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Purpose: This retrospective work aims to evaluate the possible impact on intra‐ and inter‐observer variability, contouring time, and contour accuracy of introducing a pelvis computed tomography (CT) auto‐segmentation tool in radiotherapy planning workflow. Methods: Tests were carried out on five structures (bladder, rectum, pelvic lymph‐nodes, and femoral heads) of six previously treated subjects, enrolling five radiation oncologists (ROs) to manually re‐contour and edit auto‐contours generated with a male pelvis CT atlas created with the commercial software MIM MAESTRO. The ROs first delineated manual contours (M). Then they modified the auto‐contours, producing automatic‐modified (AM) contours. The procedure was repeated to evaluate intra‐observer variability, producing M1, M2, AM1, and AM2 contour sets (each comprising 5 structures × 6 test patients × 5 ROs = 150 contours), for a total of 600 contours. Potential time savings was evaluated by comparing contouring and editing times. Structure contours were compared to a reference standard by means of Dice similarity coefficient (DSC) and mean distance to agreement (MDA), to assess intra‐ and inter‐observer variability. To exclude any automation bias, ROs evaluated both M and AM sets as "clinically acceptable" or "to be corrected" in a blind test. Results: Comparing AM to M sets, a significant reduction of both inter‐observer variability (p < 0.001) and contouring time (‐45% whole pelvis, p < 0.001) was obtained. Intra‐observer variability reduction was significant only for bladder and femoral heads (p < 0.001). The statistical test showed no significant bias. Conclusion: Our atlas‐based workflow proved to be effective for clinical practice as it can improve contour reproducibility and generate time savings. Based on these findings, institutions are encouraged to implement their auto‐segmentation method. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Evidence suggests that brain network dynamics are a key determinant of brain function and dysfunction. Here we propose a new framework to assess the dynamics of brain networks based on recurrence analysis. Our framework uses recurrence plots and recurrence quantification analysis to characterize dynamic networks. For resting‐state magnetoencephalographic dynamic functional networks (dFNs), we have found that functional networks recur more quickly in people with epilepsy than in healthy controls. This suggests that recurrence of dFNs may be used as a biomarker of epilepsy. For stereo electroencephalography data, we have found that dFNs involved in epileptic seizures emerge before seizure onset, and recurrence analysis allows us to detect seizures. We further observe distinct dFNs before and after seizures, which may inform neurostimulation strategies to prevent seizures. Our framework can also be used for understanding dFNs in healthy brain function and in other neurological disorders besides epilepsy. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this work was to establish a methodological approach for creation and optimization of an atlas for auto‐contouring, using the commercial software MIM MAESTRO (MIM Software Inc. Cleveland OH). Methods: A computed tomography (CT) male pelvis atlas was created and optimized to evaluate how different tools and options impact on the accuracy of automatic segmentation. Pelvic lymph nodes (PLN), rectum, bladder, and femurs of 55 subjects were reviewed for consistency by a senior consultant radiation oncologist with 15 yr of experience. Several atlas and workflow options were tuned to optimize the accuracy of auto‐contours. The deformable image registration (DIR), the finalization method, the k number of atlas best matching subjects, and several post‐processing options were studied. To test our atlas performances, automatic and reference manual contours of 20 test subjects were statistically compared based on dice similarity coefficient (DSC) and mean distance to agreement (MDA) indices. The effect of field of view (FOV) reduction on auto‐contouring time was also investigated. Results: With the optimized atlas and workflow, DSC and MDA median values of bladder, rectum, PLN, and femurs were 0.91 and 1.6 mm, 0.85 and 1.6 mm, 0.85 and 1.8 mm, and 0.96 and 0.5 mm, respectively. Auto‐contouring time was more than halved by strictly cropping the FOV of the subject to be contoured to the pelvic region. Conclusion: A statistically significant improvement of auto‐contours accuracy was obtained using our atlas and optimized workflow instead of the MIM Software pelvic atlas. [ABSTRACT FROM AUTHOR]

