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Brain metastasis is a rare and generally late manifestation of an advanced-stage, high-grade serous ovarian carcinoma. Nowadays, the improved control of intra-abdominal disease by surgery and platinum-based chemotherapy results in a longer survival, allowing distant metastasis to implant and grow in the brain parenchyma. Herein, we describe a unique case of a cerebellar metastasis from clear cell ovarian carcinoma that initially presented as a FIGO Stage IC cancer. Surprisingly, 6 mo after surgery, the patient was in good condition with complete disappearance of symptoms and no evidence of recurrence. This relatively good biologic behavior may be explained by the presence of a PIK3CA-activating mutation in exon 9 which as previously reported in the literature, may be associated with better prognosis. To the best of our knowledge, this is the first reported case of cerebellar metastasis from ovarian clear cell carcinoma. In the presence of neurological symptoms, both clinicians and pathologists must be aware of this rare possibility, to assure correct patient management and effective therapeutic options. Generally, the prognosis of epithelial ovarian cancer patients with brain metastases is poor. PIK3CA mutations could be a good prognostic indicator in clear cell carcinomas.

Objective: Deficient expression of mismatch repair proteins (MMR) has been suggested to be a predictor of resistance of atypical endometrial hyperplasia (AEH) and early endometrial carcinoma (EEC) to conservative treatment. Aims: To assess the predictive value of MMR immunohistochemistry in patients conservatively treated for AEH and EEC, and to calculate its predictive accuracy. Materials and methods: All patients with AEH or EEC conservatively treated with hysteroscopic resection plus progestins in two referral centers from January 2004 to July 2019 were retrospectively assessed. Immunohistochemistry for MMR was ad hoc performed. Study outcomes were: (i) the association of a deficient immunohistochemical expression of MMR with resistance and recurrence of AEH and EEC after conservative treatment, and (ii) the accuracy of MMR immunohistochemistry in predicting the outcome of conservative treatment. Relative risk (RR) for the associations, and sensitivity, specificity and area under the curve (AUC) on receiver operating characteristic curve for the predictive accuracy were calculated. Results: Sixty-nine women, (47 AEH and 22 EEC) were included; deficient MMR expression was observed in 8.7% of cases. Resistance to conservative treatment was more common in MMR-deficient than MMR-proficient cases (33.3% vs 15.9%; RR = 2.1), but with no statistical significance (p = 0.2508). On the other hand, recurrence was significantly more common in MMR-deficient than MMR-proficient cases (100% vs 26.4%; RR = 3.8; p < 0.0001). In predicting recurrence, a deficient immunohistochemical expression of MMR showed sensitivity = 22.2%, specificity = 100%, and AUC = 0.61. Conclusion: Deficient MMR immunohistochemical expression does not imply resistance of AEH/EEC to conservative treatment. On the other hand, MMR-deficiency appears as a highly specific predictor of recurrence of AEH/EEC after initial regression.

Background The aim of this study was to assess the agreement rate between intraoperative evaluation (IOE) and final diagnosis (FD) in a series of surgically resected endometrial carcinoma (EC), with a preoperative ambiguous or inconclusive diagnosis by endometrial biopsies and imaging. Methods A retrospective study was performed selecting patients who underwent surgery with IOE for suspected EC at our institution from 2012 to 2018. A K coefficient was determined with respect to the histotype, tumor grade, myometrial infiltration and cervical involvement. Results Data analysis has been performed on 202 women. The IOE evaluation was distributed as Endometrioid (n = 180) and Non-Endometrioid (n = 22). The comparison between the frozen section (FS) and the definitive histological subtype showed an overall agreement rate of 93,07% (k = 0.612) and an agreement of 97.2% for Endometrioid vs 59% for Non-Endometrioid tumors. The FIGO system grading was the same in 91,1% of patients, none was upgraded and in 8,9% downgraded. Observed agreements were 89,11% and 95,54% for myometrial and cervical involvement, respectively. Conclusions The good agreement between intraoperative grading, myometrial invasion and their histological definition on permanent sections highlights that FS is a good predictor for surgical outcome, in particular in presence of a preoperative ambiguous or inconclusive diagnostic evaluation.

Introduction/Background* Investigate the immunohistochemical (IHC) expression of biological markers as potential prognostic/therapeutic factors in vulvar squamous cell carcinoma (VSCC). Methodology A series of 101 patients surgically treated at our Center from 2016 to 2020 were retrospectively enrolled: 53 node negative (Group A) and 48 node positive (Group B). A total of 146 samples, 101 primary tumor (T) and 45 nodal metastasis (N), were investigated. The IHC panel included: p16, p53, MLH1, MSH2, MSH6, PMS2, PD-L1, CD3, HER2/neu, ER, PR, EGFR, VEGF and CD31. The reactions were evaluated on qualitative and semi-quantitative scale. Generalized Linear Model (GLM) and Cluster analysis were performed in R statistical environment. A distance plot compared the IHC panel of T with the correspondent N. Result(s)* Mismatch repair proteins (MMR), ER, PR and HER2/neu were excluded from data analysis because of homogeneous expression in all samples. Group A: the p16-positive expression (surrogate of HPV-dependent pathway) was significantly higher (20.8% vs 6.2%, p = 0.04). Group B: PD-L1-positive and high EGFR expression were found respectively in 77.1% and 97.9% patients, (T and/or N). Overall, p16-negative tumors showed a higher PD-L1 expression (60.9% vs. 50.0%). In both groups tumoral immune infiltration (CD3 expression), was mainly moderate/intense (80% vs. 95%). VEGF showed strong/moderate-diffuse expression in 13.9% of T samples. CD31 was used to study tumoral micro vessel density (MVD) with no difference between Group A and Group B. p53 and PD-L1 showed a significant association with nodal metastasis. Odds ratio (OR) for p53 mutation was 4.26 (CI 95% = 1.14 – 15.87, p = 0.03); OR for PD-L1 positivity was 2.68 (CI 95% = 1.0 – 7.19, p The cluster analysis identified 3 and 4 sub-groups of molecular profiles respectively in Group A and B, with no different prognosis. Moreover, the molecular profile of each N and corresponding T diverged significantly in 18/41 (43.9%) cases. Conclusion* These results support a potential role of immune checkpoint inhibitors and anti-EGFR drugs in a subset of patients with VSCC, especially with worse prognosis (metastatic, HPV-independent). It is mandatory to repeat the panel in the metastatic site to identify changes of marker expression.

Simple Summary PD-1/PD-L1 axis blockade immunotherapy leverages on assessment of tumour PD-L1 status by immunohistochemistry for identifying cancer patients’ who would benefit most from this therapy. Because some PD-L1 negative cancer patients also benefit from the treatment, it has been postulated that spatial heterogeneity of PD-L1 expression in tumour tissue may reduce the predictive value of the test. Here we demonstrate for the first time the presence of PD-L1+ circulating tumor–derived microvesicles in the blood stream of high grade serous ovarian cancer patients and propose the assessment of tumor-derived circulating PD-L1+ microvesicles to be inserted in predictive algorithms for complementing tumour PD-L1 status. Abstract Background: Ovarian cancer (OC) has recently attracted attention for the use of PD-1/PD-L1 axis blocking agents, with durable activity reported only in a subset of patients. The most used biomarker for sensitivity to the PD-1/PD-L1 axis blockade is tumour PD-L1 status by immunohistochemistry. However, patient stratification using this method suffers from intrinsic heterogeneity of OC, likely contributing to the unsatisfactory results obtained so far. Cells communicate with each other by releasing microvesicles (MVs) that carry parental cell surface features. Thus, we hypothesised that PD-L1+ tumour cells (TC) and infiltrating PD-L1+ leukocytes should shed MVs carrying surface PD-L1 that may serve as a proxy for the whole tumour PD-L1 status. Results: We showed for the first time the presence of measurable amounts of TC- and leukocyte-derived PD-L1+ MVs (range: 1.4–178.8 MVs/μL and 6.2–504.8 MVs/μL, respectively) in the plasma of high-grade serous OC (HGSOC) patients (n = 63), using a sensitive flow cytometry platform. The concentration of PD-L1+ MVs of either origin did not associate with the PD-L1 status of TCs and leukocytes in the tumour biopsies, suggesting that the circulating PD-L1+ MVs also included ones from locations not selected for immunohistochemistry analysis and represented the PD-L1 status of the whole tumour mass. In this study, we also describe the serendipitous discovery of circulating PD-L1+ MVs of platelet origin (10.3–2409.6 MVs/μL). Conclusions: The enumeration of circulating PD-L1+ MVs in HGSOC patients may provide a novel direction for assessing the tumour PD-L1 status and contribute to HGSOC patient stratification for immunotherapy interventions. The presence of circulating PD-L1+ MVs of platelet origin, a finding not yet reported in HGSOC patients, warrants further studies.

