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Purpose: This study analyzed inter-institute conformity and dose gradient variability of CyberKnife (CK) brain SRS/SRT plans. The feasibility of multi-center predictive models was investigated, aiming at guided/automated planning optimization., Methods: Data from 335 clinical plans, delivered for single lesions in 1-5 fractions, were collected by 8 CK centers. Conformity index (CI), Dose Gradient Index (DGI) and the effective radii defined by different isodose volumes (Reff) were computed. Predictability of dose fall-off from PTV dimensions was analyzed. DGI average, 80th and 10 th percentile values were evaluated stratifying plans by PTV size into six groups. Linear regression models were created for Reff as a function of PTV equivalent radius., Results: CI values (range 0.96---2.23) exceeded 1.20 in 88/335 plans, mostly (65 %) collected in 2 of the participating centers. DGI showed an acceptable inter-institute variability and a strong significant correlation (p < 0.0001) with PTV. Ideal and Minimal DGI for each of the six groups were respectively 95 (86), 82 (73), 77 (68), 71 (60), 59 (43) and 50 (29). The rate of DGI values passing the multicenter minimal criteria, considering each center separately, varied from 43 % to 100 %. R 2 values for the regression between Reff and PTV radius were ≥ 0.958, showing an increasing inter-center variability for decreasing isodose values., Conclusion: Observed inter-center differences enhanced the advantages of a multi-institute approach. Multicenter predictive models for dose fall-off in CK brain SR/SRT planning are feasible and easy to use. Reff models and DGI analysis may permit to partially automate planning optimization avoiding creation of suboptimal plans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Metabolic distress is often associated with heart failure with preserved ejection fraction (HFpEF) and represents a therapeutic challenge. Metabolism-induced systemic inflammation links comorbidities with HFpEF. How metabolic changes affect myocardial inflammation in the context of HFpEF is not known., Methods: We found that ApoE knockout mice fed a Western diet recapitulate many features of HFpEF. Single-cell RNA sequencing was used for expression analysis of CD45 + cardiac cells to evaluate the involvement of inflammation in diastolic dysfunction. We focused bioinformatics analysis on macrophages, obtaining high-resolution identification of subsets of these cells in the heart, enabling us to study the outcomes of metabolic distress on the cardiac macrophage infiltrate and to identify a macrophage-to-cardiomyocyte regulatory axis. To test whether a clinically relevant sodium glucose cotransporter-2 inhibitor could ameliorate the cardiac immune infiltrate profile in our model, mice were randomized to receive the sodium glucose cotransporter-2 inhibitor dapagliflozin or vehicle for 8 weeks., Results: ApoE knockout mice fed a Western diet presented with reduced diastolic function, reduced exercise tolerance, and increased pulmonary congestion associated with cardiac lipid overload and reduced polyunsaturated fatty acids. The main immune cell types infiltrating the heart included 4 subpopulations of resident and monocyte-derived macrophages, determining a proinflammatory profile exclusively in ApoE knockout-Western diet mice. Lipid overload had a direct effect on inflammatory gene activation in macrophages, mediated through endoplasmic reticulum stress pathways. Investigation of the macrophage-to-cardiomyocyte regulatory axis revealed the potential effects on cardiomyocytes of multiple inflammatory cytokines secreted by macrophages, affecting pathways such as hypertrophy, fibrosis, and autophagy. Finally, we describe an anti-inflammatory effect of sodium glucose cotransporter-2 inhibition in this model., Conclusions: Using single-cell RNA sequencing in a model of diastolic dysfunction driven by hyperlipidemia, we have determined the effects of metabolic distress on cardiac inflammatory cells, in particular on macrophages, and suggest sodium glucose cotransporter-2 inhibitors as potential therapeutic agents for the targeting of a specific phenotype of HFpEF., Competing Interests: None.

Purpose: Up to 47% of patients with localized prostate cancer (PCa) treated with radiotherapy (EBRT) eventually develop local recurrence. To date, no clear consensus exists on optimal management. A growing body of interest supports the use of stereotaxic re-irradiation (rSBRT), with promising oncological outcomes and low toxicity profile. We collected a single-center case series of locally recurrent PCa who underwent re-irradiation after a previous course of postoperative or definitive radiotherapy., Methods and Materials: Data from 101 patients treated at our institution for locally recurrent PCa from June 2012 to June 2021 were retrospectively collected. Patients underwent rSBRT with CyberKnife system (Accuray Inc., Sunnyvale, CA, USA), delivered to intraprostatic or macroscopic recurrences within the prostate bed, for a total dose of 30 Gy in 5 fractions., Results: All patients received prior EBRT. The median EQD2 total dose was 75.0 Gy (range, 60-80 Gy). Thirty-two (32%) patients were receiving androgen deprivation therapy (ADT) after prior biochemical recurrence. After a median follow-up of 57.8 months, BR occurred in 55 patients (54.5%), with a median BR-free survival (BRFS) of 40.4 months (95% C.I. 34.3-58.3). Thirty-two patients (31.7%) developed metastatic disease, with a median metastasis-free survival (MFS) not reached. PSA ≥ 2.5 ng/ml and ADT were associated with worst BRFS (26.06 vs. 39.3 months, p = 0.03 and 22.7 vs. 27 months, p = 0.01, respectively). Castration-resistant status and ADT were found to be predictive of worst MFS (34.1 vs. 50.5 months, p = 0.02 and 33.5 vs. 53.1 months, p = 0.002, respectively). Concomitant ADT was confirmed as an independent factor for MFS (HR 4.8, 95% CI 1.5-10.6, p = 0.007). No grade > /2 adverse were recorded., Conclusions: After almost 5 years of follow-up, with a median BRFS of 40.4 months and no grade ≥ 2 AEs, Cyberknife R rSBRT proved effective and safe in a cohort of 101 patients affected by locally recurrent PCa., (© 2023. Italian Society of Medical Radiology.)