Purpose: To develop and validate a robust template for VMAT SBRT of lung lesions, using the multicriterial optimization (MCO) of a commercial treatment planning system. Methods: The template was established and refined on 10 lung SBRT patients planned for 55 Gy/5 fr. To improve gradient and conformity a ring structure around the planning target volume (PTV) was set in the list of objectives. Ideal fluence optimization was conducted giving priority to organs at risk (OARs) and using the MCO, which further pushes OARs doses. Segmentation was conducted giving priority to PTV coverage. Two different templates were produced with different degrees of modulation, by setting the Fluence Smoothing parameter to Medium (MFS) and High (HFS). Each template was applied on 20 further patients. Automatic and manual plans were compared in terms of dosimetric parameters, delivery time, and complexity. Statistical significance of differences was evaluated using paired two‐sided Wilcoxon signed‐rank test. Results: No statistically significant differences in PTV coverage and maximum dose were observed, while an improvement was observed in gradient and conformity. A general improvement in dose to OARs was seen, which resulted to be significant for chest wall V30 Gy, total lung V20 Gy, and spinal cord D0.1 cc. MFS plans are characterized by a higher modulation and longer delivery time than manual plans. HFS plans have a modulation and a delivery time comparable to manual plans, but still present an advantage in terms of gradient. Conclusion: The automation of the planning process for lung SBRT using robust templates and MCO was demonstrated to be feasible and more efficient. [ABSTRACT FROM AUTHOR]

Objective: To assess the safety and effectiveness of stereotactic salvage radiotherapy (SSRT) in RT‐naïve patients affected by macroscopic prostate bed recurrence. Patients and methods: Consecutive patients treated for prostate bed macroscopic recurrence in three different Italian institutes were reviewed. Patients were treated with SSRT, with a total dose of 30–40 Gy in five fractions, the mean pre‐SSRT PSA level was 2.3 ng/mL. Two different PSA thresholds were defined and biochemical recurrence‐free survival (BCRFS) was reported, in order to better express outcome: BCRFS1 (a PSA level increase of >10% compared to the pre‐SSRT value) and BCRFS2 (a PSA level increase of >0.2 ng/mL for patients with a PSA nadir of <0.2 ng/mL or two consecutive PSA level increases of >25% compared to nadir in patients with a PSA nadir of <0.2 ng/mL). Results: In all, 90 patients were treated, with a mean (range) follow‐up of 21.2 (2–64) months, and 17 of these patients (19%) had concomitant androgen‐deprivation therapy (ADT) during SSRT. Complete biochemical response, defined as a PSA nadir of <0.2 ng/mL, was obtained in 39 of the 90 patients (43.3%). Considering BCRFS1, 25 patients (27.8%) had BCR, with an actuarial median BCRFS1 time of 36.4 months. For BCRFS2, BCR was reported in 32 patients (35.5%), with an actuarial median BCRFS2 time of 24.3 months. There was no Grade >2 toxicity. Conclusions: SSRT was found to yield significant biochemical control and allowed ADT delay despite adverse features. [ABSTRACT FROM AUTHOR]

Background: We investigated whether the pattern of intensity‐modulated radiotherapy (IMRT) dose distribution to the skin can be correlated with the development of G3/G4 radiation dermatitis (RD). Methods: A frequency‐matched cohort analysis was perfomed on patients treated with IMRT and concurrent cisplatin or cetuximab. Risk ratios were obtained by fitting Poisson regression models. Results: The incidence of G3/G4 RD was 41.1% in 90 patients included (50% vs 36.6% in the cetuximab and cisplatin cohorts, respectively). In multivariate analysis, PS ≥ 1 and weight loss at RT completion >10 kg were the only factors that retained significance. The best dosimetric predictive accuracy was provided by 19.9 cc and 5.8 cc of skin ring 2 mm V50 and V60, respectively (AUC: 0.61 for both). Conclusion: Along with clinical factors, the pattern of dose distribution to a ring structure localized 2 mm below the patient's surface may help predict the development of severe RD. [ABSTRACT FROM AUTHOR]