Postmastectomy radiation therapy is technically difficult and can be considered one of the most complex techniques concerning patient setup reproducibility. Slight patient setup variations - particularly when high-conformal treatment techniques are used - can adversely affect the accuracy of the delivered dose and the patient outcome. This research aims to investigate the inter-fraction setup variations occurring in two different scenarios of clinical practice: at the reference and at the current patient setups, when an image-guided system is used or not used, respectively. The results were used with the secondary aim of assessing the robustness of the patient setup procedure in use. Forty eight patients treated with volumetric modulated arc and intensity modulated therapies were included in this study. EPID-based in vivo dosimetry (IVD) was performed at the reference setup concomitantly with the weekly cone beam computed tomography acquisition and during the daily current setup. Three indices were analyzed: the ratio R between the reconstructed and planned isocenter doses, γ % and the mean value of γ from a transit dosimetry based on a two-dimensional γ -analysis of the electronic portal images using 5% and 5 mm as dose difference and distance to agreement gamma criteria; they were considered in tolerance if R was within 5%, γ % > 90% and γ mean < 0.4. One thousand and sixteen EPID-based IVD were analyzed and 6.3% resulted out of the tolerance level. Setup errors represented the main cause of this off tolerance with an occurrence rate of 72.2%. The percentage of results out of tolerance obtained at the current setup was three times greater (9.5% vs 3.1%) than the one obtained at the reference setup, indicating weaknesses in the setup procedure. This study highlights an EPID-based IVD system's utility in the radiotherapy routine as part of the patient's treatment quality controls and to optimize (or confirm) the performed setup procedures' accuracy.

The ability to access user-friendly, low-cost instrumentation remains a limiting factor in coastal ocean observing. The majority of currently available marine observation equipment is difficult to deploy, costly to operate, and requires specific technical skills. Moreover, a harmonized observation program for the world’s coastal waters has not yet been established despite the efforts of the global ocean organizations. Global observational systems are mainly focused on open ocean waters and do not include coastal and shelf areas, where models and satellites require large data sets for their calibration and validation. Fortunately, recent technological advances have created opportunities to improve sensors, platforms, and communications that will enable a step-change in coastal ocean observing, which will be driven by a decreasing cost of the components, the availability of cheap housing, low-cost controller/data loggers based on embedded systems, and low/no subscription costs for LPWAN communication systems. Considering the above necessities and opportunities, POGO’s OpenMODs project identified a series of general needs/requirements to be met in an Open science development framework. In order to satisfy monitoring and research necessities, the sensors to be implemented must be easily interfaced with the data acquisition and transmission system, as well as compliant with accuracy and stability requirements. Here we propose an approach to co-design a cost-effective observing modular instrument architecture based on available low-cost measurement and data transmission technologies, able to be mounted/operated on various platforms. This instrument can fit the needs of a large community that includes scientific research (including those in developing countries), non-scientific stakeholders, and educators.

This study investigates the relationship between sediment contamination and hydrodynamic conditions in the Gaeta Gulf (Tyrrhenian Sea, Italy), an anthropogenically impacted and sheltered coastal area. The pollution levels, potential toxicity, and ecological risk of trace metals were analysed in 16 sediment sampling sites using Sediment Quality Guidelines (SQGs), the Adverse Effect Index (AEI), and the Mean ERM Quotient (m-ERM-Q). The bottom shear stress of the study area, evaluated using an annual simulation of a 3D numerical model, was used to calculate a new Sediment Mobilisation Index (SMI) that detects the coastal zones where a low probability of sediment resuspension occurs. As, Ni, and Cu concentrations exceeded the Threshold Effects Level (TEL) guideline value and AEI limit in several sampling sites, indicating their ability to produce adverse effects on biota. Moreover m-ERM-Q showed the highest values of potential ecological risk in most of the sampling sites located in the inner part of the Gulf of Gaeta. In this area, the highest SMI values were also identified, demonstrating that there is a tight relationship between the two indexes (R2 = 0.8214). The application of SMI in sheltered areas will help achieve high performance of monitoring and hazard assessment tools through obtaining predictable responses on hotspot identification.

The expansion of Civitavecchia Hub Port will potentially produce an impact on the adjacent coastal areas which are characterized by the presence of SCIs (Sites of Community Importance IT6000005 northern and IT6000006 southern to the port area) which extend in front of the municipalities of Tarquinia, Civitavecchia and Santa Marinella.The two SCIs are characterized by priority habitats and species under the Habitat Directive 92/43 / EEC; in particular, they host Posidonia oceanica meadows (Priority habitat 1120 * - Posidonion oceanicae) and coralligenous bioconstructions (Habitat 1170 - Reefs), as well as individuals of Pinna nobilis (Annex IV - Habitat Directive Code 1028) and colonies of Corallium rubrum ( Annex IV - Habitat Directive Code 1001).Within VIA and VAS procedures, a series of complex activities has been implemented to reduce the potential impacts on the marine environment, leading to the presentation of an innovative ecosystem-based program of mitigation and compensation measures based on the assessment of direct and indirect impacts of construction activities as well as ecosystem services analysis. This new program is based on our project "Ecosystem-based approach applied to the evaluation of compensation and mitigation measures in marine environment: The case study of the Port Hub of Civitavecchia". The project includes for example: a detailed analysis of marine habitats and oceanographic conditions, restoration of equivalent habitats, habitats and species protection systems, actions towards an eco-sustainable use of the environment. The innovation of this approach derives from the quantification of the interventions which is based on the assessment of surfaces damage as well as on the uses affected both directly and indirectly, considering a time interval of ten years for the recovery of the damaged ecosystem functions.

We evaluated an EPID-based in-vivo dosimetry (IVD) method for the dose verification and the treatment reproducibility of lung SBRT-VMAT treatments in clinical routine. Ten patients with lung metastases treated with Elekta VMAT technique were enrolled. All patients were irradiated in five consecutive fractions, with total doses of 50 Gy. Set-up was carried out with the Elekta stereotactic body frame. Eight patients were simulated and treated using the Active Breath Control (ABC) system, a spirometer enabling patients to maintain a breath-hold at a predetermined lung volume. Two patients were simulated and treated in free-breathing using an abdominal compressor. IVD was performed using the SOFTDISO software. IVD tests were evaluated by means of (a) ratio R between daily in-vivo isocenter dose and planned dose and (b) gamma-analysis between EPID integral portal images in terms of percentage of points with gamma-value smaller than one (gamma(%)) and mean gamma-values (gamma(mean)) using a 3%(global)/3 mm criteria. Alert criteria of +/- 5% for R ratio, gamma(%) < 90%, and gamma(mean) > 0.67 were chosen. 50 transit EPID images were acquired. For the patients treated with ABC spirometer, the results reported a high level of accuracy in dose delivery with 100% of tests within +/- 5%. The gamma-analysis showed a mean value of gamma(mean) equal to 0.21 (range: 0.04-0.56) and a mean gamma(%) equal to 96.9 (range: 78-100). Relevant discrepancies were observed only for the two patients treated without ABC, mainly due to a blurring dose effect due to residual respiratory motion. Our method provided a fast and accurate procedure in clinical routine for verifying delivered dose as well as for detecting errors.

We evaluate the combined usage of two systems, the Integral Quality Monitor (IQM) transmission detector and SoftDiso software, for in vivo dose monitoring by simultaneous detection of delivery and patient setup errors in whole breast irradiation. An Alderson RANDO phantom was adapted with silicon breast prostheses to mimic the female anatomy. Plans with simulated delivery errors were created from a reference left breast plan, and patient setup errors were simulated by moving the phantom. Deviations from reference values recorded by both monitoring systems were measured for all plans and phantom positions. A 2D global gamma analysis was performed in SoftDiso for all phantom displacements. Both IQM signals and SoftDiso R-values are sensitive to small MU variations. However, only IQM is sensitive to jaw position variations. Conversely, IQM is unable to detect patient positioning errors, and the R-value has good sensitivity to phantom displacements. A gamma comparison analysis allows one to determine alert thresholds to detect phantom shifts or relatively large rotations. The combined use of the IQM and SoftDiso allows for fast identification of both delivery and setup errors and substantially reduces the impact of error identification and correction on the treatment workflow.