Purpose: A preoperative breast robotic radiosurgery trial was concluded in our centre. Purposes of the present study were to evaluate retrospectively over the enrolled patients: i) respiratory patterns ii) tracking uncertainties iii) necessity of respiratory compensation iv) tracking errors dosimetric effects., Methods: 22 patients were treated in 21 Gy single fraction using CyberKnife (CK) respiratory modelling and tracking (SynchronyResp) and data extracted from log-files. Respiratory motion and baseline drifts (BD) were analyzed. SynchronyResp uncertainties were computed and compared with errors simulated for CK fiducial tracking without respiratory compensation. Plans were perturbed by tracking errors and perturbed doses calculated on the planning CT scan in order to simulate the dosimetric consequences of intra-fraction errors., Results: After BD correction, respiratory amplitudes were below 5.5 mm except one value of 8 mm. 50% of patients showed BD above 3 mm. Standard deviations of SynchronyResp errors remained within 2.1 mm. Standard deviations of tracking errors without respiratory compensation were comparable and below 2.5 mm. Using a 3 mm PTV margin, perturbed CTV coverage was below 95% (93.7%) just for one patient. The latter case presented a large CTV-Skin interface. Perturbed OAR doses were always judged clinically acceptable., Conclusion: Intra-fraction geometric uncertainties and their effects were quantified for breast neoadjuvant CK treatments. Data indicated that in the majority of cases respiratory compensation may be disabled without increasing uncertainties and reducing treatment time, provided that fiducial intra-fraction tracking is performed to account for BD. Dosimetric effects are mostly not clinically relevant., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Background and Purpose: Preoperative partial breast irradiation (PBI) has got the advantage of treating a well-defined target. We report the results of the phase II ROCK trial (NCT03520894), enrolling early breast cancer (BC) patients treated with preoperative robotic radiosurgery (prRS), in terms of acute and early late toxicity, disease control, and cosmesis., Material and Methods: The study recruited between 2018 and 2021 at our Radiation Oncology Unit. Eligible patients were 50 + years old BC, hormonal receptors positive/human epidermal growth factor receptor 2 negative (HR+/HER2-), sized up to 25 mm. The study aimed to prospectively assess the toxicity and feasibility of a robotic single 21 Gy-fraction prRS in preoperative setting., Results: A total of 70 patients were recruited and 22 patients were successfully treated with pRS. Overall, three G1 adverse events (13.6 %) were recorded within 7 days from prRS. Three events (13.6 %) were recorded between 7 and 30 days, one G2 breast oedema and two G1 breast pain. No acute toxicity greater than G2 was recorded. Five patients experienced early late G1 toxicity. One patient reported G2 breast induration. No early late toxicity greater than G2 was observed. At a median follow up of 18 months (range 6-29.8), cosmetic results were scored excellent/good and fair in 14 and 5 patients, respectively, while 3 patients experienced a poor cosmetic outcome., Conclusions: ROCK trial showed that a single 21 Gy dose prRS represents a feasible technique for selected patients affected by early BC, showing an acceptable preliminary toxicity profile., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Icro Meattini reports occasional speaker honoraria supported by Eli Lilly, Novartis, Pfizer, Accuray, and Seagen, outside the submitted work. No other competing interests declared., (© 2022 The Author(s).)

