Development and external validation of a prediction model for the transition from mild to moderate or severe form of COVID-19.

OBJECTIVES: COVID-19 pandemic seems to be under control. However, despite the vaccines, 5 to 10% of the patients with mild disease develop moderate to critical forms with potential lethal evolution. In addition to assess lung infection spread, chest CT helps to detect complications. Developing a prediction model to identify at-risk patients of worsening from mild COVID-19 combining simple clinical and biological parameters with qualitative or quantitative data using CT would be relevant to organizing optimal patient management. METHODS: Four French hospitals were used for model training and internal validation. External validation was conducted in two independent hospitals. We used easy-to-obtain clinical (age, gender, smoking, symptoms' onset, cardiovascular comorbidities, diabetes, chronic respiratory diseases, immunosuppression) and biological parameters (lymphocytes, CRP) with qualitative or quantitative data (including radiomics) from the initial CT in mild COVID-19 patients. RESULTS: Qualitative CT scan with clinical and biological parameters can predict which patients with an initial mild presentation would develop a moderate to critical form of COVID-19, with a c-index of 0.70 (95% CI 0.63; 0.77). CT scan quantification improved the performance of the prediction up to 0.73 (95% CI 0.67; 0.79) and radiomics up to 0.77 (95% CI 0.71; 0.83). Results were similar in both validation cohorts, considering CT scans with or without injection. CONCLUSION: Adding CT scan quantification or radiomics to simple clinical and biological parameters can better predict which patients with an initial mild COVID-19 would worsen than qualitative analyses alone. This tool could help to the fair use of healthcare resources and to screen patients for potential new drugs to prevent a pejorative evolution of COVID-19. CLINICAL TRIAL REGISTRATION: NCT04481620. CLINICAL RELEVANCE STATEMENT: CT scan quantification or radiomics analysis is superior to qualitative analysis, when used with simple clinical and biological parameters, to determine which patients with an initial mild presentation of COVID-19 would worsen to a moderate to critical form. KEY POINTS: • Qualitative CT scan analyses with simple clinical and biological parameters can predict which patients with an initial mild COVID-19 and respiratory symptoms would worsen with a c-index of 0.70. • Adding CT scan quantification improves the performance of the clinical prediction model to an AUC of 0.73. • Radiomics analyses slightly improve the performance of the model to a c-index of 0.77.

A Model-Strengthened Imaging Biomarker for Survival Prediction in EGFR-Mutated Non-small-cell Lung Carcinoma Patients Treated with Tyrosine Kinase Inhibitors.

Non-small-cell lung carcinoma is a frequent type of lung cancer with a bad prognosis. Depending on the stage and genomics, several therapeutical approaches are used. Tyrosine Kinase Inhibitors (TKI) may be successful for a time in the treatment of EGFR-mutated non-small cells lung carcinoma. Our objective is here to introduce a survival assessment as their efficacy in the long run is challenging to evaluate. The study includes 17 patients diagnosed with EGFR-mutated non-small cell lung cancer and exposed to an EGFR-targeting TKI with 3 computed tomography (CT) scans of the primary tumor (one before the TKI introduction and two after). An imaging biomarker based on evolution of texture heterogeneity between the first and the third exams is derived and computed from a mathematical model and patient data. Defining the overall survival as the time between the introduction of the TKI treatment and the patient death, we obtain a statistically significant correlation between the overall survival and our imaging marker ([Formula: see text]). Using the ROC curve, the patients are separated into two populations and the comparison of the survival curves is statistically significant ([Formula: see text]). The baseline exam seems to have a significant role in the prediction of response to TKI treatment. More precisely, our imaging biomarker defined using only the CT scan before the TKI introduction allows to determine a first classification of the population which is improved over time using the imaging marker as soon as more CT scans are available. This exploratory study leads us to think that it is possible to obtain a survival assessment using only few CT scans of the primary tumor.

High-Grade Soft-Tissue Sarcomas: Can Optimizing Dynamic Contrast-Enhanced MRI Postprocessing Improve Prognostic Radiomics Models?