To investigate critical aspects and effectiveness of in vivo dosimetry (IVD) tests obtained by an electronic portal imaging device (EPID) in a multicenter and multisystem context. Eight centers with three commercial systems—SoftDiso (SD, Best Medical Italy, Chianciano, Italy), Dosimetry Check (DC, Math Resolution, LCC), and PerFRACTION (PF, Sun Nuclear Corporation, SNC, Melbourne, FL)—collected IVD results for a total of 2002 patients and 32,276 tests. Data are summarized for IVD software, radiotherapy technique, and anatomical site. Every center reported the number of patients and tests analyzed, and the percentage of tests outside of the tolerance level (OTL%). OTL% was categorized as being due to incorrect patient setup, incorrect use of immobilization devices, incorrect dose computation, anatomical variations, and unknown causes. The three systems use different approaches and customized alert indices, based on local protocols. For Volumetric Modulated Arc Therapy (VMAT) treatments OTL% mean values were up to 8.9% for SD, 18.0% for DC, and 16.0% for PF. Errors due to “anatomical variations” for head and neck were up to 9.0% for SD and DC and 8.0% for PF systems, while for abdomen and pelvis/prostate treatments were up to 9%, 17.0%, and 9.0% for SD, DC, and PF, respectively. The comparison among techniques gave 3% for Stereotactic Body Radiation Therapy, 7.0% (range 4.7–8.9%) for VMAT, 10.4% (range 7.0–12.2%) for Intensity Modulated Radiation Therapy, and 13.2% (range 8.8–21.0%) for 3D Conformal Radiation Therapy. The results obtained with different IVD software and among centers were consistent and showed an acceptable homogeneity. EPID IVD was effective in intercepting important errors.

ObjectiveWe compared ultrastaging and one-step nucleic acid amplification (OSNA) examination of sentinel lymph nodes in two homogeneous patient populations diagnosed with early stage cervical cancer. The primary aim of our study was to evaluate the rate and type of sentinel lymph node metastases detected by ultrastaging and OSNA assay. Secondary aims were to define the sensitivity and the negative predictive value of sentinel lymph node biopsy assessed with OSNA and ultrastaging and to define the role of sentinel lymph node assessment in predicting non-sentinel lymph node status.MethodsConsecutive patients who underwent surgery (radical hysterectomy or trachelectomy or cervical conization) at our institution, between January 2018 and March 2020, were enrolled. All patients had a preoperative diagnosis of early-stage cervical carcinoma (International Federation of Gynecology and Obstetrics (FIGO) 2018 stages IA–IIB) and underwent sentinel lymph node assessment with ultrastaging or OSNA. Patients with advanced FIGO stages and special histology subtypes (other than squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma) or patients with sentinel lymph nodes analyzed only with hematoxylin and eosin were excluded. Clinical data were compared using the χ2 test and Fisher’s exact test. A κ coefficient was determined with respect to lymph node assessment. A p value ResultsA total of 116 patients were included in this retrospective analysis (53 ultrastaging, 63 OSNA). Overall, 531 and 605 lymph nodes were removed in the ultrastaging and OSNA groups, respectively, and 140 and 129 sentinel lymph nodes were analyzed in the ultrastaging and OSNA groups, respectively. 22 patients had metastatic sentinel lymph nodes: 6 (11.3%) of 53 patients in the ultrastaging group and 16 (25.4%) of 63 patients in the OSNA group. The total amount of positive SLNs was 7 (5%) of 140 in the ultrastaging group and 21 (16.3%) of 129 in the OSNA group, respectively (p=0.0047). Pelvic lymphadenectomy was performed in 26 (49.1%) of 53 patients in the ultrastaging group and in 34 (54%) of 63 patients in the OSNA group due to comorbidities. Metastatic non-sentinel lymph nodes were found in 4 patients: 2 (7.7%) of 26 patients in the ultrastaging group and 2 (5.9%) of 34 patients in the OSNA group, respectively. The total amount of positive pelvic lymph nodes was 3 (0.6%) of 531 in the ultrastaging group and 4 (0.7%) of 605 in the OSNA group (p=0.61). In the OSNA group, only 2 patients with negative sentinel lymph nodes had metastatic disease in the pelvic lymph nodes. By contrast, no patients with OSNA-positive sentinel lymph nodes had metastases in the pelvic lymph nodes. In the ultrastaging group, all patients with negative sentinel lymph nodes did not have metastatic disease in other pelvic lymph nodes.ConclusionsOSNA assessment of sentinel lymph nodes was associated with a negative predictive value of 91% but poor reliability in detecting node metastases in non-sentinel pelvic lymph nodes. Of note, the ultrastaging protocol revealed higher sensitivity and more reliability in predicting pelvic non-sentinel lymph node status.

Dissolved organic matter present in natural aquatic environments is a heterogeneous mixture of allochthonous and autochthonous materials. In coastal areas vulnerable to sewage waste, its biologically active component, the chromophoric dissolved organic matter (CDOM), is expected to change its composition and distribution in relation to anthropogenic activities, suggesting the possible use of CDOM as a proxy of fecal contamination. This study aimed at testing such hypothesis by investigating and relating the optical properties of CDOM with Escherichia coli abundance, physiological state, and enzymatic activities in a bathing area of the Northern Tyrrhenian Sea (Latium, Italy) affected by urban wastewaters. The parallel factor analysis (PARAFAC) applied to the excitation&ndash, emission matrices (EEMs) of CDOM allowed us to distinguish three main components: C1 (&lambda, Ex/&lambda, Em = 342 nm/435 nm), C2 (&lambda, Em = 281&ndash, 373 nm/460 nm), and C3 (&lambda, Em = 286 nm/360 nm). C1 and C2 corresponded to humic acids of terrestrial origin, while C3 to tryptophan, whose fluorescence peak was detected close to sewage sites, strongly related to active E. coli cells. The comparison between spectral and microbiological methods is suggested as a suitable approach to monitor bathing water quality for the implementation of coastal observing system capability.

Background. Gynecological neuroendocrine neoplasms (NENs) are extremely rare, accounting for 1.2&ndash, 2.4% of the NENs. The aim of this study was to test cervical NENs for novel markers of potential utility for differential diagnosis and target therapy. Methods. All cases of our center (n = 16) were retrieved and tested by immunohistochemistry (IHC) for 12 markers including markers of neuroendocrine differentiation (chromogranin A, synaptophysin, CD56), transcription factors (CDX2 and TTF1), proteins p40, p63, p16INK4a, and p53, somatostatin receptors subtypes (SST2-SST5) and the proliferation marker Ki67 (MIB1). Results. All cases were poorly differentiated neuroendocrine carcinomas (NECs), 10 small cell types (small cell&ndash, neuroendocrine carcinomas, SCNECs) and 6 large cell types (large cell&ndash, neuroendocrine carcinomas, LCNECs), in 3 cases a predominant associated adenocarcinoma component was observed. Neuroendocrine cancer cells expressed at least 2 of the 3 tested neuroendocrine markers, p16 was intensely expressed in 14 (87.5%) cases, SST5 in 11 (56.25%, score 2&ndash, 3, in 9 cases), SST2 in 8 (50%, score 2&ndash, 3 in 8), CDX2 in 8 (50%), TTF1 in 5 (31.25%), and p53 in 1 case (0.06%). P63 and p40 expressions were negative, with the exception of one case that showed moderate expression for p63. Conclusions. P40 is a more useful marker for the differential diagnosis compared to squamous cell carcinoma. Neither CDX2 nor TTF1 expression may help the differential diagnosis versus potential cervical metastasis. P16 expression may suggest a cervical origin of NEC, however, it must be always integrated by clinical and instrumental data. The expression of SST2 and SST5 could support a role for SSAs (Somatostatin Analogues) in the diagnosis and therapy of patients with cervical NECs.

The coastal marine system is characterized by multiple uses and it represents a vulnerable area highly subjected to anthropogenic pressures. Coastal marine ecosystems monitoring therefore requires an integrated multidisciplinary approach. The modeling of marine coastal dynamics and processes and the development of new observational technologies are fundamental in order to increase the available amount of data needed for the application of integrated approaches. New technologies and coastal observation networks are therefore a priority of the Global Ocean Observation System (GOOS) and of the Agenda 2030 strategy to improve the sustainable management of marine ecosystems and to contribute to future climate change scenarios. In this context a big effort is carried out by existing observing programs (ARGO, DPCP, GO-SHIP, OceanSITES, SOOP), which focus on open ocean waters and do not cover coastal areas. To do this, a significant reduction in the costs of platforms and instruments is necessary while maintaining sufficient measurement precision and consequently data quality. To face this issue, an Arduino based technology has been developed starting from the Tree-Talker-Cloud Technology (TT-Cloud board), a data acquisition and transmission system to monitor the health of trees and the impacts of climate change. From this technology, a new low-cost board, TT-Marine, has been developed, characterized by a high modularity allowing to manage the sensors by different types of communication protocols: RS232, UART, i2c, RS485; analog sensors can be managed by 16 and 24 bit AD converters. Depending on the characteristics and opportunities of the site, the system can manage LoRa, WiFi, gprs/gsm or cable data transmission systems. The TT-Marine is designed to be used in different modes: autonomous, ship-like as a profiler, on buoys and other measuring platforms.Here we present several operating modalities, with different missions and instrumental configurations.