Aims: In 2018, we published early results from a cohort of patients treated with stereotactic body radiotherapy (SBRT) after previous radiotherapy with definitive or postoperative intent. We sought to provide extended follow-up of this cohort to confirm the safety and efficacy of this approach in a real-world scenario., Materials and Methods: Fifty patients affected by local relapse after previous definitive or postoperative radiotherapy were treated with SBRT. Treatment provided a total dose of 30 Gy in five fractions. Data about biochemical relapse-free survival (BRFS) and metastasis-free survival (MFS), together with adverse events, were analysed. Toxicity was reported according to Common Terminology Criteria for Adverse Events (CTCAE) score v.4.03., Results: After a median follow-up of 48.2 months, the median BRFS was 43 months. A Gleason score >7 and concomitant androgen deprivation therapy were shown to be predictors of the worst BRFS (hazard ratio 2.42, 95% confidence interval 1.09-5.41, P = 0.02; hazard ratio 2.83, 95% confidence interval 1.17-6.8, P = 0.02, respectively). The median MFS was not reached; concomitant androgen deprivation therapy was confirmed to be predictive of the worst MFS (hazard ratio 4.75, 95% confidence interval 1.52-14.8, P = 0.007). Late grade 1 and 2 rectal and bladder toxicity occurred in three (6%) and 13 (26%) patients, respectively. One patient experienced both grade 3 acute and chronic bladder toxicity., Conclusion: Salvage SBRT re-irradiation after previous postoperative or definitive radiotherapy for local prostate cancer recurrence confirmed promising results in terms of oncological outcomes and the safety of this approach., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Purpose: The utility of complexity metrics has been assessed for IMRT and VMAT treatment plans, but this analysis has never been performed for CyberKnife (CK) plans. The purpose of this study is to perform a complexity analysis of CK MLC plans, adapting and computing complexity indices previously defined for IMRT plans. Metrics were used to compare the complexity of plans created by two optimization systems and to study correlations between plan complexity and patient-specific quality assurance (PSQA) results. Relationships between pairs of metrics were also analyzed to get insight into possible interdependencies., Methods: Two independent in-house software platforms were developed to compute six complexity metrics: modulation complexity score (MCS), edge metric (EM), plan irregularity (PI), plan modulation (PM), leaf gap (LG), and small aperture score (SAS10). MCS and PM definitions were adapted to account for CK plans characteristics. The computed metrics were used to compare the existing optimization algorithms (sequential and VOLO) in terms of plan complexity over 24 selected cases. Metrics were then computed over a large number (103) of VOLO SBRT clinical plans from different treatment sites, mainly liver, prostate, pancreas, and spine. Pearson's r was used to study relationships between each pair of metrics. Correlation between complexity indices and PSQA results expressed as gamma index passing rates (GPR) at (3%, 1 mm) and (2%, 1 mm) was finally analyzed. Correlation was regarded as weak for absolute Pearson's r values in the range 0.2-0.39, moderate 0.4-0.59, strong 0.6-0.79, and very strong 0.8-1., Results: When compared to VOLO, sequential plans exhibited a higher complexity degree, showing lower MCS and LG values and higher EM, PM and PI values. Differences were significant for 5/6 metrics (Wilcoxon P < 0.05). The analysis of VOLO clinical plans highlighted different degrees of complexity among plans from different treatment sites, increasing from liver to prostate, pancreas, and finally, spine. Analysis of dependencies between pairs of metrics showed a very strong significant negative correlation (P < 0.01), respectively, between MCS and PM (r = -0.97), and EM and LG (-0.82). Most of the remaining pairs showed moderate to strong correlations with the exception of PI, which showed weaker correlations with the other metrics. A moderate significant correlation was observed with GPR values both at (3%, 1 mm) and (2%, 1 mm) for all metrics except PI, which showed no correlation., Conclusions: Modulation complexity metrics were computed for CK MLC-based plans for the first time and some metrics' definitions were adapted to CK plans peculiarities. The computed metrics proved a useful tool for comparing optimization algorithms and for characterizing CK clinical plans. Strong and very strong correlations were found between some pairs of metrics. Some significant correlations were found with PSQA GPR, indicating that some indices are promising for rationalizing and reducing PSQA workload. Our results set the basis for evaluating new optimization algorithms and TPS versions in the future, as well as for comparing the complexity of CK MLC-based plans in multicenter and multiplatform comparisons., (© 2020 American Association of Physicists in Medicine.)

Purpose: To assess the performance of a new optimization system, VOLO, for CyberKnife MLC-based SBRT plans in comparison with the existing Sequential optimizer., Methods: MLC-plans were created for 25 SBRT cases (liver, prostate, pancreas and spine) using both VOLO and Sequential. Monitor units (MU), delivery time (DT), PTV coverage, conformity (nCI), dose gradient (R50%) and OAR doses were used for comparison and combined to obtain a mathematical score (MS) of plan quality for each solution. MS strength was validated by changing parameter weights and by a blinded clinical plan evaluation. The optimization times (OT) and the average segment areas (SA) were also compared., Results: VOLO solutions offered significantly lower mean DT (-19%) and MU (-13%). OT were below 15 min for VOLO, whereas for Sequential, values spanned from 8 to 160 min. SAs were significantly larger for VOLO: on average 10 cm 2 versus 7 cm 2 . VOLO optimized plans achieved a higher MS than Sequential for all tested parameter combinations. PTV coverage and OAR sparing were comparable for both groups of solutions. Although slight differences in R50% and nCI were found, the parameters most affecting MS were MU and DT. VOLO solutions were selected in 80% of cases by both physicians with 88% inter-observer agreement., Conclusions: The good performance of the VOLO optimization system, together with the large reduction in OT, make it a useful tool to improve the efficiency of CK SBRT planning and delivery. The proposed methodology for comparing different planning solutions can be applied in other contexts., (Copyright © 2020 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Background: The dosimetric variability in spine stereotactic body radiation therapy (SBRT) planning was investigated in a large number of centres to identify crowd knowledge-based solutions., Methods: Two spinal cases were planned by 48 planners (38 centres). The required prescription dose (PD) was 3 × 10 Gy and the planning target volume (PTV) coverage request was: V PD  > 90% (minimum request: V PD  > 80%). The dose constraints were: planning risk volume (PRV) spinal cord: V 18Gy  < 0.35 cm 3 , V 21.9 Gy  < 0.03 cm 3 ; oesophagus: V 17.7 Gy  < 5 cm 3 , V 25.2 Gy  < 0.03 cm 3 . Planners who did not fulfil the protocol requirements were asked to re-optimize the plans, using the results of planners with the same technology. Statistical analysis was performed to assess correlations between dosimetric results and planning parameters. A quality index (QI) was defined for scoring plans., Results: In all, 12.5% of plans did not meet the protocol requirements. After re-optimization, 98% of plans fulfilled the constraints, showing the positive impact of knowledge sharing. Statistical analysis showed a significant correlation (p < 0.05) between the homogeneity index (HI) and PTV coverage for both cases, while the correlation between HI and spinal cord sparing was significant only for the single dorsal PTV case. Moreover, the multileaf collimator leaf thickness correlated with the spinal cord sparing. Planners using comparable delivery/planning system techniques produced different QI, highlighting the impact of the planner's skills in the optimization process., Conclusion: Both the technology and the planner's skills are fundamentally important in spine SBRT planning optimization. Knowledge sharing helped to follow the plan objectives.

