Two-dimensional and doppler echocardiographic evaluation in twenty-one healthy Python regius.

Echocardiographic evaluation is a diagnostic tool for the in vivo diagnosis of heart diseases. Specific and unique anatomical characteristics of the ophidian heart such as the single ventricular cavity, a tubular sinus venosus opening into the right atrium, the presence of three arterial trunks and extreme mobility in the coelomic cavity during the cardiac cycle directly affect echocardiographic examination. Twenty-one awake, healthy ball pythons (Python regius) were analysed based on guidelines for performing echocardiographic examinations. Imaging in the sagittal plane demonstrated the caudal vena cava, sinus venosus valve (SVV) and right atrium and the various portions of the ventricle, horizontal septum, left aortic arch and pulmonary artery. Transverse imaging depicted the spatial relationship of the left and right aortic arches, the pulmonary artery and the horizontal septum. Basic knowledge of cardiac blood flow in reptiles is necessary to understand the echocardiographic anatomy. The flow of the arterial trunks and SVV was analysed using pulsed-wave Doppler based on the approach used for humans and companion mammals. The walls and diameters of the cavum arteriosum, cavum venosum and cavum pulmonale were also evaluated. This study should improve the veterinarian's knowledge of ophidian heart basal physiology and contribute to the development of cardiology in reptiles.

Predicting Knee Joint Instability Using a Tibio-Femoral Statistical Shape Model.

Statistical shape models (SSMs) are a well established computational technique to represent the morphological variability spread in a set of matching surfaces by means of compact descriptive quantities, traditionally called "modes of variation" (MoVs). SSMs of bony surfaces have been proposed in biomechanics and orthopedic clinics to investigate the relation between bone shape and joint biomechanics. In this work, an SSM of the tibio-femoral joint has been developed to elucidate the relation between MoVs and bone angular deformities causing knee instability. The SSM was built using 99 bony shapes (distal femur and proximal tibia surfaces obtained from segmented CT scans) of osteoarthritic patients. Hip-knee-ankle (HKA) angle, femoral varus-valgus (FVV) angle, internal-external femoral rotation (IER), tibial varus-valgus (TVV) angles, and tibial slope (TS) were available across the patient set. Discriminant analysis (DA) and logistic regression (LR) classifiers were adopted to underline specific MoVs accounting for knee instability. First, it was found that thirty-four MoVs were enough to describe 95% of the shape variability in the dataset. The most relevant MoVs were the one encoding the height of the femoral and tibial shafts (MoV #2) and the one representing variations of the axial section of the femoral shaft and its bending in the frontal plane (MoV #5). Second, using quadratic DA, the sensitivity results of the classification were very accurate, being all >0.85 (HKA: 0.96, FVV: 0.99, IER: 0.88, TVV: 1, TS: 0.87). The results of the LR classifier were mostly in agreement with DA, confirming statistical significance for MoV #2 (p = 0.02) in correspondence to IER and MoV #5 in correspondence to HKA (p = 0.0001), FVV (p = 0.001), and TS (p = 0.02). We can argue that the SSM successfully identified specific MoVs encoding ranges of alignment variability between distal femur and proximal tibia. This discloses the opportunity to use the SSM to predict potential misalignment in the knee for a new patient by processing the bone shapes, removing the need for measuring clinical landmarks as the rotation centers and mechanical axes.

A multi-metric registration strategy for the alignment of longitudinal brain images in pediatric oncology.