In this paper we propose the notion of “subjective reference” as a conceptual tool that explains how and why human-robot sexual interactions could reframe users approach to human-human sexual interactions. First, we introduce the current debate about Sexual Robotics, situated in the wider discussion about Social Robots, stating the urgency of a regulative framework. We underline the importance of a social-relational approach, mostly concerned about Social Robots impact in human social structures. Then, we point out the absence of a precise framework conceptualizing why Social Robots, and Sexual Robots in particular, may modify users’ sociality and relationality. Within a psychological framework, we propose to consider Sexual Robots as “subjective references”, namely objects symbolically referring to human subjects: we claim that, for the user experience, every action performed upon a Sexual Robot is symbolically directed toward a human subject, including degrading and violent practices. This shifting mechanism may transfer the user relational setting from human-robot interactions to human-human interactions.

The progressive integration of Environmental, Social and Governance (ESG) issues into the corporate decision making is a cultural change process, which can be described, planned, measured. It speeds up sustainable transformation of governance, strategies and business models of companies. The first edition of this Report analysed the changes in some key behaviours of the company organisation and of the board of directors (BoDs) in the occasion of the first year of implementation of the Directive 2014/95/UE, transposed in Italy by the Legislative Decree no. 254/2016 (the Decree). This second edition of the Report measures the progression of behaviours analysed in 2019 and surveys additional actions considered important for the transformation. The first section focuses on non-financial reporting and on the abstracts of Strategic plans presented to investors in order to study the evolution of corporate culture and organisation towards ESG/multicapital integration. Subsequently, the Report explores whether companies consider non-financial issues relevant also at the board level, through both a documental analysis (based on the examination of the guidelines issued by companies prior to the 2019 board appointment and of the corporate governance reports; second section) and a Survey involving directors and statutory auditors that are members of Nedcommunity, the Italian Association of non-executive and independent directors, carried out for the fourth year by Nedcommunity and Methodos (third section). In order to track the progression of the cultural transformation, the information collected in this Report was clustered in three stages: Awareness, Capabilities and Engagement (see the chart below). Awareness is the precondition for change. It gathers behaviours of the company structure and the BoDs that are coherent with a first acknowledgement of the importance of ESG issues and that could kick-off the transformation process. Compared to 2018, the number of companies acting the different behaviours in the Awareness cluster is unchanged or has in some cases increased. The area Capabilities is intermediate in the transformation journey, when new skills, behaviours and mindsets are trained to accelerate the process. Compared to the previous year, this area records improvements, which in some cases are significant. This is the case of the behaviours linked to stakeholder engagement in the materiality analysis: external stakeholder engagement is indeed described in 70 cases (44 last year); engagement with the top management rose from 47 to 69 cases. There is also a slight increase in the number of companies integrating their reporting tools (from 9 to 11). With regards to boards, improvements are found in the integration of ESG into board renewal guidelines and in the board self-evaluation. The integration of remuneration packages with ESG criteria is also included in this intermediate phase because it is considered a driver towards change. The area Engagement is the most advanced in the ESG/multicapital transformation of strategies and business models. In this phase new behaviours are spontaneously carried out by the boards and the corporate organisation. This part of the analysis covers the abstracts of the Strategic plans presented to investors in the road shows, published in the Investor Relation section of the websites of the companies, in order to verify how and to what extent they describe a strategy that integrates financial and non-financial issues. Five companies (all in the Energy/Oil and Gas industry) fully integrate in their strategy issues that generate value in the short and long term and describe the connections between financial and non-financial matters. Among these companies, one mentions the materiality analysis as a pillar of its Strategic plan.

Background: The chemotherapy response score (CRS) has emerged as a simple and reproducible histopathological grading system for assessing chemotherapy response in patients affected by ovarian high-grade serous carcinoma. Objective: To evaluate the prognostic impact of histological tumor response in ovarian and omental surgical specimens from patients with advanced stage ovarian high-grade serous carcinoma. Study Design: A cohort of 161 women were identified from the database of Department of Gynecology, “Fondazione Policlinico Universitario Agostino Gemelli IRCCS” of Rome, Italy between January 2014 and December 2017 with a follow-up of 65 months. All the omentum, the ovarian tissue and peritoneal samples, defined as “other sites,” were reviewed by gynecological pathologists to assign a CRS of 1–3 to the omentum and ovarian sites and a score of 0–1 to the peritoneal tissue. The Cox proportional hazards regression and the log-rank test were used to assess the survival pattern and the prognostic value of the CRS adjusting for age and stage. The Kaplan-Meier method was applied to estimate the progression free and overall survival. Results: The evaluation of adnexal disease showed significant differences in PFS, both in univariate and in multivariate analyses. On PFS univariate analysis, ovCRS1 vs. ovCRS3: HR, 2.27; 95% CI, 1.37–3.77; p = 0.001; ovCRS2 vs. ovCRS3: HR, 1.83; 95% CI, 1.03–3.23; p = 0.04, and on PFS multivariate model ovCRS1 vs. ovCRS3; HR, 2.53; 95% CI, 1.5–4.24; p = 0.001 and ovCRS2 vs. ovCRS3; HR, 1.90; 95% CI, 1.08–3.37; p = 0.03. Regarding the omental residual disease, as expected, CRS showed a significant prognostic value for OS and PFS; in detail the median PFS of patients with CRS1, 2 and 3 was 15, 15, and 22 months, respectively, the median OS was 41 and >50 months, respectively. Moreover, the univariate analysis for OS suggested that in our cohort the “other sites” score of 0 was significantly associated with an improvement in overall survival compared to score 1. Conclusions: We demonstrated for the first time the prognostic significance of adnexal CRS confirming also the prognostic role of omental CRS.

Celiac disease (CD) is a systemic inflammatory disease, which primarily affects the gastrointestinal tract. It has been recently demonstrated that adipose-tissue infiltration by proinflammatory immune cells causes a chronic low-grade inflammation in obese patients. Magnetic resonance imaging (MRI) has already proved to be useful in evaluation of inflammatory states. The aim of the present study was to determine whether alterations of visceral and subcutaneous adipose tissue, identified with MRI, could serve as markers of local and systemic inflammation in patients with CD. A pilot study was conducted comparing alterations in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in CD patients vs obese patients and healthy controls. Fifty patients were enrolled and assigned to one of the following groups: Group A: 11 active CD patients; Group B: 11 CD patients in remission; Group C: 16 obese patients; Group D: 12 healthy controls. A 3-T MRI unit was used and T2-weighted TSE images of VAT and SAT were obtained in specific regions of interest. Serum cytokine concentrations (TNF-α, IL-6, adiponectin, leptin, IL-2, IFN-γ) were determined. There was a significant difference in VAT T2 relaxation time between Group A and B (p

Since financial inclusion has become a policy target in many countries, it is crucial to measure it properly. The usual indexes of financial inclusion include inappropriate variables and do not take into account other relevant aspects, thus misrepresenting the phenomenon. In this paper, we focus on the distribution of electronic cards, generally not included in the usual indexes of financial inclusion even if they provide alternatives to usual saving practices and make transactions across larger markets and wider geographic areas less costly. We show that if we also take account of these instruments, the comparative valuation of the degree of financial inclusion across the main euro-area countries changes substantially. We also employ survey data to analyse cross-country differences in the degree of financial inclusion and the distribution of multidimensional deprivations of specific sub-groups of populations.

Industrial and commercial, together with touristic and ecological, are two of the main uses of the Civitavecchia coastal area that bring wealth and of course influence this marine ecosystem. The port, one of the most important in the Mediterranean Sea, recorded in the last three decades a major increment of its commercial traffic, becoming also strategic for important Mediterranean cruise routes and for passenger flow. New passenger facilities and enhanced and enlarged wharfs allowed to increment the hosted cruise liners from 50 ships in 1996 to 500 in 2003. The creation of new quays and the extension of the anti-mural dame caused on the ecosystems a direct and indirect impact due to the modification of the currents and the dispersion of the dredged materials. The characterisation and assessment of the coastal marine environment of Civitavecchia and its surroundings constitutes, since its creation in 2001, is one of the main activities of the Laboratory of Experimental Oceanology and Marine Ecology (LOSEM) of Tuscia University, who studied the impact of anthropic activities and the influence of climatic events, investigating the chemical and physical parameters of both water column and sediments. Benthic biocenoses and Posidonia oceanica were used to evaluate benthos geochemical and ecological characteristics and a specific effort was devoted to hypothesize the possible incidence of dredging works on the benthic ecosystem. The results of the research activities are synthetically reviewed in this paper.