BACKGROUND: Heterogeneity on pretreatment dynamic contrast-enhanced (DCE)-MRI of sarcomas may be prognostic, but the best technique to capture this characteristic remains unknown. PURPOSE: To investigate the best method to extract prognostic data from baseline DCE-MRI. STUDY TYPE: Retrospective, single-center. POPULATION: Fifty consecutive uniformly-treated adults with nonmetastatic high-grade sarcomas. FIELD STRENGTH/SEQUENCE: 1.5T; T2 -weighted-imaging, fat-suppressed fast spoiled gradient echo DCE-MRI. ASSESSMENT: Ninety-two radiomics features (RFs) were extracted at each DCE-MRI phase (11, from t = 0-88 sec). Relative changes in RFs (rRFs) since the acquisition baseline were calculated (11 × 92 rRFs). Curves of rRF as function of time postinjection were integrated (92 integrated-rRFs [irRFs]). Ktrans and area under the time-intensity curve at 88-sec parametric maps were computed and 2 × 92 parametric-RFs (pRFs) were extracted. Five DCE-MRI-based radiomics models were built on: an RFs subset (32 sec, 64 sec, 88 sec); all rRFs; all irRFs; and all pRFs. Two models were elaborated as reference, on: conventional radiological features; and T2 -WI RFs. STATISTICAL TESTS: A common machine-learning approach was applied to radiomics models. Features with P < 0.05 at univariate analysis were entered in a LASSO-penalized Cox regression including bootstrapped 10-fold cross-validation. The resulting radiomics scores (RScores) were dichotomized per their median and entered in multivariate Cox models for predicting metastatic relapse-free survival. Models were compared with integrative area under the curve (AUC) and concordance index. RESULTS: Only dichotomized RScores from models based on rRFs subset, all rRFS and irRFS correlated with prognostic (P = 0.0107-0.0377). The models including all rRFs and irRFs had the highest c-index (0.83), followed by the radiological model. The radiological model had the highest integrative AUC (0.87), followed by models including all rRFs and irRFs. The radiological and full rRFs models were significantly better than the T2 -based radiomics model (P = 0.02). DATA CONCLUSION: The initial DCE-MRI of STS contains prognostic information. It seems more relevant to make predictions on rRFs instead of pRFs. Evidence Level: 3 Technical Efficacy: 3 J. Magn. Reson. Imaging 2020;52:282-297.

Influence of temporal parameters of DCE-MRI on the quantification of heterogeneity in tumor vascularization.

BACKGROUND: Evaluating heterogeneity in tumor vascularization through texture analysis could improve predictions of patients' outcome and response evaluation. PURPOSE: To investigate the influence of temporal parameters on texture features extracted from dynamic contrast-enhanced (DCE)-MRI parametric maps. STUDY TYPE: Prospective cross-sectional study. SUBJECTS: Twenty-five adults with soft-tissue sarcoma (STS), median age: 68 years. FIELD STRENGTH/SEQUENCE: DCE-MRI acquisition using a CAIPIRINHA-Dixon-TWIST-VIBE sequence at 1.5T (temporal resolutions: 2 sec, duration: 5 min). ASSESSMENT: The area under time-intensity curve (AUC) and Ktrans maps were generated for several temporal resolution (dt = 2 sec, 4 sec, 6 sec, 8 sec, 10 sec, 12 sec, 20 sec) and scan durations (T = 3 min, 4 min, 5 min for a 6-sec sampling) by downsampling and truncating the initial DCE-MRI sequence. Tumor volume was manually segmented and propagated on all parametric maps. Thirty-two first- and second order-texture features were extracted per map to quantify the intratumoral heterogeneity. STATISTICAL TESTS: The influence of temporal parameters on texture features was studied with repeated-measures analysis of variance (or nonparametric equivalent). The dispersion of each texture feature depending on temporal parameters was estimated with coefficients of variation (CVs). The performances of multivariate models to predict the response to chemotherapy (ie, binary logistic regression based on the baseline texture features) were compared. RESULTS: The temporal resolution had a significant influence on 12/32 (37.5%) and 14/32 (43.8%) texture features evaluated on AUC and Ktrans maps, respectively (range of P < 0.0001-0.0395). Scan duration had a significant influence on 23/32 (71.9%) texture features from Ktrans map (range of P < 0.0001-0.0321). Dispersion was high (mean CV >0.5) with sampling for 2/32 (6.3%) and 10/32 (31.3%) features from AUC and Ktrans maps, respectively; and with truncating for 6/32 (18.8%) features from Ktrans map. The area under the receiver operating characteristics curve of predictive models ranged from 0.77 (95% confidence interval [CI] = [0.54-1.00], with dt = 6 sec T = 4 min) to 0.90 (95% CI = [0.74-1.00], with dt = 6 sec T = 5 min). DATA CONCLUSION: The values of texture features extracted from DCE-MRI parametric maps can be influenced by temporal parameters, which can lead to variations in performance of predictive models. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1773-1788.