Purpose: This study evaluated the plan quality of CyberKnife MLC-based treatment planning in comparison to the Iris collimator for abdominal and pelvic SBRT. Multiple dosimetric parameters were considered together with a global scoring index validated by clinical scoring., Methods and Materials: Iris and MLC plans were created for 28 liver, 15 pancreas and 13 prostate cases including a wide range of PTV sizes (24-643 cm 3 ). Plans were compared in terms of coverage, conformity (nCI), dose gradient (R50%), homogeneity (HI), OAR doses, PTV gEUD, MU, treatment time both estimated by TPS (t TPS ) and measured. A global plan quality score index was calculated for IRIS and MLC solutions and validated by a clinical score given independently by two observers., Results: Compared to Iris, MLC achieved equivalent coverage and conformity without compromising OAR sparing and improving R50% (p < 0.001). MLC gEUD was slightly lower than Iris (p < 0.05) for abdominal cases. MLC reduced significantly MU (-15%) and t TPS (-22%). Time reduction was partially lost when measured. The global score index was significantly higher for MLC solutions which were selected in 73% and 64% of cases respectively by the first and second observer., Conclusion: Iris and MLC comparison was not straightforward when based on multiple dosimetric parameters. The use of a mathematical overall score index integrated with a clinical scoring was essential to confirm MLC plans advantages over Iris solutions., (Copyright © 2018 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Purpose: To investigate the quality of treatment plans of spinal radiosurgery derived from different planning and delivery systems. The comparisons include robotic delivery and intensity modulated arc therapy (IMAT) approaches. Multiple centers with equal systems were used to reduce a bias based on individual's planning abilities. The study used a series of three complex spine lesions to maximize the difference in plan quality among the various approaches., Methods: Internationally recognized experts in the field of treatment planning and spinal radiosurgery from 12 centers with various treatment planning systems participated. For a complex spinal lesion, the results were compared against a previously published benchmark plan derived for CyberKnife radiosurgery (CKRS) using circular cones only. For two additional cases, one with multiple small lesions infiltrating three vertebrae and a single vertebra lesion treated with integrated boost, the results were compared against a benchmark plan generated using a best practice guideline for CKRS. All plans were rated based on a previously established ranking system., Results: All 12 centers could reach equality (n = 4) or outperform (n = 8) the benchmark plan. For the multiple lesions and the single vertebra lesion plan only 5 and 3 of the 12 centers, respectively, reached equality or outperformed the best practice benchmark plan. However, the absolute differences in target and critical structure dosimetry were small and strongly planner-dependent rather than system-dependent. Overall, gantry-based IMAT with simple planning techniques (two coplanar arcs) produced faster treatments and significantly outperformed static gantry intensity modulated radiation therapy (IMRT) and multileaf collimator (MLC) or non-MLC CKRS treatment plan quality regardless of the system (mean rank out of 4 was 1.2 vs. 3.1, p = 0.002)., Conclusions: High plan quality for complex spinal radiosurgery was achieved among all systems and all participating centers in this planning challenge. This study concludes that simple IMAT techniques can generate significantly better plan quality compared to previous established CKRS benchmarks.

Purpose: Radiosurgery (RS) is a well-established treatment in selected patients with brain metastasis. The aim of this study is to compare the differences between CyberKnife (CK) and TomoTherapy (HT) treatment plans of RS of single brain metastasis (BM) to define when HT should be used in cases beyond Cyberknife-when both systems are readily available for the radiation oncologist., Methods and Materials: Nineteen patients with single brain metastasis treated with CK were re-planned for radiosurgery using TomoTherapy Hi-ART system. Two planning approaches have been used for TomoTherapy plans: the classical one (HT) and the improved conformity (icHT) that produces dose distributions more similar to those of RS plans. PTV coverage, Conformity Index (CI), Paddick Conformity Index (nCI), Homogeneity Index (HI), Gradient Index (GI), and beam on time of CK, HT, and icHT plans were evaluated and compared., Results: A good coverage was found for CK, HT, and icHT plans. A difference between mean HI of CK and icHT plans was observed (p = 0.007). Better dose gradients compared to both icHT and HT modalities were observed in CK plans. icHT modality showed improved mean CI respect to HT modality, similar to that obtained in CK plans., Conclusions: CK plans show higher conformity and lower GI than icHT and HT plans. TomoTherapy demonstrates the advantage of being a device capable to reach different clinical objectives depending on the different planning modality employed. CyberKnife and TomoTherapy are both optimal RS devices, the choice to use one over another has to be clinically guided.

