Radiomics in the characterization of lipid-poor adrenal adenomas at unenhanced CT: time to look beyond usual density metrics.

OBJECTIVES: In this study, we developed a radiomic signature for the classification of benign lipid-poor adenomas, which may potentially help clinicians limit the number of unnecessary investigations in clinical practice. Indeterminate adrenal lesions of benign and malignant nature may exhibit different values of key radiomics features. METHODS: Patients who had available histopathology reports and a non-contrast-enhanced CT scan were included in the study. Radiomics feature extraction was done after the adrenal lesions were contoured. The primary feature selection and prediction performance scores were calculated using the least absolute shrinkage and selection operator (LASSO). To eliminate redundancy, the best-performing features were further examined using the Pearson correlation coefficient, and new predictive models were created. RESULTS: This investigation covered 50 lesions in 48 patients. After LASSO-based radiomics feature selection, the test dataset's 30 iterations of logistic regression models produced an average performance of 0.72. The model with the best performance, made up of 13 radiomics features, had an AUC of 0.99 in the training phase and 1.00 in the test phase. The number of features was lowered to 5 after performing Pearson's correlation to prevent overfitting. The final radiomic signature trained a number of machine learning classifiers, with an average AUC of 0.93. CONCLUSIONS: Including more radiomics features in the identification of adenomas may improve the accuracy of NECT and reduce the need for additional imaging procedures and clinical workup, according to this and other recent radiomics studies that have clear points of contact with current clinical practice. CLINICAL RELEVANCE STATEMENT: The study developed a radiomic signature using unenhanced CT scans for classifying lipid-poor adenomas, potentially reducing unnecessary investigations that scored a final accuracy of 93%. KEY POINTS: • Radiomics has potential for differentiating lipid-poor adenomas and avoiding unnecessary further investigations. • Quadratic mean, strength, maximum 3D diameter, volume density, and area density are promising predictors for adenomas. • Radiomics models reach high performance with average AUC of 0.95 in the training phase and 0.72 in the test phase.

A Novel Benchmarking Approach to Assess the Agreement among Radiomic Tools.

Background The translation of radiomic models into clinical practice is hindered by the limited reproducibility of features across software and studies. Standardization is needed to accelerate this process and to bring radiomics closer to clinical deployment. Purpose To assess the standardization level of seven radiomic software programs and investigate software agreement as a function of built-in image preprocessing (eg, interpolation and discretization), feature aggregation methods, and the morphological characteristics (ie, volume and shape) of the region of interest (ROI). Materials and Methods The study was organized into two phases: In phase I, the two Image Biomarker Standardization Initiative (IBSI) phantoms were used to evaluate the IBSI compliance of seven software programs. In phase II, the reproducibility of all IBSI-standardized radiomic features across tools was assessed with two custom Italian multicenter Shared Understanding of Radiomic Extractors (ImSURE) digital phantoms that allowed, in conjunction with a systematic feature extraction, observations on whether and how feature matches between program pairs varied depending on the preprocessing steps, aggregation methods, and ROI characteristics. Results In phase I, the software programs showed different levels of completeness (ie, the number of computable IBSI benchmark values). However, the IBSI-compliance assessment revealed that they were all standardized in terms of feature implementation. When considering additional preprocessing steps, for each individual program, match percentages fell by up to 30%. In phase II, the ImSURE phantoms showed that software agreement was dependent on discretization and aggregation as well as on ROI shape and volume factors. Conclusion The agreement of radiomic software varied in relation to factors that had already been standardized (eg, interpolation and discretization methods) and factors that need standardization. Both dependences must be resolved to ensure the reproducibility of radiomic features and to pave the way toward the clinical adoption of radiomic models. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Steiger in this issue. An earlier incorrect version appeared online and in print. This article was corrected on March 2, 2022.

Efficacy of different sequences of radio- and chemotherapy in experimental models of human melanoma.