Survival of pediatric patients with brain tumor has increased over the past 20 years, and increasing evidence of iatrogenic toxicities has been reported. In follow-ups, images are acquired at different time points where substantial changes of brain morphology occur, due to childhood physiological development and treatment effects. To address the image registration complexity, we propose two multi-metric approaches (Mplus, Mdot), combining mutual information (MI) and normalized gradient field filter (NGF). The registration performance of the proposed metrics was assessed on a simulated dataset (Brainweb) and compared with those obtained by MI and NGF separately, using mean magnitude and mean angular errors. The most promising metric (Mplus) was then selected and tested on a retrospective dataset comprising 45 pediatric patients who underwent focal radiotherapy for brain cancer. The quality of the realignment was scored by a radiation oncologist using a perceived misalignment metric (PM). All patients but one were assessed as PM ≤ 2 (good alignment), but the remaining one, severely affected by hydrocephalus and pneumocephalus at the first MRI acquisition, scored PM = 5 (unacceptable). These preliminary findings suggest that Mplus might improve the registration accuracy in complex applications such as pediatric oncology, when data are acquired throughout the years of follow-up, and is worth investigating. Graphical abstract Graphical abstract showing the clinical workflow of the overall registration procedure including the three rigid steps, the fourth deformable step, the reference MRI and the registered MRI as well as the contoured ROIs. The registration performance is assessed by means of the Perceived Misalignment score (PM).

T2w-MRI signal normalization affects radiomics features reproducibility.

PURPOSE: Despite its increasing application, radiomics has not yet demonstrated a solid reliability, due to the difficulty in replicating analyses. The extraction of radiomic features from clinical MRI (T1w/T2w) presents even more challenges because of the absence of well-defined units (e.g. HU). Some preprocessing steps are required before the estimation of radiomic features and one of this is the intensity normalization, that can be performed using different methods. The aim of this work was to evaluate the effect of three different normalization techniques, applied on T2w-MRI images of the pelvic region, on radiomic features reproducibility. METHODS: T2w-MRI acquired before (MRI1) and 12 months after radiotherapy (MRI2) from 14 patients treated for prostate cancer were considered. Four different conditions were analyzed: (a) the original MRI (No_Norm); (b) MRI normalized by the mean image value (Norm_Mean); (c) MRI normalized by the mean value of the urine in the bladder (Norm_ROI); (d) MRI normalized by the histogram-matching method (Norm_HM). Ninety-one radiomic features were extracted from three organs of interest (prostate, internal obturator muscles and bulb) at both time-points and on each image discretized using a fixed bin-width approach and the difference between the two time-points was calculated (Δfeature). To estimate the effect of normalization methods on the reproducibility of radiomic features, ICC was calculated in three analyses: (a) considering the features extracted on MRI2 in the four conditions together and considering the influence of each method separately, with respect to No_Norm; (b) considering the features extracted on MRI2 in the four conditions with respect to the inter-observer variability in region of interest (ROI) contouring, considering also the effect of the discretization approach; (c) considering Δfeature to evaluate if some indices can recover some consistency when differences are calculated. RESULTS: Nearly 60% of the features have shown poor reproducibility (ICC < 0.5) on MRI2 and the method that most affected features reliability was Norm_ROI (average ICC of 0.45). The other two methods were similar, except for first-order features, where Norm_HM outperformed Norm_Mean (average ICC = 0.33 and 0.76 for Norm_Mean and Norm_HM, respectively). In the inter-observer setting, the number of reproducible features varied in the three structures, being higher in the prostate than in the penile bulb and in the obturators. The analysis on Δfeature highlighted that more than 60% of the features were not consistent with respect to the normalization method and confirmed the high reproducibility of the features between Norm_Mean and Norm_HM, whereas Norm_ROI was the less reproducible method. CONCLUSIONS: The normalization process impacts the reproducibility of radiomic features, both in terms of changes in the image information content and in the inter-observer setting. Among the considered methods, Norm_Mean and Norm_HM seem to provide the most reproducible features with respect to the original image and also between themselves, whereas Norm_ROI generates less reproducible features. Only a very small subset of feature remained reproducible and independent in any tested condition, regardless the ROI and the adopted algorithm: skewness or kurtosis, correlation and one among Imc2, Idmn and Idn from GLCM group.

Representative 3D shape of the distal femur, modes of variation and relationship with abnormality of the trochlear region.