A quantitative evaluation of the performances of the deformable image registration (DIR) algorithm implemented in MIM‐Maestro was performed using multiple similarity indices. Two phantoms, capable of mimicking different anatomical bending and tumor shrinking were built and computed tomography (CT) studies were acquired after applying different deformations. Three different contrast levels between internal structures were artificially created modifying the original CT values of one dataset. DIR algorithm was applied between datasets with increasing deformations and different contrast levels and manually refined with the Reg Refine tool. DIR algorithm ability in reproducing positions, volumes, and shapes of deformed structures was evaluated using similarity indices such as: landmark distances, Dice coefficients, Hausdorff distances, and maximum diameter differences between segmented structures. Similarity indices values worsen with increasing bending and volume difference between reference and target image sets. Registrations between images with low contrast (40 HU) obtain scores lower than those between images with high contrast (970 HU). The use of Reg Refine tool leads generally to an improvement of similarity parameters values, but the advantage is generally less evident for images with low contrast or when structures with large volume differences are involved. The dependence of DIR algorithm on image deformation extent and different contrast levels is well characterized through the combined use of multiple similarity indices. [ABSTRACT FROM AUTHOR]

Abstract: Tumor resistance to apoptosis is one the main causes of anticancer treatment failure. Previous studies showed that LMW‐PTP overexpression enhances resistance of cancer cells to traditional anticancer drugs. Today, the role of LMW‐PTP in inducing resistance to apoptosis in melanoma cells remains to be elucidated. Experimental setting include MTT assay, Annexin V/Pi method, and colony assay to assess whether silencing of LMW‐PTP improves the sensitivity of A375 to dacarbazine, 5‐FU, and radiotherapy. Pharmacological targeting of LMW‐PTP was obtained using Morin, a LMW‐PTP inhibitor. The ability of Morin to improve the effectiveness of anticancer drugs and radiotherapy was also studied. Moreover, PC3 cells were used as an alternative cellular model to confirm the data obtained with melanoma cells. We found that LMW‐PTP silencing improves the effectiveness of dacarbazine, 5‐FU, and radiotherapy. Identical results were obtained in vivo when Morin was used to target LMW‐PTP. We demonstrated that Morin synergizes with dacarbazine, improving its cytotoxic activity. However, we showed that the combined treatment, Morin‐anticancer drug, does not affect the viability of noncancerous cells. Knockdown of LMW‐PTP sensitizes also PC3 cells to docetaxel and radiotherapy. In conclusion, we showed that LMW‐PTP targeting improves effectiveness of anticancer drugs used for treatment of melanoma. Moreover, our results suggest that Morin could be used as adjuvant to improve the outcome of patients affected by metastatic melanoma. [ABSTRACT FROM AUTHOR]