Purpose: New promising detectors are available for measuring small field size output factors (OFs). This study focused on a multicenter evaluation of two new generation detectors for OF measurements on CyberKnife systems., Methods: PTW-60019 microDiamond and W1 plastic scintillation detector (PSD) were used to measure OFs on eight CyberKnife units of various generations for 5-60mm fixed cones. MicroDiamond and PSD OF were compared to routinely used silicon diodes data corrected applying published Monte Carlo (MC) factors. PSD data were corrected for Čerenkov Light Ratio (CLR). The uncertainties related to CLR determination were estimated., Results: Considering OF values averaged over all centers, the differences between MC corrected diode and the other two detectors were within 1.5%. MicroDiamond exhibited an over-response of 1.3% at 7.5mm and a trend inversion at 5mm with a difference of 0.2%. This behavior was consistent among the different units. OFs measured by PSD slightly under-responded compared to MC corrected diode for the smaller cones and the differences were within 1%. The observed CLR variability was 2.5% and the related variation in OF values was 1.9%., Conclusion: This study indicates that CyberKnife microDiamond OF require corrections below 2%. The results are enhanced by the consistency observed among different units. Scintillator shows a good agreement to MC corrected diode but CLR determination remains critical requiring further investigations. The results emphasized the value of a multi-center validation over a single center approach., (Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Purpose: To report a clinical experience of stereotactic body radiation therapy (SBRT) for isolated recurrence in the prostatic bed from prostate cancer., Materials and Methods: Between November 2011 and November 2013, 16 patients were treated with SBRT for a macroscopic isolated recurrence of prostate cancer in the prostatic bed. All patients were initially treated with radical prostatectomy, and half of them also received radiotherapy. Two schedules of SBRT were used: 30 Gy in 5 fractions in previously irradiated patients, 35 Gy in five fractions in radiotherapy-naïve patients., Results: At a median follow-up of 10 months (range 2-21 months), a significant biochemical response was found in all but one patient. At imaging evaluation, no local progression was noted: 10 patients showed partial response while four stable disease. At the moment of analysis, all 16 patients were alive. Seven of them experienced distant relapse, while nine maintained biochemical control, with no further therapy. Median time to relapse was 9.3 months (range 3-15.2 months). The treatment was well tolerated: One patient experienced G2 acute genitourinary and gastrointestinal toxicity., Conclusions: Our experience shows that SBRT with CyberKnife for isolated nodal relapse is a safe and well-tolerated treatment.

Purpose: To report a clinical experience in stereotactic body radiation therapy (SBRT) for isolated nodal metastases from prostate cancer., Materials and Methods: Between November 2011 and December 2013, 30 patients (39 lesions) were treated with SBRT, delivered using Cyberknife, for recurrent prostate cancer with isolated nodal metastases. Prescribed doses and schedules of fractionation varied, ranging from 24 Gy in 1 fraction to 36 Gy in 3 fractions. Most commonly used schedules were 30 Gy in 3 fractions and 36 in Gy in 3 fractions on alternating days. Biochemical response, acute and late toxicity were analyzed., Results: At a median follow-up of 12 months (range 2-24.9), a significant reduction of PSA was observed in 24 cases, while PSA was stable in 1 case and raised in 9 cases. At the time of analysis, among the 30 patients treated, two were dead for systemic disease; 12 patients experienced a relapse of disease in other sites. Sixteen patients were still free of disease. In 24 cases, imaging evaluation 3 months after treatment was available. No in-field recurrence was detected. SBRT was well tolerated: One patient experienced G2 acute genitourinary toxicity. Late toxicity was evaluated in patients with more than 6 months of follow-up, and only one complained G1 proctitis. We did not observe any acute or late severe toxicity (≥G3)., Conclusions: Our experience shows that SBRT for isolated nodal relapse from prostate cancer is a safe treatment, with promising results in terms of efficacy.

Cyberknife is an emerging treatment for early stage prostate cancer. Between October 2012 and January 2014, 32 patients were treated in our institution. Prescribed dose was 35-36.25 Gy in five fractions. Biochemical response was observed in 22 patients. Four patients experienced G2 acute genitourinary toxicity and in two cases we recorded G3 acute GU toxicity. 5 patients experienced G2 acute proctitis. At last follow up visit, all patients were still alive. 29 remained free of disease at last follow up appointment, while three developed a biochemical recurrence. Our experience confirms the efficacy and safety of Cyberknife for localized prostate cancer.

Aims and Background: Radiobiological and technical considerations have traditionally limited the role of radiation therapy in the context of primary and secondary cardiac malignancies. Stereotactic body radiotherapy (SBRT) is a promising modality for the delivery of focused high-dose radiation with ablative potential to complex targets such as small, deep-seated, moving lesions, allowing also for re-irradiation., Methods: Between January 2013 and October 2013, 3 patients underwent SBRT for cardiac lesions: 2 patients had recurrent, previously irradiated cardiac angiosarcomas (PCA) and 1 patient had a cardiac metastasis from melanoma. They were treated with fiducial-guided robotic radiotherapy with CyberKnife. As for dose prescription, 24 Gy in 3 fractions (80% isodose) and 30 Gy in 5 fractions (80% isodose) were administered to the recurrent PCAs and cardiac metastasis, respectively., Results: At 2 months after SBRT, cardiac MRI showed a partial response in the patients treated for recurrent PCA while the cardiac metastasis remained stable. In all cases, absence of local progression was subsequently confirmed by contrast-enhanced cardiac MRI after 6 months, without any evidence of treatment-related side effects., Conclusions: Fiducial-guided SBRT proved to be feasible and effective in preventing local disease progression in selected patients with cardiac malignancies.