The anatomy of the distal femur has a predominant influence on the mechanics of both patello- and tibio-femoral joints. Especially, the morphological degeneration of the trochlear region dramatically affects the overall knee biomechanics and, from a clinical point of view, the staging of such a degeneration is fundamental to tailor the optimal therapeutic solution. The description of morphological variability and pathological inter-subject differences of the trochlea can be achieved by means of statistical shape modeling of a set of three-dimensional surfaces. This representation encodes information, spread into the dataset, in terms of modes of variations that model global, regional and even local morphological features. In view of that, the aim of this study was to develop a statistical shape model of the distal femur to capture the variability of the trochlear region into specific modes of variation and to study the interplay between the variation of the trochlea and the condylar regions. Using CT scans of patients affected by different levels of abnormality of the trochlear region, the distal femur geometries were co-registered to a reference shape using the pair-wise correspondence approach and principal component analysis provided the key modes of variation (MoVs). Apart from the first two MoVs, which described the global magnitude of the femur and the shaft length, the main following ones showed high correlation with sulcus depth (r2=0.70), sulcus angle (r2=0.70), lateral trochlear inclination (r2=0.66), and height of the two condylar facets in the anterior direction (r2=0.66), whose abnormal variations are typical signs of trochlear degeneration. High interplay between trochlear abnormalities and notch width (r2=0.71), lateral condylar size (r2=0.67), and medial condylar size (r2=0.99) was found. Interestingly, the model predicted morphological associations not included in the training dataset, nonetheless difficult to demonstrate physiologically. Interestingly from a biomechanical point of view, the distribution of some MoVs was found statistically different across the patients featuring physiological and pathological ranges of hip-knee-ankle alignment, femoral internal-external rotation and tibial slope. However, no linear correlation was found between the angular indexes and such MoVs. As a result, we can assert that statistical modeling of the distal femur are to date an effective way to visualize and quantify abnormalities of the trochlear regions supporting the introduction of advanced analysis, diagnostic and treatment support tools to elucidate physiologic and pathological variability in the morphology, to drive the staging and assist the selection of the optimal treatment option tailored to the patient.

Pair-wise vs group-wise registration in statistical shape model construction: representation of physiological and pathological variability of bony surface morphology.

Statistical shape models (SSM) of bony surfaces have been widely proposed in orthopedics, especially for anatomical bone modeling, joint kinematic analysis, staging of morphological abnormality, and pre- and intra-operative shape reconstruction. In the SSM computation, reference shape selection, shape registration and point correspondence computation are fundamental aspects determining the quality (generality, specificity and compactness) of the SSM. Such procedures can be made critical by the presence of large morphological dissimilarities within the surfaces, not only because of anthropometrical variability but also mainly due to pathological abnormalities. In this work, we proposed a SW pipeline for SSM construction based on pair-wise (PW) shape registration, which requires the a-priori selection of the reference shape, and on a custom iterative point correspondence algorithm. We addressed large morphological deformations in five different bony surface sets, namely proximal femur, distal femur, patella, proximal fibula and proximal tibia, extracted from a retrospective patient dataset. The technique was compared to a method from the literature, based on group-wise (GW) shape registration. As a main finding, the proposed technique provided generalization and specificity median errors, for all the five bony regions, lower than 2 mm. The comparative analysis provided basically similar results. Particularly, for the distal femur that was the shape affected by the largest pathological deformations, the differences in generalization, specificity and compactness were lower than 0.5 mm, 0.5 mm, and 1%, respectively. We can argue the proposed pipeline, along with the robust correspondence algorithm, is able to compute high-quality SSM of bony shapes, even affected by large morphological variability.

Model-Supported Radiotherapy Personalization: In silico Test of Hyper- and Hypo-Fractionation Effects.