Although combination chemotherapy and radiotherapy have become the standard of care in numerous tumors, the mechanisms of interaction are often still unclear. The purpose of this study was to analyze the efficacy of radiation treatment and cisplatin sequences and to investigate their mechanisms of interaction. Three melanoma cell lines were used to evaluate in vitro radiation-induced cytotoxicity before and after cisplatin treatment. Expression levels of a panel of genes were determined by real-time RT-PCR. Cytotoxic effect was evaluated by flow cytometry analysis and Comet assay. We also used normal human dermal fibroblasts (HUDE) to evaluate the cytotoxicity of the two treatments by clonogenic assay. Radiation and cisplatin used singly were not particularly effective in reducing proliferation in melanoma cells. Conversely, radiation treatment followed by cisplatin showed a strong synergistic interaction in all cell lines, with a ratio index ranging from 16 to >100. The synergistic effect was accompanied by apoptosis induction (up to 40%) and an increase in the percentage of comet-shaped nucleoids from 85% to 99%. In parallel, our results also showed that radiation treatment of HUDE fibroblasts followed by cisplatin only induced weak cytotoxicity. Our findings highlight the efficacy of the sequence radiation → cisplatin in reducing cell proliferation and in inducing apoptosis in melanoma cell lines. This sequence also modulated a network of proteins involved in DNA damage repair.

Radiomics Analysis on [68Ga]Ga-PSMA-11 PET and MRI-ADC for the Prediction of Prostate Cancer ISUP Grades: Preliminary Results of the BIOPSTAGE Trial.

Prostate cancer (PCa) risk categorization based on clinical/PSA testing results in a substantial number of men being overdiagnosed with indolent, early-stage PCa. Clinically non-significant PCa is characterized as the presence of ISUP grade one, where PCa is found in no more than two prostate biopsy cores.MRI-ADC and [68Ga]Ga-PSMA-11 PET have been proposed as tools to predict ISUP grade one patients and consequently reduce overdiagnosis. In this study, Radiomics analysis is applied to MRI-ADC and [68Ga]Ga-PSMA-11 PET maps to quantify tumor characteristics and predict histology-proven ISUP grades. ICC was applied with a threshold of 0.6 to assess the features' stability with variations in contouring. Logistic regression predictive models based on imaging features were trained on 31 lesions to differentiate ISUP grade one patients from ISUP two+ patients. The best model based on [68Ga]Ga-PSMA-11 PET returned a prediction efficiency of 95% in the training phase and 100% in the test phase whereas the best model based on MRI-ADC had an efficiency of 100% in both phases. Employing both imaging modalities, prediction efficiency was 100% in the training phase and 93% in the test phase. Although our patient cohort was small, it was possible to assess that both imaging modalities add information to the prediction models and show promising results for further investigations.

Radiation protection and dosimetry issues for patients with prostate cancer after I-125 low-dose-rate brachytherapy permanent implant.

PURPOSE: The aim of this work was to analyze the exposure rates measured in the proximity of patients who underwent prostate low-dose-rate brachytherapy with I-125 implant. Effective doses to relatives and to population were computed to estimate the time to reach radioprotection dose constraints. METHODS AND MATERIALS: Measurements were obtained from 180 patients, whereas the body mass index was calculated and reported for 77 patients. The day after the implant, K˙ measurements were conducted at various skin distances and positions and converted to effective doses. A theoretical model was developed to estimate effective doses from total implanted activity. The latter was approximated with a 10-mL vial inside the patient. RESULTS: The K˙ measurements showed a low correlation with the total implanted activity, albeit an increasing trend of K˙ was observed on increasing the activity. A stronger correlation was found between body mass index and K˙ measurements. The effective dose to population is in general lower than dose constraints as well as the effective doses to relatives, with the exception of children and pregnant women, who command special precautions. We report differences between the experimental model- and theoretical model-based dose evaluation together with their comparison with previous studies found in literature. CONCLUSIONS: Based on the K˙ measurements and the results of the present analysis, it is possible to provide the patient with radiation safety instructions specifically tailored to his relatives' habits and working environment.

A Multicentre Evaluation of Dosiomics Features Reproducibility, Stability and Sensitivity.