Purpose: The aim of our study was to retrospectively evaluate the feasibility and clinical benefit of cyberknife stereotactic radiosurgery (CSRS) in patients treated at Florence University for recurrent, pre-irradiated brain lesions., Materials and Methods: Thirteen patients were retreated with cyberknife. Mean age was 47.1 years (range 33-77 years). Karnofsky performance status ranged from 60 to 100 (median 80). Eleven (84.6%) out of 13 patients had metastatic lesions: four (36.4%) had primary lung, three (27.2%) had primary breast cancer and four (36.4%) other types of solid malignancies. Two (15.4%) out of 13 patients had recurrent of glioblastoma., Results: In terms of compliance with CSRS, the majority of patients did not develop any acute side effects. However, two (15.4%) out of 13 patients developed acute grade 2 toxicity requiring an increase of steroid medication. At the time of the last follow-up, response rates were as follows: complete response in one case (16.6%), partial response in three (50%) and stable disease in two (33.4%)., Conclusions: Re-irradiation with CSRS is a feasible and effective option for pre-irradiated, recurrent brain lesions to obtain clinical benefit without excessive acute toxicity.

Aims and Background: We report the toxicity and preliminary clinical outcome in patients affected by locally recurrent head and neck cancer treated with stereotactic re-irradiation., Methods: Between February 2012 and August 2013, 17 patients were treated with CyberKnife as stereotactic re-irradiation for locally recurrent head and neck cancer. All patients had previously received a full dose radiation treatment with radical intent, with a median total dose of 66 Gy (range, 50-70) delivered with standard fractionation. The median interval between the primary radiotherapy and re-irradiation was 24 months (range, 10-168)., Results: All patients completed the prescribed treatment, which was delivered in 5 fractions. The median tumor dose administered was 30 Gy (range, 25-35) prescribed to the 80% isodose line. Treatment sites were as follows: neck lymph nodes in 5 patients, paranasal sinuses in 5, oropharynx in 2, nasopharynx, and larynx, oral cavity, nasal fossa and parotid gland each in 1 patient. The median target volume treated was 58.7 cm3 (range, 8.5-211.3). Sixteen patients (94%) were evaluated for response. At a median follow-up of 7.5 months (range, 2-17), 4 patients achieved complete response (25%), 5 had partial response (31%) and 7 showed stable disease (44%). No patient showed in-field progression after re-irradiation. Grade 3 acute toxicity was noted in one patient only; no late side effect was observed during the follow-up., Conclusions: Stereotactic re-irradiation with CyberKnife is an appealing non-surgical salvage treatment for selected patients with local-regionally recurrent head and neck cancer.

Aims: With the aim to identify the instruments validated for Italian nursing practice, a systematic review of the literature was undertaken., Results: A total of 101 instruments emerged. The majority (89; 88.1%) were developed in other countries; the remaining (14; 13.9%) were developed and validated in the Italian context. The instruments were developed to measure patient's problems (63/101; 62.4%), outcomes (27/101; 26.7%), risks (4/101; 4%) and others issues (7/101; 6.9%). The majority of participants involved in the validation processes were younger adults (49; 48.5%), older adults (40; 39.5%), children (4; 4%), adolescents (3; 3%), and children/adolescents (1; 1%). The instruments were structured primarily in the form of questionnaires (61; 60.4%), as a grid for direct observation (27; 26.7%) or in other forms (12; 11.9%). Among the 101 instruments emerged, there were 1 to 7 validation measures documented with on average 3.2 (95% CI 2.86-3.54) for each instrument., Conclusions: Developing validation studies giving priority to those instruments widely adopted in the clinical nursing practice is recommended.

Purpose: This study sought to evaluate acute toxicity and local control in patients who underwent extracranial stereotactic body radiation therapy (SBRT) for paracardiac and cardiac metastatic lesions, defined as such when located at a maximum distance of 1 cm from the heart or inside its parenchyma., Materials and Methods: Between January 2009 and May 2011, 16 patients with paracardiac and cardiac lesions were treated with SBRT. For dose specification, in 15 of 16 patients, the prescription dosage was 36 Gy in three fractions (70% isodose). In one patient, the target lesion was inside the heart, and the prescription dosage was 30 Gy in three fractions (70% isodose)., Results: Regarding response to stereotactic radiotherapy, we recorded one (6%) complete response (CR), six (37%) partial responses (PR), five (32%) stable disease (SD) and four (25%) local failures. Median interval to local failure was 5.2 (range, 3-12) months. The cause of death was distant progression of disease in all four patients. Compliance to treatment was excellent; no patient developed cardiological symptoms or electrocardiographic abnormalities, even months after SBRT., Conclusions: Results of our retrospective study indicate that SBRT represents a safe and effective treatment option for patients with cardiac and paracardiac metastases.

Aims and background. To report the clinical outcome of linac-based or robotic, image-guided stereotactic body radiotherapy in patients affected by abdominal lymph node metastases from different primary cancers. Methods and methods. Twenty-six patients with 32 abdominal lymph node metastases were consecutively treated at the University of Florence between April 2011 and May 2012. The mean follow-up was 4.6 months (SD, 3.9; range, 0.3-13). The dose prescription ranged between 24 Gy and 36 Gy delivered in 1-5 fractions. Results. In terms of local control, complete response to stereotactic body radiotherapy was obtained in 18 cases (66.7%), partial response in 7 (25.9%), and stable disease in 2 (7.4%). At the Cox univariate regression analysis, an increased risk of partial response or absence of local response to radiotherapy was found for subjects of the female sex (P = 0.036), age less than 50 years (P = 0.022), primary tumor of the genital tract (P = 0.007), and previous chemotherapy (P = 0.057). An excellent local control rate (90.9%) was obtained in patients affected by abdominal lymph node metastases of prostatic origin. Conclusions. Stereotactic body radiotherapy for abdominal lymph node metastases is a safe and effective treatment in terms of high rates of local control, especially in a subset of patients affected by prostate cancer.

