9 (95% confidence interval 3.1–5.1) and 3.4 (95% confidence interval 2.5–4.4) years, respectively. On multivariate analysis, extracranial location and late failure (≥31 months after proton therapy) were independent favourable prognostic factors for DSS. Conclusion The survival of chordoma patients after a treatment failure following proton therapy is poor, particularly for patients who relapse early or recur in the skull base. Although salvage treatment is administered to most patients with uncontrolled disease, they will ultimately die as a result of disease progression in most cases.

Objective: To assess the radiation-induced optic neuropathy (RION) prevalence, following high dose pencil beam scanning proton therapy (PBSPT) to skull base and head and neck (H&N) tumours Methods: Between 1999 and 2014, 216 adult patients, median age 47 years (range, 18–77), were treated with PBS PT for skull base or H&N malignancies, delivering ≥45 GyRBE to the optic nerve(s) (ON) and/or optic chiasma (OC). The median administered dose to the planning target volume was 74.0 GyRBE (range, 54.0–77.4). The median follow-up was 5.3 years (range, 0.8–15.9). Results: RION was observed in 14 (6.5%) patients at a median time of 13.2 months (range, 4.8–42.6) following PBSPT. Most (92.9%) of RION were symptomatic. Most affected patients (11/14; 79%) developed unilateral toxicity. Grade 4, 3, 2 and 1 toxicity was observed in 10, 2, 1 and 1 patients, respectively. On univariate analyses, age (RBE was of border line significance (p = 0.06). None of the other evaluated OC–ON dose/volume metrics (Dmax, Dmean, V40-60) were significantly associated with this complication. Conclusion: These data suggest that high-dose PBS PT for skull base and H&N tumours is associated with a low prevalence of RION. Caution should be however exercised when treating elderly/hypertensive patients with tumours abutting the optic apparatus. Advances in knowledge: This is the first study reporting the risk of developing RION following proton therapy with PBS technique, demonstrating the safety of this treatment.

Purpose Synchrotron-based X-ray Phase Contrast Imaging (SR X–PCI) allows, thanks to a highly coherent and powerful X-ray beam, the imaging of surface and cross-sectional tissue properties with high absorption-contrast. The objective of this study is to investigate the sub-micron structure of the ossicular chain. The understanding of its morphological properties at sub-micron scale will help to refine the understanding of its structural properties. The investigation of intact, non-decalcified and unstained ossicular bones allows to study the spatial relationship between surface properties, internal structure and tomographical slides. Main results The tomography datasets with a pixel size of 0.65 μm were reconstructed and 3D volume rendering models of all specimens were analyzed. Based on surface models, the surfaces of the articulations, the insertion of the tensor tympani and stapedial muscle tendons and the nutritional foramina, where the vessels penetrate the ossicles, were visualized. Moreover, a branched network of inner channels could be represented and its connection to the nutritional foramen was demonstrated. Looking at the tomographic structure of the three ossicles a mineralization pattern for every auditory bone was described, indicating a considerable variation throughout the bones. Conclusions This study investigates the submicron-structure of the auditory ossicles at a pixel size of 0.65 μm, which is to the best of our knowledge the highest resolution reported in the investigation of the human auditory system so far. The provided data helps in the further understanding of the anatomical conformation of the ossicular chain.

Geotourism is a useful way to educate societies in the field of geomorphology and related natural hazards. Geosites, including geomorphosites, represent the basis for the development of this type of tourism. This study describes 12 representative gully regions within nine European countries. The characteristics of 42 permanent gullies, gully systems, and badland landscapes are presented. Based on scientific values of the sites, educational lessons to be learned were identified that are mainly related to (i) gullies as a geological window, (ii) present-day geomorphological processes and (iii) stages of historical gully erosion reflecting past human¿environment interactions. To evaluate possible education activities, a geotouristic assessment of the studied gullies and badlands was made, based on scientific, educational, functional and touristic indicators. This assessment demonstrates a large difference between the selected gully and badland sites, particularly with regard to functional and tourist values. The geotouristic potential of gullies (badlands) is the highest in Italy and Spain and the lowest in Romania and Latvia. In some countries, permanent gullies are not regarded as geotouristic attractions at all,while in others, they constitute a significant element of their tourism development strategy. In our opinion, all activities must be part of a broader strategy for the development of geotourism in gully and badland regions, for example, gullies may be included as geosites within existing or planned geoparks., The research in Slovakia was supported by the Slovak Research and Development Agency under the contract no. APVV0625-11. Estela Nadal-Romero was the recipient of a Ramón y Cajal postdoctoral contract (Spanish Ministry of Economy and Competitiveness). Geomorphic reclamation initiatives on gullies degraded by mining, in Central Spain, are supported by the Ecological Restoration Network 502 REMEDINAL-3 of the Madrid Community (S2013/MAE-2719).