Dosiomics is a texture analysis method to produce dose features that encode the spatial 3D distribution of radiotherapy dose. Dosiomic studies, in a multicentre setting, require assessing the features' stability to dose calculation settings and the features' capability in distinguishing different dose distributions. Dose distributions were generated by eight Italian centres on a shared image dataset acquired on a dedicated phantom. Treatment planning protocols, in terms of planning target volume coverage and dose-volume constraints to the organs at risk, were shared among the centres to produce comparable dose distributions for measuring reproducibility/stability and sensitivity of dosiomic features. In addition, coefficient of variation (CV) was employed to evaluate the dosiomic features' variation. We extracted 38,160 features from 30 different dose distributions from six regions of interest, grouped by four features' families. A selected group of features (CV < 3 for the reproducibility/stability studies, CV > 1 for the sensitivity studies) were identified to support future multicentre studies, assuring both stable features when dose distributions variation is minimal and sensitive features when dose distribution variations need to be clearly identified. Dosiomic is a promising tool that could support multicentre studies, especially for predictive models, and encode the spatial and statistical characteristics of the 3D dose distribution.

The potential role of MR based radiomic biomarkers in the characterization of focal testicular lesions.

How to differentiate with MRI-based techniques testicular germ (TGCTs) and testicular non-germ cell tumors (TNGCTs) is still under debate and Radiomics may be the turning key. Our purpose is to investigate the performance of MRI-based Radiomics signatures for the preoperative prediction of testicular neoplasm histology. The aim is twofold: (i), differentiating TGCTs and TNGCTs status and (ii) differentiating seminomas (SGCTs) from non-seminomatous (NSGCTs). Forty-two patients with pathology-proven testicular neoplasms and referred for pre-treatment MRI, were retrospectively enrolled. Thirty-two out of 44 lesions were TGCTs. Twelve out of 44 were TNGCTs or other histologies. Two radiologists segmented the volume of interest on T2-weighted images. Approximately 500 imaging features were extracted. Least Absolute Shrinkage and Selection Operator (LASSO) was applied as method for variable selection. A linear model and a linear support vector machine (SVM) were trained with selected features to assess discrimination scores for the two endpoints. LASSO identified 3 features that were employed to build fivefold validated linear discriminant and linear SVM classifiers for the TGCT-TNGCT endpoint giving an overall accuracy of 89%. Four features were employed to build another SVM for the SGCT-SNGCT endpoint with an overall accuracy of 86%. The data obtained proved that T2-weighted-based Radiomics is a promising tool in the diagnostic workup of testicular neoplasms by discriminating germ cell from non-gem cell tumors, and seminomas from non-seminomas.

The influence of basic plan parameters on calculated small field output factors - A multicenter study.

PURPOSE: The influence of basic plan parameters such as slice thickness, grid resolution, algorithm type and field size on calculated small field output factors (OFs) was evaluated in a multicentric study. METHODS AND MATERIALS: Three computational homogeneous water phantoms with slice thicknesses (ST) 1, 2 and 3 mm were shared among twenty-one centers to calculate OFs for 1x1, 2x2 and 3x3 cm2 field sizes (FSs) (normalized to 10x10 cm2 FS), with their own treatment planning system (TPS) and the energy clinically used for stereotactic body radiation therapy delivery. OFs were calculated for each combination of grid resolution (GR) (1, 2 and 3 mm) and ST and finally compared with the OFs measured for the TPS commissioning. A multivariate analysis was performed to test the effect of basic plan parameters on calculated OFs. RESULTS: A total of 509 data points were collected. Calculated OFs are slightly higher than measured ones. The multivariate analysis showed that Center, GR, algorithm type, and FS are predictive variables of the difference between calculated and measured OFs (p < 0.001). As FS decreases, the spread in the difference between calculated and measured OFs became larger when increasing the GR. Monte Carlo and Analytical Anisotropic Algorithms, presented a dependence on GR (p < 0.01), while Collapsed Cone Convolution and Acuros did not. The effect of the ST was found to be negligible. CONCLUSIONS: Modern TPSs slightly overestimate the calculated small field OFs compared with measured ones. Grid resolution, algorithm, center number and field size influence the calculation of small field OFs.

Computed Tomography to Cone Beam Computed Tomography Deformable Image Registration for Contour Propagation Using Head and Neck, Patient-Based Computational Phantoms: A Multicenter Study.