Purpose: To evaluate the effect of plan parameters on volumetric modulated arc therapy (VMAT) dosimetric accuracy, together with the possibility of scoring plan complexity., Methods: 142 clinical VMAT plans initially optimized using a 4° control point (CP) separation were evaluated. All plans were delivered by a 6 MV Linac to a biplanar diode array for patient-specific quality assurance (QA). Local Γ index analysis (3%, 3 mm and 2%, 2 mm) enabled the comparison between delivered and calculated dose. The following parameters were considered for each plan: average leaf travel (LT), modulation complexity score applied to VMAT (MCSv), MU value, and a multiplicative combination of LT and MCSv (LTMCS). Pearson's correlation analysis was performed between Γ passing rates and each parameter. The effects of CP angular separation on VMAT dosimetric accuracy were also analyzed by focusing on plans with high LT values. Forty out of 142 plans with LT above 350 mm were further optimized using a finer angle spacing (3° or 2°) and Γ analysis was performed. The average Γ passing rates obtained at 4° and at 3°∕2° sampling were compared. A further correlation analysis between all parameters and the Γ pass-rates was performed on 142 plans, but including the newly optimized 40 plans (CP every 3° or 2°) in place of the old ones (CP every 4°)., Results: A moderate significant (p < 0.05) correlation between each examined parameter and Γ passing rates was observed for the original 142 plans at 4° CP discretization. A negative correlation was found for LT with Pearson's r absolute values above 0.6, suggesting that a lower dosimetric accuracy may be expected for higher LT values when a 4° CP sampling is used. A positive correlation was observed for MCSv and LTMCS with r values above 0.5. In order to score plan complexity, threshold values of LTMCS were defined. The average Γ passing rates were significantly higher for the plans created using the finer CP spacing (3°∕2°) compared to the plans optimized using the standard 4° spacing (Student t-test p < 0.05). The correlation between LT and passing rates was strongly diminished when plans with finer angular separations were considered, yielding Pearson's r absolute values below 0.45., Conclusions: At 4° CP sampling, LT, MCSv, and LTMCS were found to be significantly correlated with VMAT dosimetric accuracy, expressed as Γ pass-rates. These parameters were found to be possible candidates for scoring plan complexity using threshold values. A finer CP separation (3°∕2°) led to a significant increase in dosimetric accuracy for plans with high leaf travel values, and to a decrease in correlation between LT and Γ passing rates. These results indicated that the influence of LT on VMAT dosimetric accuracy can be controlled by reducing CP separation. CP spacing for all plans requiring large leaf motion should not exceed 3°. The reported data were integrated to optimize our clinical workflow for plan creation, optimization, selection among rival plans, and patient-specific QA of VMAT treatments.

Purpose: To evaluate a retrospective single-institution outcome after hypofractionated stereotactic body radiotherapy (SBRT) for adrenal metastases., Methods and Materials: Between February 2002 and December 2009, we treated 48 patients with SBRT for adrenal metastases. The median age of the patient population was 62.7 years (range, 43-77 years). In the majority of patients, the prescription dose was 36 Gy in 3 fractions (70% isodose, 17.14 Gy per fraction at the isocenter). Eight patients were treated with single-fraction stereotactic radiosurgery and forty patients with multi-fraction stereotactic radiotherapy., Results: Overall, the series of patients was followed up for a median of 16.2 months (range, 3-63 months). At the time of analysis, 20 patients were alive and 28 patients were dead. The 1- and 2-year actuarial overall survival rates were 39.7% and 14.5%, respectively. We recorded 48 distant failures and 2 local failures, with a median interval to local failure of 4.9 months. The actuarial 1-year disease control rate was 9%; the actuarial 1- and 2-year local control rate was 90%., Conclusion: Our retrospective study indicated that SBRT for the treatment of adrenal metastases represents a safe and effective option with a control rate of 90% at 2 years., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To compare and evaluate different dosimetric techniques and devices for the QA of VMAT plans created by two treatment planning systems (TPSs)., Methods: A total of 50 VMAT plans were optimized for treatment of anatomical sites of various complexities by two TPSs which use rather different approaches to VMAT optimization. Dosimetric plan verifications were performed both as part of commissioning and as patient specific QA of clinical treatments. Absolute point doses were measured for all plans by a micro ion chamber inserted in a dedicated water-filled cylindrical phantom. Delivered dose distributions were verified by four techniques based on different detectors: radiographic and gafchromic films, two systems based on 2D diode arrays and an ion chamber array. Gamma index analysis with various tolerance levels (3%, 3 mm and 3%, 2 mm) was used to analyze differences between calculated and delivered doses. Sensitivity to possible delivery errors was also evaluated for three of the considered devices introducing +/-3 mm shifts along the three directions and a 3 degrees gantry offset., Results: Ion chamber measured point doses were within 3% of calculated ones for 48 out of 50 values. For delivered dose distribution, the average fraction of passed gamma values using 3% and 3 mm criteria was above 95% for both TPSs and all detectors except gafchromic film which yielded on average of 91.4%. For 49 out of 50 plans, a pass-rate above 94% was obtained by at least one of the four techniques. Shrinking the tolerance to 3% and 2 mm, the average pass-rate by all detectors (except film) was still above 95% for one of the two TPSs, but lower for the other one. The detector sensitivity to 3 mm shifts and to gantry angle offset was strongly plan and partially detector dependent: the obtained pass-rate reduction ranged from 2% to 30%., Conclusions: The presented results for VMAT plans QA assess the reliability of the delivered doses for both TPSs. The slightly lower pass-rate obtained for one of the considered TPS can be attributed to a higher level of complexity of the optimized plans. The results by different dosimetric techniques are coherent, apart from a few measurements by gafchromic films. The detector sensitivity to delivery errors, being strongly plan dependent, is not easy to evaluate.