T2 -based MRI Delta-radiomics improve response prediction in soft-tissue sarcomas treated by neoadjuvant chemotherapy.

BACKGROUND: Standard of care for patients with high-grade soft-tissue sarcoma (STS) are being redefined since neoadjuvant chemotherapy (NAC) has demonstrated a positive effect on patients' outcome. Yet response evaluation in clinical trials still relies on RECIST criteria. PURPOSE: To investigate the added value of a Delta-radiomics approach for early response prediction in patients with STS undergoing NAC. STUDY TYPE: Retrospective. POPULATION: Sixty-five adult patients with newly-diagnosed, locally-advanced, histologically proven high-grade STS of trunk and extremities. All were treated by anthracycline-based NAC followed by surgery and had available MRI at baseline and after two chemotherapy cycles. FIELD STRENGTH/SEQUENCE: Pre- and postcontrast enhanced T1 -weighted imaging (T1 -WI), turbo spin echo T2 -WI at 1.5 T. ASSESSMENT: A threshold of <10% viable cells on surgical specimens defined good response (Good-HR). Two senior radiologists performed a semantic analysis of the MRI. After 3D manual segmentation of tumors at baseline and early evaluation, and standardization of voxel-sizes and intensities, absolute changes in 33 texture and shape features were calculated. STATISTICAL TESTS: Classification models based on logistic regression, support vector machine, k-nearest neighbors, and random forests were elaborated using crossvalidation (training and validation) on 50 patients ("training cohort") and was validated on 15 other patients ("test cohort"). RESULTS: Sixteen patients were good-HR. Neither RECIST status (P = 0.112) nor semantic radiological variables were associated with response (range of P-values: 0.134-0.490) except an edema decrease (P = 0.003), although 14 shape and texture features were (range of P-values: 0.002-0.037). On the training cohort, the highest diagnostic performances were obtained with random forests built on three features: Δ_Histogram_Entropy, Δ_Elongation, Δ_Surrounding_Edema, which provided: area under the curve the receiver operating characteristic = 0.86, accuracy = 88.1%, sensitivity = 94.1%, and specificity = 66.3%. On the test cohort, this model provided an accuracy of 74.6% but 3/5 good-HR were systematically ill-classified. DATA CONCLUSION: A T2 -based Delta-radiomics approach might improve early response assessment in STS patients with a limited number of features. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:497-510.

Tumor growth model of ductal carcinoma: from in situ phase to stroma invasion.