Background. Extra-mammary Paget’s disease (EMPD) is a rare neoplasm of epithelial origin, whose precise incidence is not clear. Starting from what is already known, we performed a systematic review and meta-analysis to investigate in male and female patients the immunohistochemical expression of biological markers that could serve as potential prognostic/therapeutic factors, including only human epidermal growth factor receptor 2 (HER2/neu), Estrogen Receptor (ER), Progesterone Receptor (PR), and Androgen Receptor (AR). Methods. A literature search was performed of the PubMed, Scopus, and Web of Science databases for English-language studies published from January 2000 to June 2020. Results. A total of 27 studies with 713 patients assessed the role of HER2/neu, AR, ER, and PR expression in male and female with EMPD. The overall rate of HER2/neu expression was 30%, the expression’s rate for ER and AR was 13% and 40%, respectively, and the overall rate for PR was 8%. The subgroup analysis revealed that there is a different expression of molecular markers between male and female patients. Conclusions. This study revealed that AR status and HER2/neu overexpression/amplification have been shown as two fundamental pathogenetic pathways in both female and male patients affected by EMPD.

Background This investigation focused on the clinical implications of the use of the Collapsed Cone Convolution algorithm (CCC) in breast radiotherapy and investigated the dosimetric differences as respect to Pencil Beam Convolution algorithm (PBC). Material and methods 15 breast treatment plans produced using the PBC algorithm were re-calculated using the CCC algorithm with the same MUs. In a second step, plans were re-optimized using CCC algorithm with modification of wedges and beam weightings to achieve optimal coverage (CCCr plans). For each patient, dosimetric comparison was performed using the standard tangential technique (SWT) and a forward-planned IMRT technique (f-IMRT). Results The CCC algorithm showed significant increased dose inhomogeneity. Mean and minimum PTV doses decreased by 1.4% and 2.8% (both techniques). Mean V95% decreased to 83.7% and 90.3%, respectively for the SWT and f-IMRT. V95% was correlated to the ratio of PTV and lung volumes into the treatment field. The re-optimized CCCr plans achieved similar target coverage, but high-dose volume was significantly larger (V107%: 7.6% vs 2.3% (SWT), 7.1% vs 2.1% (f-IMRT). There was a significantly increase in the ipsilateral lung volume receiving low doses (V5 Gy: 31.3% vs 26.2% in SWT, 27.0% vs 23.0% in f-IMRT). MUs needed for PTV coverage in CCCr plans were higher by 3%. Conclusions The PBC algorithm overestimated PTV coverage in terms of all important dosimetric metrics. If previous clinical experience are based on the use of PBC model, especially needed is discussion between medical physicists and radiation oncologists to fully understand the dosimetric changes.

High resolution 3D models produced from photographs acquired with consumer-grade cameras are becoming increasingly common in the fields of geosciences. However, the quality of an image-based 3D model depends on the planning of the photogrammetric surveys. This means that the geometric configuration of the multi-view camera network and the control data have to be designed in accordance with the required accuracy, resolution and completeness. From a practical application point of view, a proper planning (of both photos and control data) of the photogrammetric survey especially for terrestrial acquisition, is not always ensured due to limited accessibility of the target object and the presence of occlusions. To solve these problems, we propose a different image acquisition strategy and we test different geo-referencing scenarios to deal with the practical issues of a terrestrial photogrammetric survey. The proposed photogrammetric survey procedure is based on the acquisition of a sequence of images in panorama mode by rotating the camera on a standard tripod. The offset of the pivot point from the projection center prevents the stitching of these images into a panorama. We demonstrate how to still take advantage of this capturing mode. The geo-referencing investigation consists of testing the use of directly observed coordinates of the camera positions, different ground control point (GCP) configurations, and GCPs with different accuracies, i.e. artificial targets vs. natural features. Images of the test field in a low-slope hill were acquired from the ground using an SLR camera. To validate the photogrammetric results a terrestrial laser scanner survey is used as benchmark.

ntensity-modulated radiotherapy (IMRT) allowed the simultaneous delivery of different doses to different target volumes within a single fraction, an approach called simultaneous integrated boost (SIB). As consequence, the fraction dose to the boost volume can be increased while keeping low doses to the elective volumes, and the number of fractions and overall treatment time will be reduced, translating into better radiobiological effectiveness. In recent years, volumetric-modulated arc therapy (VMAT) has been shown to provide similar plan quality with respect to fixed-field IMRT but with large reduction in treatment time and monitor units (MUs) number. However, the feasibility of VMAT when used with SIB strategy has few investigations to date. We explored the potential of VMAT in a SIB strategy for complex cancer sites. A total of 15 patients were selected, including 5 head-and-neck, 5 high-risk prostate, and 5 rectal cancer cases. Both a double-arc VMAT and a 7-field IMRT plan were generated for each case using Oncentra MasterPlan treatment planning system for an Elekta Precise linac. Dosimetric indexes for targets and organs at risk (OARs) were compared based on dose-volume histograms. Conformity index, homogeneity index, and dose-contrast index were used for target analyses. The equivalent uniform doses and the normal tissue complication probabilities were calculated for main OARs. MUs number and treatment time were analyzed to score treatment efficiency. Pretreatment dosimetry was performed using 2-dimensional (2D)-array dosimeter. SIB-VMAT plans showed a high level of fluence modulation needed for SIB treatments, high conformal dose distribution, similar target coverage, and a tendency to improve OARs sparing compared with the benchmark SIB-IMRT plans. The median treatment times reduced from 13 to 20 minutes to approximately 5 minutes for all cases with SIB-VMAT, with a MUs reduction up to 22.5%. The 2D-array ion-chambers' measurements reported an agreement of more than 95% for a criterion of 3% to 3. mm. SIB-VMAT was able to combine the advantages of conventional SIB-IMRT with its highly conformal dose distribution and OARs sparing and the advantages of 3D-conformal radiotherapy with its fast delivery.

This is the accepted manuscript of the paper "A multi-platform approach to marine environment assessment in Civitavecchia (Rome) area", published as final paper in "JOURNAL OF OPERATIONAL OCEANOGRAPHY, 9(sup1), s131-s143" https://doi.org/10.1080/1755876X.2015.1119561 Multi-platform systems for coastal environment monitoring are important tools that enable a better understanding of the dynamics of coastal ecosystems and their forcings; these observation networks can be used to highlight changes in marine ecosystems in response to anthropogenic impacts, identifying specific evolution. trends. This paper reports the results of a field study conducted in summer 2012 to test the efficacy of the multi-platform Civitavecchia Coastal Environment Monitoring System (C-CEMS). An observation programme was employed to analyse the fate of the Escherichia coli (E. coli) in bathing areas, to predict its dynamics and to prevent the sanitary risk associated with the presence of this microorganism in seawater.

The understanding of the coastal environment is fundamental for efficiently and effectively facing the pollution phenomena as expected by the Marine Strategy Framework Directive, and for limiting the conflicts between anthropic activities and sensitivity areas, as stated by Maritime Spatial Planning Directive. To address this, the Laboratory of Experimental Oceanology and Marine Ecology developed a multi-platform observing network that has been in operation since 2005 in the coastal marine area of Civitavecchia (Latium, Italy) where multiple uses and high ecological values closely coexist. The Civitavecchia Coastal Environment Monitoring System (C-CEMS), implemented in the current configuration, includes various components allowing one to analyze the coastal conflicts by an ecosystem-based approach. The long-term observations acquired by the fixed stations are integrated with in situ data collected for the analysis of the physical, chemical and biological parameters of the water column, sea bottom and pollution sources detected along the coast. The in situ data, integrated with satellite observations (e.g., temperature, chlorophyll a and TSM), are used to feed and validate the numerical models, which allow the analysis and forecasting of the dynamics of pollutant dispersion under different conditions. To test the potential capabilities of C-CEMS, two case studies are reported here: (1) the analysis of fecal bacteria dispersion for bathing water quality assessment, and (2) the evaluation of the effects of the dredged activities on Posidonia meadows, which make up most of the two sites of community importance located along the Civitavecchia coastal zone. The simulation outputs are overlapped by the thematic maps showing bathing areas and Posidonia oceanica distribution, thus giving a first practical tool that could improve the resolution of the conflicts between coastal uses (in terms of stress produced by anthropic activities) and sensitivity areas.

The purpose of this pilot study was to determine the efficacy of an extremely low-frequency magnetic field (ELF-MF) in decreasing chronic pain in fibromyalgia (FM) patients. Thirty-seven females were recruited and randomized into two groups: one group was first exposed to systemic ELF-MF therapy (100 microtesla, 1 to 80 Hz) and then to sham therapy, and the other group received the opposite sequence of intervention. Pain, FM-related symptoms, and the ability to perform daily tasks were measured using the Visual Analog Scale, Fibromyalgia Impact Questionnaire (FIQ), Fibromyalgia Assessment Scale (FAS), and Health Assessment Questionnaire (HAQ) at baseline, end of first treatment cycle, beginning of second treatment cycle (after 1 mo washout), end of second treatment cycle, and end of 1 mo follow-up. ELF-MF treatment significantly reduced pain, which increased on cessation of therapy but remained significantly lower than baseline levels. Short-term benefits were also observed in FIQ, FAS, and HAQ scores, with less significant effects seen in the medium term. ELF-MF therapy can be recommended as part of a multimodal approach for mitigating pain in FM subjects and improving the efficacy of drug therapy or physiotherapy.