PURPOSE: To investigate the performance of various algorithms for deformable image registration (DIR) for propagating regions of interest (ROIs) using multiple commercial platforms, from computed tomography to cone beam computed tomography (CBCT) and megavoltage computed tomography. METHODS AND MATERIALS: Fourteen institutions participated in the study using 5 commercial platforms: RayStation (RaySearch Laboratories, Stockholm, Sweden), MIM (Cleveland, OH), VelocityAI and SmartAdapt (Varian Medical Systems, Palo Alto, CA), and ABAS (Elekta AB, Stockholm, Sweden). Algorithms were tested on synthetic images generated with the ImSimQA (Oncology Systems Limited, Shrewsbury, UK) package by applying 2 specific deformation vector fields (DVF) to real head and neck patient datasets. On-board images from 3 systems were used: megavoltage computed tomography from Tomotherapy and 2 kinds of CBCT from a clinical linear accelerator. Image quality of the system was evaluated. The algorithms' accuracy was assessed by comparing the DIR-mapped ROIs returned by each center with those of the reference, using the Dice similarity coefficient and mean distance to conformity metrics. Statistical inference on the validation results was carried out to identify the prognostic factors of DIR performance. RESULTS: Analyzing 840 DIR-mapped ROIs returned by the centers, it was demonstrated that DVF intensity and image quality were significant prognostic factors of DIR performance. The accuracy of the propagated contours was generally high, and acceptable DIR performance can be obtained with lower-dose CBCT image protocols. CONCLUSIONS: The performance of the systems proved to be image quality specific, depending on the DVF type and only partially on the platforms. All systems proved to be robust against image artifacts and noise, except the demon-based software.

Performance of commercially available deformable image registration platforms for contour propagation using patient-based computational phantoms: A multi-institutional study.

PURPOSE: To investigate the performance of various algorithms for deformable image registration (DIR) to propagate regions of interest (ROIs) using multiple commercial platforms. METHODS AND MATERIALS: Thirteen institutions participated in the study with six commercial platforms: RayStation (RaySearch Laboratories, Stockholm, Sweden), MIM (Cleveland, OH, USA), VelocityAI and Smart Adapt (Varian Medical Systems, Palo Alto, CA, USA), Mirada XD (Mirada Medical Ltd, Oxford, UK), and ABAS (Elekta AB, Stockholm, Sweden). The DIR algorithms were tested on synthetic images generated with the ImSimQA package (Oncology Systems Limited, Shrewsbury, UK) by applying two specific Deformation Vector Fields (DVF) to real patient data-sets. Head-and-neck (HN), thorax, and pelvis sites were included. The accuracy of the algorithms was assessed by comparing the DIR-mapped ROIs from each center with those of reference, using the Dice Similarity Coefficient (DSC) and Mean Distance to Conformity (MDC) metrics. Statistical inference on validation results was carried out in order to identify the prognostic factors of DIR performances. RESULTS: DVF intensity, anatomic site and participating center were significant prognostic factors of DIR performances. Sub-voxel accuracy was obtained in the HN by all algorithms. Large errors, with MDC ranging up to 6 mm, were observed in low-contrast regions that underwent significant deformation, such as in the pelvis, or large DVF with strong contrast, such as the clinical tumor volume (CTV) in the lung. Under these conditions, the hybrid DIR algorithms performed significantly better than the free-form intensity based algorithms and resulted robust against intercenter variability. CONCLUSIONS: The performances of the systems proved to be site specific, depending on the DVF type and the platforms and the procedures used at the various centers. The pelvis was the most challenging site for most of the algorithms, which failed to achieve sub-voxel accuracy. Improved reproducibility was observed among the centers using the same hybrid registration algorithm.

Monte Carlo dose voxel kernel calculations of beta-emitting and Auger-emitting radionuclides for internal dosimetry: A comparison between EGSnrcMP and EGS4.