Abstract: Background: Oral mucositis is a side effect of treatment regimens containing 5‐fluorouracil (5‐FU). The purpose of this study was to present our evaluation to see if rosiglitazone (RGZ) protected normal tissues from chemotherapy‐induced oral mucositis. Methods: C57BL/6J mice were treated with 5‐FU for 5 days, with or without RGZ. Mice were euthanized after 5, 8, 11, or 15 days, and mucosal segments were collected. Results: The RGZ did not affect the 5‐FU‐induced decrease in mouse body weight. The 5‐FU caused loss of epithelial architecture, collagen fiber impairment, and inflammatory infiltration. The RGZ reduced leukocyte infiltration, preserved tissue structure, and dampened the 5‐FU‐induced expression of p53 and matrix metalloproteinase (Mmp)‐2 after 5 days, and of Mmp‐2 and interleukin (Il‐1β after 15 days. The RGZ inhibited the 5‐FU‐induced increase of transforming growth factor‐beta (TGF‐β) and nuclear factor‐kappa B (NF‐κB) proteins and restored collagen protein levels. Conclusion: The RGZ had a protective effect on oral mucosa damaged by chemotherapy. These data encourage the further study of RGZ for the prevention of 5‐FU‐induced mucositis in patients with cancer. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis To review toxicity and outcomes in patients with head and neck cancer treated with simultaneous integrated boost-intensity-modulated radiotherapy (SIB-IMRT). Study Design Review of experience with the SIB-IMRT technique. Methods Fifty patients were treated with the SIB-IMRT technique. Two possible schedules of radiation therapy (RT) were used: SIB 70 (70/60/54 in 33 fractions) and SIB 66 (66/60/54 in 33 fractions). Forty-one patients also received chemotherapy. Results All but two patients completed treatment as prescribed. No G4 acute toxicity has been reported in our series. We did not observe any G3 to G4 chronic toxicity, apart from one case of cutaneous necrosis. After a median follow-up of 23.3 months (range, 1-60 months), 41 patients (82%) were alive and negative for disease, and one patient (2%) was alive with distant metastases. Eight patients (16%) died, seven because of progressive disease and one for other causes. Conclusions SIB-IMRT is a highly effective and safe technique of RT in the treatment of head and neck cancer. Level of Evidence 4 Laryngoscope, 123:E97-E103, 2013 [ABSTRACT FROM AUTHOR]

BACKGROUND: The objective of this study was to evaluate prognostic factors of local and distant recurrence in patients diagnosed with T1a and T1b, lymph node-negative breast carcinoma (BC) with emphasis on human epidermal growth factor receptor 2 (HER2) status. METHODS: The authors reviewed 704 women with T1aT1bN0M0 BC who received treatment at the Radiation-Oncology Center of Florence University between November 2002 and December 2008. Patients with ductal carcinoma in situ or recurrent BC at presentation and patients who received adjuvant chemotherapy were excluded from the analysis. RESULTS: In total, 75 patients had HER2-positive BC (10.7%). At a mean follow-up of 4.9 years (standard deviation, 2.6 years; range, 0.5-10.8 years), 19 events were identified, including 10 distant recurrences. Patients with HER2-positive BC had worse distant recurrence-free survival (DRFS) than patients with HER2-negative BC (hazard ratio, 3.66; 95% confidence interval, 0.94-14.69; P = .045). Negative hormone receptor (HR) status was associated significantly with worse DRFS (hazard ratio, 0.26; 95% confidence interval, 0.07-0.93; P = .026). In multivariate analysis, younger age was the only significant risk factor for an event of recurrence (hazard ratio, 0.61;95% confidence interval, 0.20-1.82; P = .029). CONCLUSIONS: The current results indicated that patients with T1a/T1b, lymph node-negative BC have a low risk of distant and local recurrence, but younger age is a significant risk factor for events occurrence. Young women with HER2-positive and HR-negative status have a significant risk of distant recurrence and should be considered for future clinical trials with anti-HER2 adjuvant therapy. Cancer 2011. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

We present the case of a 52-year-old woman with a history of excised cutaneous malignant melanoma complaining of abnormal uterine bleeding 11 years after initial diagnosis. Hysteroscopic examination showed an endometrial lesion with polypoid shape and endometrial biopsy was suggestive for melanoma. After a complete clinical work-up ruling out other metastatic sites, the patient underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy and pelvic lymphadenectomy. Final histopathological and immunohistochemical analysis confirmed the diagnosis of endometrial melanoma with initial myometrial invasion. After a 6-month follow-up period, the patient was disease free. Even after many years of negative follow up, gynecologists should be aware of the possibility that abnormal uterine bleeding could represent the clinical expression of metastatic melanoma in order to offer a prompt diagnosis and a personalized strategy of treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]