The need for radiotherapy personalization is now widely recognized, however, it would require considerations not only on the probability of control and survival of the tumor, but also on the possible toxic effects, on the quality of the expected life and the economic efficiency of the treatment. In this paper, we propose a simulation tool that can be integrated into a decision support system that allows selection of the most suitable irradiation regimen. We used a macroscale mathematical model, which includes active and necrotic tumor dynamics and the role of oxygenation to simulate the effects of different hypo-/hyper-fractional regimens using retrospective data of seven virtual patients from as many cervical cancer patients used for its training in a previous study. The results confirmed the heterogeneous response across the patients as a function of treatment regimen and suggested the tumor growth rate as a main factor in the final tumor regression. In addition to the maximum regression, another criterion was suggested to select the most suitable regimen (minimum number of fractions to achieve a regression of 80%) minimizing the toxicity and maximizing the cost-effectiveness ratio. Despite the lack of direct validation, the simulation results are in agreement with the literature findings that suggest the need for hypo-fractionated regimens in case of aggressive tumor phenotypes. Finally, the paper suggests a possible exploitation of the model within a tool to support clinical decisions.

Stacked sparse autoencoder networks and statistical shape models for automatic staging of distal femur trochlear dysplasia.

BACKGROUND: The quantitative morphological analysis of the trochlear region in the distal femur and the precise staging of the potential dysplastic condition constitute a key point for the use of personalized treatment options for the patella-femoral joint. In this paper, we integrated statistical shape models (SSM), able to represent the individual morphology of the trochlea by means of a set of parameters and stacked sparse autoencoder (SSPA) networks, which exploit the parameters to discriminate among different levels of abnormalities. METHODS: Two datasets of distal femur reconstructions were obtained from CT scans, including pathologic and physiologic shapes. Both of them were processed to compute SSM of healthy and dysplastic trochlear regions. The parameters obtained by the 3D-3D reconstruction of a femur shape were fed into a trained SSPA classifier to automatically establish the membership to one of three clinical conditions, namely, healthy, mild dysplasia, and severe dysplasia of the trochlea. The validation was performed on a subset of the shapes not used in the construction of the SSM, by verifying the occurrence of a correct classification. RESULTS: A major finding of the work is that SSM are able to represent anomalies of the trochlear geometry by means of specific eigenmodes of variation and to model the interplay between morphologic features related to dysplasia. Exploiting the patient-specific morphing parameters of SSM, computed by means of a 3D-3D reconstruction, SSPA is demonstrated to outperform traditional discriminant analysis in classifying healthy, mild, and severe trochlear dysplasia providing 99%, 97%, and 98% accuracy for each of the three classes, respectively (discriminant analysis accuracy: 85%, 89%, and 77%). CONCLUSIONS: From a clinical point of view, this paper contributes to support the increasing role of SSM, integrated with deep learning techniques, in diagnostics and therapy definition as quantitative and advanced visualization tools.

Comparison between model-predicted tumor oxygenation dynamics and vascular-/flow-related Doppler indices.