This paper aims at modeling breast cancer transition from the in situ stage -when the tumor is confined to the duct- to the invasive phase. Such a transition occurs thanks to the degradation of the duct membrane under the action of specific enzymes so-called matrix metalloproteinases (MMPs). The model consists of advection-reaction equations that hold in the duct and in the surrounding tissue, in order to describe the proliferation and the necrosis of the cancer cells in each subdomain. The divergence of the velocity is given by the increase of the cell densities. Darcy law is imposed in order to close the system. The key-point of the modeling lies in the description of the transmission conditions across the duct. Nonlinear Kedem-Katchalsky transmission conditions across the membrane describe the discontinuity of the pressure as a linear function of the flux. These transmission conditions make it possible to describe the transition from the in situ stage to the invasive phase at the macroscopic level. More precisely, the membrane permeability increases with respect to the local concentration of MMPs. The cancer cells are no more confined to the duct and the tumor invades the surrounding tissue. The model is enriched by the description of nutrients concentration, tumor necrosis factors, and MMPs production. The mathematical model is implemented in a 3D C++-code, which is based on well-adapted finite difference schemes on Cartesian grid. The membrane interface is described by a level-set, and the transmission conditions are precisely approached at the second order thanks to well-suited sharp stencils. Our continuous approach provides new significant insights in the macroscopic modeling of the breast cancer phase transition, due to the membrane degradation by MMP enzymes.

Computational Modelling of Metastasis Development in Renal Cell Carcinoma.

The biology of the metastatic colonization process remains a poorly understood phenomenon. To improve our knowledge of its dynamics, we conducted a modelling study based on multi-modal data from an orthotopic murine experimental system of metastatic renal cell carcinoma. The standard theory of metastatic colonization usually assumes that secondary tumours, once established at a distant site, grow independently from each other and from the primary tumour. Using a mathematical model that translates this assumption into equations, we challenged this theory against our data that included: 1) dynamics of primary tumour cells in the kidney and metastatic cells in the lungs, retrieved by green fluorescent protein tracking, and 2) magnetic resonance images (MRI) informing on the number and size of macroscopic lesions. Critically, when calibrated on the growth of the primary tumour and total metastatic burden, the predicted theoretical size distributions were not in agreement with the MRI observations. Moreover, tumour expansion only based on proliferation was not able to explain the volume increase of the metastatic lesions. These findings strongly suggested rejection of the standard theory, demonstrating that the time development of the size distribution of metastases could not be explained by independent growth of metastatic foci. This led us to investigate the effect of spatial interactions between merging metastatic tumours on the dynamics of the global metastatic burden. We derived a mathematical model of spatial tumour growth, confronted it with experimental data of single metastatic tumour growth, and used it to provide insights on the dynamics of multiple tumours growing in close vicinity. Together, our results have implications for theories of the metastatic process and suggest that global dynamics of metastasis development is dependent on spatial interactions between metastatic lesions.

A multilayer grow-or-go model for GBM: effects of invasive cells and anti-angiogenesis on growth.

The recent use of anti-angiogenesis (AA) drugs for the treatment of glioblastoma multiforme (GBM) has uncovered unusual tumor responses. Here, we derive a new mathematical model that takes into account the ability of proliferative cells to become invasive under hypoxic conditions; model simulations generate the multilayer structure of GBM, namely proliferation, brain invasion, and necrosis. The model is able to replicate and justify the clinical observation of rebound growth when AA therapy is discontinued in some patients. The model is interrogated to derive fundamental insights int cancer biology and on the clinical and biological effects of AA drugs. Invasive cells promote tumor growth, which in the long run exceeds the effects of angiogenesis alone. Furthermore, AA drugs increase the fraction of invasive cells in the tumor, which explain progression by fluid-attenuated inversion recovery (FLAIR) signal and the rebound tumor growth when AA is discontinued.

Evaluation of four tumour growth models to describe the natural history of meningiomas.