Purpose: The aim of the in vivo dosimetry, during the fractionated radiation therapy, is the verification of the correct dose delivery to patient. Nowadays, in vivo dosimetry procedures for photon beams are based on the use of the electronic portal imaging device and dedicated software to elaborate electronic portal imaging device images. Methods: In total, 8474 in vivo dosimetry tests were carried out for 386 patients treated with 3-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and volumetric modulated arc therapy techniques, using the SOFTDISO. SOFTDISO is a dedicated software that uses electronic portal imaging device images in order to (1) calculate the R index, that is, the ratio between daily reconstructed dose and the planned one at isocenter and (2) perform a γ-like analysis between the signals, S, of a reference electronic portal imaging device image and that obtained in a daily fraction. It supplies 2 indexes, the percentage γ% of points with γ < 1 and the mean γ value, γmean. In γ-like analysis, the pass criteria for the signals agreement ΔS% and distance to agreement Δd have been selected based on the clinical experience and technology used. The adopted tolerance levels for the 3 indexes were fixed in 0.95 ≤ R ≤ 1.05, γ% ≥ 90%, and γmean ≤ 0.5. Results: The results of R ratio, γ-like, and a visual inspection of these data reported on a monitor screen permitted to individuate 2 classes of errors (1) class 1 that included errors due to inadequate standard quality controls and (2) class 2, due to patient morphological changes. Depending on the technique and anatomical site, a maximum of 18% of tests had at least 1 index out of tolerance; once removed the causes of class-1 errors, almost all patients (except patients with 4 lung and 2 breast cancer treated with 3-dimensional conformal radiotherapy) presented mean indexes values (R¯, γ¯%, and γ¯mean ) within tolerance at the end of treatment course. Class-2 errors were found in some patients. Conclusions: The in vivo dosimetry procedure with SOFTDISO resulted easily implementable, able to individuate errors with a limited workload.

This is the accepted manuscript of the paper "Cost-Effective Technologies to Study the Arctic Ocean Environment", published as final paper in "Sensors 2018, 18, 2257;doi:10.3390/s18072257". Piermattei, V., Madonia, A., Bonamano, S., Martellucci, R., Bruzzone, G., Ferretti, R., Odetti, A., Azzaro, M., Zappalà, G., & Marcelli, M. (2018). Cost-Effective Technologies to Study the Arctic Ocean Environment†.Sensors (Basel, Switzerland),18(7), 2257. https://doi.org/10.3390/s18072257 The Arctic region is known to be severely affected by climate change, with evident alterations in both physical and biological processes. Monitoring the Arctic Ocean ecosystem is key to understanding the impact of natural and human-induced change on the environment. Large data sets are required to monitor the Arctic marine ecosystem and validate high-resolution satellite observations (e.g., Sentinel), which are necessary to feed climatic and biogeochemical forecasting models. However, the Global Observing System needs to complete its geographic coverage, particularly for the harsh, extreme environment of the Arctic Region. In this scenario, autonomous systems are proving to be valuable tools for increasing the resolution of existing data. To this end, a low-cost, miniaturized and flexible probe, ArLoC (Arctic Low-Cost probe), was designed, built and installed on an innovative unmanned marine vehicle, the PROTEUS (Portable RObotic TEchnology for Unmanned Surveys), during a preliminary scientific campaign in the Svalbard Archipelago within the UVASS project. This study outlines the instrumentation used and its design features, its preliminary integration on PROTEUS and its test results.

Purpose To present In-Vivo Dosimetry (IVD) results obtained elaborating EPID images by a commercial software. Methods 8474 IVD tests for 386 cancer patients treated with 3DCRT, IMRT and VMAT techniques, were performed using the SOFTDISO software. SOFTDISO uses EPID-images to calculate for each beam (i) the R index, i.e. the ratio between daily reconstructed dose and the planned one at isocenter point and (ii) a γ -like analysis between the reference EPID image and that obtained in a daily fraction. γ -like analysis supplies two indexes: the percentage of points with γ 1 ( γ % ) and the mean γ value, ( γ mean ) . For each test, the pass criteria for the signals (S) agreement Δ S% and distance to agreement Δ d, were: 0.95 ⩽ R ⩽ 1.05, γ % ⩾ 90% and γ mean ⩽ 0.5. Results The results of R ratios, the γ -like analysis and the visual inspection of out of tolerance tests, together with the patient anatomical images, permitted to individuate 2 classes of errors: class-1, due to inadequate standard quality controls and class-2, due to patient morphological changes. Depending on the technique and anatomical site, a maximum of 18% of tests had at least one index out of tolerance level (OTL). Once removed the causes of class-1 errors, all patients (except four lung and two breast cancer patients treated with 3DCRT) presented mean indexes values ( R ¯ , γ ¯ % and γ ¯ mean ) within tolerance at the end of treatment course. Class-2 errors were found in some patients. As an example, the Table reports the results of 1810 tests for prostate and H&N tumours treated with VMAT technique with 163 OTL tests (9%). As regards the workload, it took 20 min for 10 patients per day. Conclusions The IVD procedure with SOFTDISO resulted easily implementable and able to individuate errors with a limited workload.

The aim of this analysis is to present the methodology used to promote clinical research in a peripheral Italian department of radiotherapy (RT) and the results in terms of scientific output. Internal treatment guidelines were developed, available on the computer network of the department, containing a schematic summary 1–2 pages long of each protocol. Furthermore, a home-made database was designed to be used both as a medical record and for prospective data recording. Data entry was subjected to an “independent check” by a second radiation oncologist. Regular meetings were organized to update all staff on the aim and conduct of the various running trials and to promote the enrollment of patients and the involvement of other specialists in clinical research. In a period of about 11 years: (1) 34 protocols for clinical trials were written and approved; (2) 7463 patients had undergone RT; of these patients, 6321 patients (85 %) were enrolled in clinical trials; (3) 345 papers/book chapters/abstracts were published; of them, 127 papers have been published in journals currently featured on PUBMED; (4) 119 scientific meetings were held. This experience shows that an independent clinical research is possible even in a non-academic and peripheral RT department. In particular, our experience suggests that personnel and resource constraints can be at least partially overcome by a strong personal and group motivation and with the adoption of flexible solutions.

We reported our initial experience in using Elekta volumetric modulated arc therapy (VMAT) and an anatomy-based treatment planning system (TPS) for single high-dose radiosurgery (SRS-VMAT) of liver metastases. This study included a cohort of 12 patients treated with a 26-Gy single fraction. Single-arc VMAT plans were generated with Ergo++ TPS. The prescription isodose surface (IDS) was selected to fulfill the 2 following criteria: 95% of planning target volume (PTV) reached 100% of the prescription dose and 99% of PTV reached a minimum of 90% of prescription dose. A 1-mm multileaf collimator (MLC) block margin was added around the PTV. For a comparison of dose distributions with literature data, several conformity indexes (conformity index [CI], conformation number [CN], and gradient index [GI]) were calculated. Treatment efficiency and pretreatment dosimetric verification were assessed. Early clinical data were also reported. Our results reported that target and organ-at-risk objectives were met for all patients. Mean and maximum doses to PTVs were on average 112.9% and 121.5% of prescribed dose, respectively. A very high degree of dose conformity was obtained, with CI, CN, and GI average values equal to 1.29, 0.80, and 3.63, respectively. The beam-on-time was on average 9.3 minutes, i.e., 0.36. min/Gy. The mean number of monitor units was 3162, i.e., 121.6. MU/Gy. Pretreatment verification (3%-3. mm) showed an optimal agreement with calculated values; mean γ value was 0.27 and 98.2% of measured points resulted with γ < 1. With a median follow-up of 16 months complete response was observed in 12/14 (86%) lesions; partial response was observed in 2/14 (14%) lesions. No radiation-induced liver disease (RILD) was observed in any patients as well no duodenal ulceration or esophagitis or gastric hemorrhage. In conclusion, this analysis demonstrated the feasibility and the appropriateness of high-dose single-fraction SRS-VMAT in liver metastases performed with Elekta VMAT and Ergo++ TPS. Preliminary clinical outcomes showed a high rate of local control and minimum incidence of acute toxicity.