PURPOSE: Mathematical modeling is a powerful and flexible method to investigate complex phenomena. It discloses the possibility of reproducing expensive as well as invasive experiments in a safe environment with limited costs. This makes it suitable to mimic tumor evolution and response to radiotherapy although the reliability of the results remains an issue. Complexity reduction is therefore a critical aspect in order to be able to compare model outcomes to clinical data. Among the factors affecting treatment efficacy, tumor oxygenation is known to play a key role in radiotherapy response. In this work, we aim at relating the oxygenation dynamics, predicted by a macroscale model trained on tumor volumetric data of uterine cervical cancer patients, to vascularization and blood flux indices assessed on Ultrasound Doppler images. METHODS: We propose a macroscale model of tumor evolution based on three dynamics, namely active portion, necrotic portion, and oxygenation. The model parameters were assessed on the volume size of seven cervical cancer patients administered with 28 fractions of intensity modulated radiation therapy (IMRT) (1.8 Gy/fraction). For each patient, five Doppler ultrasound tests were acquired before, during, and after the treatment. The lesion was manually contoured by an expert physician using 4D View® (General Electric Company - Fairfield, Connecticut, United States), which automatically provided the overall tumor volume size along with three vascularization and/or blood flow indices. Volume data only were fed to the model for training purpose, while the predicted oxygenation was compared a posteriori to the measured Doppler indices. RESULTS: The model was able to fit the tumor volume evolution within 8% error (range: 3-8%). A strong correlation between the intrapatient longitudinal indices from Doppler measurements and oxygen predicted by the model (about 90% or above) was found in three cases. Two patients showed an average correlation value (50-70%) and the remaining two presented poor correlations. The latter patients were the ones featuring the smallest tumor reduction throughout the treatment, typical of hypoxic conditions. Moreover, the average oxygenation value predicted by the model was close to the average vascularization-flow index (average difference: 7%). CONCLUSIONS: The results suggest that the modeled relation between tumor evolution and oxygen dynamics was reasonable enough to provide realistic oxygenation curves in five cases (correlation greater than 50%) out of seven. In case of nonresponsive tumors, the model failed in predicting the oxygenation trend while succeeded in reproducing the average oxygenation value according to the mean vascularization-flow index. Despite the need for deeper investigations, the outcomes of the present work support the hypothesis that a simple macroscale model of tumor response to radiotherapy is able to predict the tumor oxygenation. The possibility of an objective and quantitative validation on imaging data discloses the possibility to translate them as decision support tools in clinical practice and to move a step forward in the treatment personalization.

Tumor radio-sensitivity assessment by means of volume data and magnetic resonance indices measured on prostate tumor bearing rats.

PURPOSE: Radiation therapy is one of the most common treatments in the fight against prostate cancer, since it is used to control the tumor (early stages), to slow its progression, and even to control pain (metastasis). Although many factors (e.g., tumor oxygenation) are known to influence treatment efficacy, radiotherapy doses and fractionation schedules are often prescribed according to the principle "one-fits-all," with little personalization. Therefore, the authors aim at predicting the outcome of radiation therapy a priori starting from morphologic and functional information to move a step forward in the treatment customization. METHODS: The authors propose a two-step protocol to predict the effects of radiation therapy on individual basis. First, one macroscopic mathematical model of tumor evolution was trained on tumor volume progression, measured by caliper, of eighteen Dunning R3327-AT1 bearing rats. Nine rats inhaled 100% O2 during irradiation (oxy), while the others were allowed to breathe air. Second, a supervised learning of the weight and biases of two feedforward neural networks was performed to predict the radio-sensitivity (target) from the initial volume and oxygenation-related information (inputs) for each rat group (air and oxygen breathing). To this purpose, four MRI-based indices related to blood and tissue oxygenation were computed, namely, the variation of signal intensity ΔSI in interleaved blood oxygen level dependent and tissue oxygen level dependent (IBT) sequences as well as changes in longitudinal ΔR1 and transverse ΔR2(*) relaxation rates. RESULTS: An inverse correlation of the radio-sensitivity parameter, assessed by the model, was found with respect the ΔR2(*) (-0.65) for the oxy group. A further subdivision according to positive and negative values of ΔR2(*) showed a larger average radio-sensitivity for the oxy rats with ΔR2(*)<0 and a significant difference in the two distributions (p < 0.05). Finally, a leave-one-out procedure yielded a radio-sensitivity error lower than 20% in both neural networks. CONCLUSIONS: While preliminary, these specific results suggest that subjects affected by the same pathology can benefit differently from the same irradiation modalities and support the usefulness of IBT in discriminating between different responses.

Modeling the Interplay Between Tumor Volume Regression and Oxygenation in Uterine Cervical Cancer During Radiotherapy Treatment.