Dose-point kernels (DPKs) can be widely applied to therapeutic nuclear medicine to obtain more accurate absorbed dose assessments in internal dosimetry assuming a spherical geometry. Recently, EGSnrc-the latest in the family of EGS Monte Carlo codes--has been tested for isotropic monoenergetic electrons and Y-90 beta spectrum in spherical geometry. The availability of SPECT images allows one to take into account heterogeneities in activity distribution within tumors, and to perform dose calculations using voxel dosimetry based on Monte Carlo simulations in a Cartesian geometry. The purpose of this study is to evaluate the differences of dose distributions scored in Cartesian voxels also known as Dose Voxel Kernels (DVKs) for five beta-emitting (131I, 89Sr, 153Sm, 186Re, and 90Y) and Auger-emitting (111In) radionuclides, when their computation is made using these two Monte Carlo codes from the same family to check if the new physics in EGSnrc simulation system produces DVK very different from those calculated with EGS4. We have calculated the DVKs for point and voxel sources in Cartesian scoring grids of different spatial resolutions. Our results for the point source, scored in the finer spatial resolution, show a poor agreement between EGSnrc and EGS4 (up to about 20%) for voxels closer to the origin, and a better agreement (below 5%) for longer distances for all radionuclides. For the voxel source, where doses were scored in the coarser spatial resolution, dose deposition in the central voxel is in good agreement for all the radionuclides; while surrounding voxels exhibit a slightly worse agreement.

MR Spectroscopy in Prostate Cancer: New Algorithms to Optimize Metabolite Quantification.

Prostate cancer (PCa) is the most common non-cutaneous cancer in male subjects and the second leading cause of cancer-related death in developed countries. The necessity of a non-invasive technique for the diagnosis of PCa in early stage has grown through years. Proton magnetic resonance spectroscopy (1H-MRS) and proton magnetic resonance spectroscopy imaging (1H-MRSI) are advanced magnetic resonance techniques that can mark the presence of metabolites such as citrate, choline, creatine and polyamines in a selected voxel, or in an array of voxels (in MRSI) inside prostatic tissue. Abundance or lack of these metabolites can discriminate between pathological and healthy tissue. Although the use of magnetic resonance spectroscopy (MRS) is well established in brain and liver with dedicated software for spectral analysis, quantification of metabolites in prostate can be very difficult to achieve, due to poor signal to noise ratio and strong J-coupling of the citrate. The aim of this work is to develop a software prototype for automatic quantification of citrate, choline and creatine in prostate. Its core is an original fitting routine that makes use of a fixed step gradient descent minimization algorithm (FSGD) and MRS simulations developed with the GAMMA libraries in C++. The accurate simulation of the citrate spin systems allows to predict the correct J-modulation under different NMR sequences and under different coupling parameters. The accuracy of the quantifications was tested on measurements performed on a Philips Ingenia 3T scanner using homemade phantoms. Some acquisitions in healthy volunteers have been also carried out to test the software performance in vivo.

Preliminary Retrospective Analysis of Daily Tomotherapy Output Constancy Checks Using Statistical Process Control.

The purpose of this study was to retrospectively evaluate the results from a Helical TomoTherapy Hi-Art treatment system relating to quality controls based on daily static and dynamic output checks using statistical process control methods. Individual value X-charts, exponentially weighted moving average charts, and process capability and acceptability indices were used to monitor the treatment system performance. Daily output values measured from January 2014 to January 2015 were considered. The results obtained showed that, although the process was in control, there was an out-of-control situation in the principal maintenance intervention for the treatment system. In particular, process capability indices showed a decreasing percentage of points in control which was, however, acceptable according to AAPM TG148 guidelines. Our findings underline the importance of restricting the acceptable range of daily output checks and suggest a future line of investigation for a detailed process control of daily output checks for the Helical TomoTherapy Hi-Art treatment system.

Lung stereotactic ablative body radiotherapy: A large scale multi-institutional planning comparison for interpreting results of multi-institutional studies.

PURPOSE: A large-scale multi-institutional planning comparison on lung cancer SABR is presented with the aim of investigating possible criticism in carrying out retrospective multicentre data analysis from a dosimetric perspective. METHODS: Five CT series were sent to the participants. The dose prescription to PTV was 54Gy in 3 fractions of 18Gy. The plans were compared in terms of PTV-gEUD2 (generalized Equivalent Uniform Dose equivalent to 2Gy), mean dose to PTV, Homogeneity Index (PTV-HI), Conformity Index (PTV-CI) and Gradient Index (PTV-GI). We calculated the maximum dose for each OAR (organ at risk) considered as well as the MLD2 (mean lung dose equivalent to 2Gy). The data were stratified according to expertise and technology. RESULTS: Twenty-six centers equipped with Linacs, 3DCRT (4% - 1 center), static IMRT (8% - 2 centers), VMAT (76% - 20 centers), CyberKnife (4% - 1 center), and Tomotherapy (8% - 2 centers) collaborated. Significant PTV-gEUD2 differences were observed (range: 105-161Gy); mean-PTV dose, PTV-HI, PTV-CI, and PTV-GI were, respectively, 56.8±3.4Gy, 14.2±10.1%, 0.70±0.15, and 4.9±1.9. Significant correlations for PTV-gEUD2 versus PTV-HI, and MLD2 versus PTV-GI, were observed. CONCLUSIONS: The differences in terms of PTV-gEUD2 may suggest the inclusion of PTV-gEUD2 calculation for retrospective data inter-comparison.