OBJECTIVE: To explore the potential of volumetric-modulated arc therapy (VMAT) to reduce the risk of swallowing problems after curative chemoradiotherapy. METHODS: 20 patients with head and neck cancer who previously underwent radiotherapy were selected. Radiotherapy was prescribed according to simultaneous integrated boost technique with all targets irradiated simultaneously over 30 daily fractions. Doses of 70.5 (67.5), 60.0 and 55.5 Gy were prescribed to primary tumour, high-risk nodal regions and low-risk nodal regions, respectively. Pharyngeal constrictor muscles (PCM) and glottic and supraglottic larynx (SGL) were considered organs at risk related to swallowing dysfunction (SW-OARs). Upper pharyngeal constrictor muscles (uPCM), middle pharyngeal constrictor muscles (mPCM) and lower pharyngeal constrictor muscles (lPCM) part of PCM were also outlined separately. Clinical standard plans (standard-VMAT) and plans aiming to spare SW-OARs (swallowing dysfunction-VMAT) were also created. Normal tissue complication probabilities (NTCP) for physician-rated swallowing dysfunction were calculated using a recently predictive model developed by Christianen et al. RESULTS: Planning with two strategies demonstrated comparable planning target volume coverage and no differences in sparing of parotid glands and other non-swallowing organs at risk. SW-VMAT plans provided mean dose reduction for uPCM and SGL by 3.9 and 4.5 Gy, respectively. NTCP values for Radiation Therapy Oncology Group grade 2-4 swallowing dysfunction was decreased by 9.2%. Dose reductions with SW-VMAT depended on tumour location and overlap with SW-OARs. CONCLUSION: VMAT plans aiming at sparing swallowing structures are feasible, providing a significant reduction in NTCP swallowing dysfunction with respect to conventional VMAT. ADVANCES IN KNOWLEDGE: Dysphagia is today considered one of the dose-limiting toxicities of chemoradiotherapy. The dose sparing of swallowing structures represents a major challenge in radiotherapy. VMAT is a complex new technology having the potential to significantly reduce the risk of dysphagia after curative chemoradiotherapy.

Objective. To report dosimetric and acute toxicity data in prospectively enrolled high-intermediate risk endometrial cancer (HIR-EC) patients postoperatively irradiated by simultaneous integrated boost volumetric modulated arc therapy (SIB-VMAT). Methods. Thirty prospectively enrolled HIR-EC patients were postoperatively treated by SIB-VMAT. Target coverage, dose homogeneity, and sparing of organs at risk (OARs) were compared with corresponding data retrieved from an historical control (30 consecutive selected matched patients) treated by concomitant boost three-dimensional conformal radiotherapy (3D CRT CB) from a previously published study (ADA-I trial). All patients received 45 Gy on pelvic lymph nodes plus 10 Gy boost on the vaginal vault. Results. The SIB-VMAT technique produced more inhomogeneous plans than 3D CRT CB, but showed significantly better conformity index (CIs) for both PTVs. SIB-VMAT was associated with significant reduction in the irradiated small bowel (SB) volume compared with 3D CRT CB for all dose range > 10 Gy (e.g. V15: 163.5 cm3 vs. 341.3 cm3, p = 0.001 and V40: 43.8 cm3 vs. 85.2 cm3, p = 0.008). With regard to bladder and rectum, SIB-VMAT showed a significant sparing advantage at all dose levels with respect to 3D CRT CB retrieved plans. Moreover, overall OARs Dmean were significantly reduced by the SIB-VMAT (p = 0.001). According to CTCAE v.4.0, acute (within three months) GI toxicities were more frequent in 3D CRT CB versus SIB-VMAT (90.0% vs. 66.7%; p-value 0.028). Conclusions. Compared to data from a historical database of patients administered 3D CRT CB, SIB-VMAT significantly improves the dose conformity and sparing of OARs in HIR-EC patients undergoing postoperative radiotherapy. The improvement in terms of acute toxicity justifies further prospective clinical evaluation.

Neurologic disease diagnosis and treatment is challenging. Multiple Sclerosis (MS) is a demyelinating autoimmune disease with few clinical forms and uncertain etiology. Current studies suggest that it is likely caused by infection(s) triggering a systemic immune response resulting in antigen/non-antigen-related autoimmune response in central nervous system (CNS). New therapeutic approaches are needed. Secreted by viable embryos, PreImplantation Factor (PIF) possesses a local and systemic immunity regulatory role. Synthetic PIF (PIF) duplicates endogenous peptide's protective effect in pre-clinical autoimmune and transplantation models. PIF protects against brain hypoxia-ischemia by directly targeting microglia and neurons. In chronic experimental autoimmune encephalitis (EAE) model PIF reverses paralysis while promoting neural repair. Herein we report that PIF directly promotes brain re-myelination and reverses paralysis in relapsing remitting EAE MS model. PIF crosses the blood-brain barrier targeting microglia. Systemically, PIF decreases pro-inflammatory IL23/IL17 cytokines, while preserving CNS-specific T-cell repertoire. Global brain gene analysis revealed that PIF regulates critical Na+/K+/Ca++ ions, amino acid and glucose transport genes expression. Further, PIF modulates oxidative stress, DNA methylation, cell cycle regulation, and protein ubiquitination while regulating multiple genes. In cultured astrocytes, PIF promotes BDNF-myelin synthesis promoter and SLC2A1 (glucose transport) while reducing deleterious E2F5, and HSP90ab1 (oxidative stress) genes expression. In cultured microglia, PIF increases anti-inflammatory IL10 while reducing pro-inflammatory IFNγ expression. Collectively, PIF promotes brain re-myelination and neuroprotection in relapsing remitting EAE MS model. Coupled with ongoing, Fast-Track FDA approved clinical trial, NCT#02239562 (immune disorder), current data supports PIF's translation for neurodegenerative disorders therapy.

Background and Purpose: Quality assurance procedures (QA) may reduce the risk of errors in radiotherapy. The aim of this study was to assess a QA program based on independent check (IC) procedures in patients undergoing 3D, intensity modulated (IMRT) and extracranial stereotactic (ESRT) radiotherapy. Materials and methods: IC for set-up (IC1) and for radiotherapy treatments (IC2) was tested on 622 patients over a year. Fifteen events/parameters and 17 parameters were verified by IC1 and IC2, respectively. A third evaluation check (IC3) was performed before treatment. Potential errors were classified based on their magnitude. Incidents involving only incorrect or incomplete documentation were segregated. Treatments were classified based on a complexity index (COMIX). Results: With IC1, 75 documentation incidents and 31 potential errors were checked, and with IC2 111 documentation incidents and 6 potential errors were checked. During the study period 10 errors undetected by standard procedures (IC1, IC2) were detected by chance or by IC3. The incidence of errors and serious errors undetected by standard procedures was 1.6% and 0.6%, respectively. There was no higher incidence of errors undetected in patients undergoing IMRT or ESRT, while there was a higher incidence of errors undetected in more complex treatments (p < 0.001). Conclusions: Systematic QA procedures can reduce the risk of errors. The risk of errors undetected by standard procedures is not correlated with the treatment technological level (3D versus IMRT/ESRT). © 2008 Elsevier Ireland Ltd. All rights reserved.

A 2D-array equipped with 729 vented plane parallel ion-chambers has been calibrated as a portal dose detector for radiotherapy in vivo measurements. The array has been positioned by a radiographic film stand at 120 cm from the source orthogonal to the radiotherapy beam delivered with the gantry angle at 180°. The collision between the 2D-array and the patient's couch have been avoided. In this work, using the measurements of the portal detector, we present a method to reconstruct the dose variations in the patient treated with step and shoot intensity-modulated beams (IMRT) for head-neck tumours. For this treatment morphological changes often occur during the fractionated therapy. In a first step an in-house software supplied the comparison between the measured portal dose and the one computed by a commercial treatment planning system within the field of view of the computed tomography (CT) scanner. For each patient, the percentage Pγ of chambers, where the comparison is in agreement within a selected acceptance criteria, was determined 8 times. At the first radiotherapy fraction the γ-index analysis supplied Pγ values of about 95%, within acceptance criteria in terms of dose-difference, ΔD, and distance-agreement, Δd, that was equal to 5% and 4 mm, respectively. These acceptance criteria were taken into account for small errors in the patient's set-up reproducibility and for the accuracy of the portal dose calculated by the treatment planning system (TPS) in particular when the beam was attenuated by inhomogeneous tissues and the shape of the head-neck body contours were irregular. During the treatment, some patients showed a reduction of the Pγ below 90% because due to radiotherapy treatment there was a change of the patient's morphology. In a second step a method, based on dosimetric measurements that used standard phantoms, supplied the percentage dose variations in a coronal plane of the patient using the percentage dose variations measured by the 2D-array portal detector. The results showed that the dose variations due to the change of the patient's morphology reached 15% and such discrepancies were displayed on the digitally reconstructed radiography of the patient. The dose discrepancies were confirmed by the hybrid plan obtained by the treatment planning system. The good results here reported show that once it is possible to have the portal dose distributions even for other gantry angles, these tests could be introduced in the clinical protocol to have major support to decide when to repeat the patient's CT scan and to re-plan the new IMRT dose calculation. © 2008 Elsevier B.V. All rights reserved.