This paper describes a patient-specific mathematical model to predict the evolution of uterine cervical tumors at a macroscopic scale, during fractionated external radiotherapy. The model provides estimates of tumor regrowth and dead-cell reabsorption, incorporating the interplay between tumor regression rate and radiosensitivity, as a function of the tumor oxygenation level. Model parameters were estimated by minimizing the difference between predicted and measured tumor volumes, these latter being obtained from a set of 154 serial cone-beam computed tomography scans acquired on 16 patients along the course of the therapy. The model stratified patients according to two different estimated dynamics of dead-cell removal and to the predicted initial value of the tumor oxygenation. The comparison with a simpler model demonstrated an improvement in fitting properties of this approach (fitting error average value <5%, p < 0.01), especially in case of tumor late responses, which can hardly be handled by models entailing a constant radiosensitivity, failing to model changes from initial severe hypoxia to aerobic conditions during the treatment course. The model predictive capabilities suggest the need of clustering patients accounting for cancer cell line, tumor staging, as well as microenvironment conditions (e.g., oxygenation level).

Kinetic Models for Predicting Cervical Cancer Response to Radiation Therapy on Individual Basis Using Tumor Regression Measured In Vivo With Volumetric Imaging.

This article describes a macroscopic mathematical modeling approach to capture the interplay between solid tumor evolution and cell damage during radiotherapy. Volume regression profiles of 15 patients with uterine cervical cancer were reconstructed from serial cone-beam computed tomography data sets, acquired for image-guided radiotherapy, and used for model parameter learning by means of a genetic-based optimization. Patients, diagnosed with either squamous cell carcinoma or adenocarcinoma, underwent different treatment modalities (image-guided radiotherapy and image-guided chemo-radiotherapy). The mean volume at the beginning of radiotherapy and the end of radiotherapy was on average 23.7 cm(3) (range: 12.7-44.4 cm(3)) and 8.6 cm(3) (range: 3.6-17.1 cm(3)), respectively. Two different tumor dynamics were taken into account in the model: the viable (active) and the necrotic cancer cells. However, according to the results of a preliminary volume regression analysis, we assumed a short dead cell resolving time and the model was simplified to the active tumor volume. Model learning was performed both on the complete patient cohort (cohort-based model learning) and on each single patient (patient-specific model learning). The fitting results (mean error: ∼ 16% and ∼ 6% for the cohort-based model and patient-specific model, respectively) highlighted the model ability to quantitatively reproduce tumor regression. Volume prediction errors of about 18% on average were obtained using cohort-based model computed on all but 1 patient at a time (leave-one-out technique). Finally, a sensitivity analysis was performed and the data uncertainty effects evaluated by simulating an average volume perturbation of about 1.5 cm(3) obtaining an error increase within 0.2%. In conclusion, we showed that simple time-continuous models can represent tumor regression curves both on a patient cohort and patient-specific basis; this discloses the opportunity in the future to exploit such models to predict how changes in the treatment schedule (number of fractions, doses, intervals among fractions) might affect the tumor regression on an individual basis.

Mathematical modeling of tumor response to radiation: radio-sensitivity correlation with BOLD, TOLD, ΔR1 and ΔR2* investigated in large Dunning R3327-AT1 rat prostate tumors.

Tumor response to radiation therapy can vary highly across patients. Several factors, both tumor- and environment-specific, can influence the radio-sensitivity, one of the most well-known being hypoxia. In this work, we investigated possible correlations between the radio-sensitivity parameters determined by means of a simple mathematical model of tumor volume evolution, and the MRI-based indicators of oxygenation in Dunning R3327-AT1 rats. Prior to irradiation the rats were subjected to an oxygen-breathing challenge, which was evaluated by MRI. The tumors were administered a single irradiation dose (30 Gy), while breathing air or oxygen. Despite a poor fitting performance, the model was able to identify two different tumor volume regression patterns. Moreover, the radio-sensitivity of the oxygen-breathing group was found to correlate with the variation of the transverse relaxation rate ΔR2* (-0.89). This suggests that MRI-based indices of tumor oxygenation may provide information about radio-sensitivity.