SLUG silencing increases radiosensitivity of melanoma cells in vitro.

BACKGROUND: Melanoma radioresistance has been attributed to the presence of tumor cells with highly efficient DNA damage repair mechanisms. We examined the expression of genes involved in DNA damage repair and DNA damage sensing, and assessed their modulation by SLUG silencing, which is potentially capable of increasing radiosensitivity. METHODS: Two melanoma cell lines (M14 and M79) were used to evaluate in vitro radiation-induced cytotoxicity before and after SLUG silencing. mRNA expression levels of BRCA1, ERCC1, DNA-PK, PARP, MGMT, ATM and TGM2 were determined by real-time RT-PCR, and protein expression levels of SLUG, caspase 3, p21, PUMA and pMAPK by Western blotting. RESULTS: The cytotoxic effect of radiation was high in M14 and low in M79 cells. SLUG silencing increased the interference of radiation on cell cycle distribution and cell killing by 60 % and 80 % in M79 cells after a 2.4 Gy and 5 Gy radiation dose, respectively. It also led to a significant inhibition of expression of genes involved in DNA damage repair and DNA damage sensing in all cell lines maintained after radiation. An almost total inhibition was observed for TGM2, which is expressed at a high basal level in the most radioresistant cell line (M79). Protein expression of PUMA was induced by radiation and was enhanced after SLUG silencing. CONCLUSIONS: Our results reveal a pivotal role of SLUG in regulating a cellular network involved in the response to DNA damage, and highlight the importance of TGM2 in radiosensitivity modulation. SLUG silencing appears to increase radiation sensitivity of the melanoma cells tested.

In vitro irradiation system for radiobiological experiments.

BACKGROUND: Although two-dimensional (2-D) monolayer cell cultures provide important information on basic tumor biology and radiobiology, they are not representative of the complexity of three-dimensional (3-D) solid tumors. In particular, new models reproducing clinical conditions as closely as possible are needed for radiobiological studies to provide information that can be translated from bench to bedside. METHODS: We developed a novel system for the irradiation, under sterile conditions, of 3-D tumor spheroids, the in vitro model considered as a bridge between the complex architectural organization of in vivo tumors and the very simple one of in vitro monolayer cell cultures. The system exploits the same equipment as that used for patient treatments, without the need for dedicated and highly expensive instruments. To mimic the passage of radiation beams through human tissues before they reach the target tumor mass, 96-multiwell plates containing the multicellular tumor spheroids (MCTS) are inserted into a custom-built phantom made of plexiglass, the material most similar to water, the main component of human tissue. RESULTS: The system was used to irradiate CAEP- and A549-derived MCTS, pre-treated or not with 20 µM cisplatin, with a dose of 20 Gy delivered in one session. We also tested the same treatment schemes on monolayer CAEP and A549 cells. Our preliminary results indicated a significant increment in radiotoxicity 20 days after the end of irradiation in the CAEP spheroids pre-treated with cisplatin compared to those treated with cisplatin or irradiation alone. Conversely, the effect of the radio- chemotherapy combination in A549-derived MCTS was similar to that induced by cisplatin or irradiation alone. Finally, the 20 Gy dose did not affect cell survival in monolayer CAEP and A549 cells, whereas cisplatin or cisplatin plus radiation caused 100% cell death, regardless of the type of cell line used. CONCLUSIONS: We set up a system for the irradiation, under sterile conditions, of tumor cells grown in 3-D which allows for the use of the same dose intensities and schedules utilized in clinical practice. This irradiation system, coupled with 3-D cell cultures, has the potential to generate information that could be used to individually tailor radiotherapy.