BACKGROUND the purpose of this study is to compare the therapeutic effects of extracorporeal shock wave therapy (ESWT) to those of cryoultrasound (Cryo-US) therapy in chronic lateral epicondylitis during a 12-month period. METHODS single-blinded, randomized, controlled study of 80 participants treated for chronic LE with 3 ESWT sessions at 48/72-hours intervals (n=40) or 12 Cryo-US therapy sessions (4 sessions per week) (n=40). VAS and satisfactory results, considered as the sum of excellent and good scores in the Roles and Maudsley score, were used as outcome measures at baseline and 3, 6 and 12 months post-treatment. RESULTS the results show statistically significant differences in VAS between the two groups at 6 (p

This work reports the results of the application of a practical method to determine the in vivo dose at the isocenter point, D(iso), of brain thorax and pelvic treatments using a transit signal S(t). The use of a stable detector for the measurement of the signal S(t) (obtained by the x-ray beam transmitted through the patient) reduces many of the disadvantages associated with the use of solid-state detectors positioned on the patient as their periodic recalibration, and their positioning is time consuming. The method makes use of a set of correlation functions, obtained by the ratio between S(t) and the mid-plane dose value, D(m), in standard water-equivalent phantoms, both determined along the beam central axis. The in vivo measurement of D(iso) required the determination of the water-equivalent thickness of the patient along the beam central axis by the treatment planning system that uses the electron densities supplied by calibrated Hounsfield numbers of the computed tomography scanner. This way it is, therefore, possible to compare D(iso) with the stated doses, D(iso,TPS), generally used by the treatment planning system for the determination of the monitor units. The method was applied in five Italian centers that used beams of 6 MV, 10 MV, 15 MV x-rays and (60)Co gamma-rays. In particular, in four centers small ion-chambers were positioned below the patient and used for the S(t) measurement. In only one center, the S(t) signals were obtained directly by the central pixels of an EPID (electronic portal imaging device) equipped with commercial software that enabled its use as a stable detector. In the four centers where an ion-chamber was positioned on the EPID, 60 pelvic treatments were followed for two fields, an anterior-posterior or a posterior-anterior irradiation and a lateral-lateral irradiation. Moreover, ten brain tumors were checked for a lateral-lateral irradiation, and five lung tumors carried out with three irradiations with different gantry angles were followed. One center used the EPID as a detector for the S(t) measurement and five pelvic treatments with six fields (many with oblique incidence) were followed. These last results are reported together with those obtained in the same center during a pilot study on ten pelvic treatments carried out by four orthogonal fields. The tolerance/action levels for every radiotherapy fraction were 4% and 5% for the brain (symmetric inhomogeneities) and thorax/pelvic (asymmetric inhomogeneities) irradiations, respectively. This way the variations between the total measured and prescribed doses at the isocenter point in five fractions were well within 2% for the brain treatment, and 4% for thorax/pelvic treatments. Only 4 out of 90 patients needed new replanning, 2 patients of which needed a new CT scan.

We evaluated an EPID-based in-vivo dosimetry algorithm (IVD) for complex VMAT treatments in clinical routine. 19 consecutive patients with head-and-neck tumors and treated with Elekta VMAT technique using Simultaneous Integrated Boost strategy were enrolled. In-vivo tests were evaluated by means of (i) ratio R between daily in-vivo isocenter dose and planned dose and (ii) γ-analysis between EPID integral portal images in terms of percentage of points with γ-value smaller than one (γ%) and mean γ-values (γmean), using a global 3%-3 mm criteria. Alert criteria of ±5% for R ratio, γ% < 90% and γmean > 0.67 were chosen. A total of 350 transit EPID images were acquired during the treatment fractions. The overall mean R ratio was equal to 1.002 ± 0.019 (1 SD), with 95.9% of tests within ±5%. The 2D portal images of γ-analysis showed an overall γmean of 0.42 ± 0.16 with 93.3% of tests within alert criteria, and a mean γ% equal to 92.9 ± 5.1% with 85.9% of tests within alert criteria. Relevant discrepancies were observed in three patients: a set-up error was detected for one patient and two patients showed major anatomical variations (weight loss/tumor shrinkage) in the second half of treatment. The results are supplied in quasi real-time, with IVD tests displayed after only 1 minute from the end of arc delivery. This procedure was able to detect when delivery was inconsistent with the original plans, allowing physics and medical staff to promptly act in case of major deviations between measured and planned dose.

In vivo dosimetry (IVD) is the last step of a radiotherapy quality control program aimed to ensure that the dose delivered is in agreement with that prescribed. IVD procedures based on single detectors are time-consuming and impossible to use for the modern radiotherapy techniques, based on static or kinetic beams (modulated in intensity fluence); this means that more efficient and practical methods are highly recommended. The practical method SOFTDISO, based on the use of electronic portal image device (EPID), provides two tests (i) the R ratio between the reconstructed and the planned isocenter doses to verify an agreement within 5% and (ii) the γ-analysis of the EPID images, to verify γ% ≥ 90% and γmean ≤ 0.4. This paper reports the results of 11,357 IVD tests carried out for 823 patients treated by three-dimensional conformal radiation therapy and volumetric modulated arc therapy techniques. In particular, the dose disagreements are reported distinguishing two kinds of causes, those of (i) class 1 that includes the errors due to inadequate quality controls and (ii) the class 2, due to patient morphological changes. About the tests out of tolerance, 6% were by VMAT and 21% by 3DCRT, but taking into account the only class 1 of errors, i.e., removing the causes of class 2, only 7% of patients examined presented at least one of the three mean indexes out of tolerance. The workload for IVD on 9 patients/day per linac is about 52 min/day but recently, a new automated SOFTDISO version has been implemented to reduce the time to about 34 min/day.

Aims: To present the interim results of a phase I trial on stereotactic radiosurgery (SRS) delivered using volumetric modulated arc therapy (VMAT) in patients with primary or metastatic tumours in different extracranial sites. Materials and methods: Patients were enrolled in different arms according to tumour site and clinical stage, and sequentially assigned to a given dose level. Acute toxicity, tumour response and early local control were investigated and reported. Results: One hundred lesions in 65 consecutive patients (male/female: 30/35, median age: 66 years; range: 40-89) were treated. Of these 100 lesions, 21 were primary or metastatic lung tumours, 24 were liver metastases, 30 were bone metastases, 24 were nodal metastases and one was a primary vulvar melanoma. The prescribed dose ranged from 12 (BED2Gy,α/β:10=26.4Gy) to 28Gy (BED2Gy,α/β:10=106.4Gy) to the planning target volume. Twenty-one patients (32.3%) experienced grade 1-2 acute toxicity, which was grade 2 in only two cases. The overall response rate based on computed tomography/magnetic resonance imaging was 52% (95% confidence interval 40.1-63.2%) and based on positron emission tomography scan was 90% (95% confidence interval 76.2-96.4%). As of November 2013, the median duration of follow-up was 11 months (range=1-38). Recurrence/progression within the SRS-VMAT treated field was observed in nine patients (total lesions=18): the inside SRS-VMAT field local control expressed on a per lesion basis was 87.8% at 12 months and 71.9% at 24 months. Conclusions: The maximum tolerable dose has not yet been reached in any study arm. SRS-VMAT resulted in positive early clinical results in terms of tumour response, local control rate and acute toxicity.

BACKGROUND: The perception of body image and the deformity of the trunk in patients with adolescent idiopathic scoliosis (AIS) are a silver lining that has yet to be discussed in the relevant literature during brace rehabilitation treatment. OBJECTIVE: To determine whether and how the use of the brace changes perception of the trunk in patients with AIS by the drawing test. METHODS: We observed 32 subjects with AIS from our Rehabilitation outpatient clinic and divided them into the brace treatment (BG-16 subjects) and the non-brace treatment (CG-16 subjects). Trunk perception and quality of life were evaluated using the Trunk Appearance Perception Scale and Scoliosis Research Society-22 questionnaire, and the perception of one’s back was measured by the drawing test. RESULTS: Pain was lower in BG versus CG (p = 0.095). Satisfaction with the treatment was higher in BG than in CG (p = 0.002). Self-image did not differ significantly between the groups in terms of TAPS. Drawings of the most severe cases of scoliosis were made by the group without the brace. CONCLUSIONS: The use of the brace corrects the function of the trunk and has a positive influence on its perception.