Introduction: Free-breathing stereotactic radiotherapy for lung malignancies requires reliable prediction of respiratory motion and accurate target localization. A protocol was adopted for reproducibility and reduction of respiratory motion and for target localization by CBCT image guidance. Tumor respiratory displacements and tumor positioning errors relative to bony anatomy alignment are analyzed., Materials and Method: Image guided SRT was performed for 99 lung malignancies. Two groups of patients were considered: group A did not perform any breathing control; group B controlled visually their respiratory cycle and volumes on an Active Breathing Coordinator (ABC) monitor during the acquisition of simulation CT and CBCT, and treatment delivery. GTV on end inhale and exhale CT data sets were fused in an ITV and the extent of tumor motion evaluated between these 2 phases. A pre-treatment CBCT was acquired and aligned to the reference CT using bony anatomy; for tumor positioning the ITV contour on the reference CT was matched to the visible tumor on CBCT. Interobserver variability of tumor positioning was evaluated. ITV and CBCT tumor dimensions were compared., Results: 3D tumor breathing displacement (mean+/-SD) was significantly higher for group A (14.7+/-9.9 mm) than for group B (4.7+/-3.1 mm). The detected differences between tumor and bony structure alignment below 3 mm were 68% for group B and 45% for group A, reaching statistical significance. Interobserver variability was 1.7+/-1.1 mm (mean+/-SD). Dimensions of tumor image on CBCT were consistent with ITV dimensions for group B (max difference 14%)., Conclusions: The adopted protocol seems effective in reducing respiratory internal movements and margin. Tumor positioning errors relative to bony anatomy are also reduced. However bony anatomy as a surrogate of the target may still lead to some relevant positioning errors. Target visualization on CBCT is essential for an accurate localization in lung SRT.

Background: Cystic fibrosis (CF) may strongly condition the life of affected people. CF may be associated with relevant painful conditions caused by complications of the illness and also by therapy itself, which may represent an additional load of suffering. This study was aimed at evaluating the prevalence of pain symptoms in adult CF patients, if they are noticed and treated, and the influence of pain symptoms on patients' life., Method: Using a questionnaire, we examined 239 adults with CF (17% of the whole Italian adult CF population)., Results: We found a high prevalence of painful episodes among CF adult patients, as for both intensity and frequency. In a 2 months period 32.6% of patients experienced episodes of pain described as intense to severe, and 29.7% had more than 10 occurrences of pain in the same location. Headache, gastric pain and backache were the most frequently reported kind of pain. 59.8% of subjects perceived pain episodes as the cause of unfavorable effects on their life. Only 42.6% of those with pain asked a CF center physician for help and another 3.5% a general practitioner., Conclusion: Painful symptoms can be the cause of a worsening of the quality of life for adults with CF; the relevance of pain in CF adult patients may often be underestimated; the assessment of pain should be routinely performed as a part of care in CF centers.

Infections caused by respiratory pathogens such as Burkholderia cepacia and Pseudomonas aeruginosa are associated with an increased morbidity and mortality in people affected by cystic fibrosis, the most common lethal genetic disease in Caucasian populations. Preventing the acquisition of these pathogens is paramount for these patients. The goal of this survey was to assess the distribution and the prevalence of the measures adopted for the prevention and control of infections caused by respiratory pathogens in the 28 italian centres for cystic fibrosis. 21 questionnaires were returned and some important differences can be observed in the adoption of segregation measures. Although results may be influenced by other factors, specific segregation policies appear to be more directly associated than other measures (e.g., intensive disinfection; behavioural rules to minimise patient' contacts) with lower prevalence of Pseudomonas aeruginosa (OR 0.36 CI95% 0.31-0.42), of multidrug-resistant Pseudomonas aeruginosa (OR 0.30 CI95% 0.22-0.40), and of methicillin-resistant Staphylococcus aureus (OR 0.67 CI95% 0.48-0.94).

In view of the possible relation between pancreatic function and cystic fibrosis (CF) gene mutations, a detailed study on Italian patients was performed. Seventy pancreatic insufficient and 48 pancreatic sufficient patients were included after very accurate characterisation of their pancreatic and digestive function, all performed in the same CF centre. The CF gene deletion F508 was tested to define the patients' genotypes. The results confirm that the mutation correlates with pancreatic insufficiency, and is recessive to other, as yet unreported, mutant alleles that determine pancreatic sufficiency. An indication that duodenal bicarbonate output is more severely reduced in the presence of deletion F508 is also presented. The data are discussed in relation to a hypothesis on the primary effects of CF gene deletion F508.