BACKGROUND: The incidence of newly diagnosed meningiomas, particularly those diagnosed incidentally, is continually increasing. The indication for treatment is empirical because, despite numerous studies, the natural history of these tumours remains difficult to describe and predict. METHODS: This retrospective single-centre study included 294 consecutive patients with 333 meningiomas who underwent three or more brain imaging scans. Linear, exponential, power, and Gompertz models were constructed to derive volume-time curves, by using a mixed-effect approach. The most accurate model was used to analyse tumour growth and predictors of rapid growth. FINDINGS: The Gompertz model provided the best results. Hierarchical clustering at the time of diagnosis and at the end of follow-up revealed at least three distinct groups, which can be described as pseudoexponential, linear, and slowing growth with respect to their parameters. Younger patients and smaller tumours were more frequent in the pseudo-exponential clusters. We found that the more "aggressive" the cluster, the higher the proportion of patients with grade II meningiomas and who have had a cranial radiotherapy. Over a mean observation period of 56.5 months, 21% of the tumours moved to a cluster with a lower growth rate, consistent with the Gompertz's law. INTERPRETATION: Meningiomas exhibit multiple growth phases, as described by the Gompertz model. The management of meningiomas should be discussed according to the growth phase, comorbidities, tumour location, size, and growth rate. Further research is needed to evaluate the associations between radiomics features and the growth phases of meningiomas. FUNDING: No funding.

Differentiation of Small Clear Renal Cell Carcinoma and Oncocytoma through Magnetic Resonance Imaging-Based Radiomics Analysis: Toward the End of Percutaneous Biopsy.

PURPOSE: The aim of this study was to ascertain whether radiomics data can assist in differentiating small (<4 cm) clear cell renal cell carcinomas (ccRCCs) from small oncocytomas using T2-weighted magnetic resonance imaging (MRI). MATERIAL AND METHODS: This retrospective study incorporated 48 tumors, 28 of which were ccRCCs and 20 were oncocytomas. All tumors were less than 4 cm in size and had undergone pre-biopsy or pre-surgery MRI. Following image pre-processing, 102 radiomics features were evaluated. A univariate analysis was performed using the Wilcoxon rank-sum test with Bonferroni correction. We compared multiple radiomics pipelines of normalization, feature selection, and machine learning (ML) algorithms, including random forest (RF), logistic regression (LR), AdaBoost, K-nearest neighbor, and support vector machine, using a supervised ML approach. RESULTS: No statistically significant features were identified via the univariate analysis with Bonferroni correction. The most effective algorithm was identified using a pipeline incorporating standard normalization, RF-based feature selection, and LR, which achieved an area under the curve (AUC) of 83%, accuracy of 73%, sensitivity of 79%, and specificity of 65%. Subsequently, the most significant features were identified from this algorithm, and two groups of uncorrelated features were established based on Pearson correlation scores. Using these features, an algorithm was established after a pipeline of standard normalization and LR, achieving an AUC of 90%, an accuracy of 77%, sensitivity of 83%, and specificity of 69% for distinguishing ccRCCs from oncocytomas. CONCLUSIONS: Radiomics analysis based on T2-weighted MRI can aid in distinguishing small ccRCCs from small oncocytomas. However, it is not superior to standard multiparameter renal MRI and does not yet allow us to dispense with percutaneous biopsy.

Comparison of MRI-based response criteria and radiomics for the prediction of early response to transarterial radioembolization in patients with hepatocellular carcinoma.

PURPOSE: The purpose of this study was to evaluate the capabilities of radiomics using magnetic resonance imaging (MRI) data in the assessment of treatment response to 90yttrium transarterial radioembolization (TARE) in patients with locally advanced hepatocellular carcinoma (HCC) by comparison with predictions based on European Association for the Study of the Liver (EASL) criteria. PATIENTS AND METHODS: Twenty-two patients with HCC (19 men, 3 women; mean age: 66.7 ± 9.8 [SD]; age range: 37-82 years) who underwent contrast-enhanced MRI 4 ± 1 weeks before and 4 ± 4 weeks after TARE, were enrolled in this retrospective study. Regions of interest were placed manually along the contours of the treated tumor on each axial slice of arterial and portal phase images using the ITK-SNAP post-processing software. For each MRI, the Pyradiomics Python package was used to extract 107 radiomics features on both arterial and portal phases, and resulting delta-features were computed. The Mann-Whitney U test with Bonferroni correction was used to select statistically different features between responders and non-responders (i.e., those with progressive or stable disease) at 6-month follow-up, according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Finally, for each selected feature, univariable logistic regression with leave-one-out cross validation procedure was used to perform receiver operating characteristic (ROC) curve analysis and compare radiomics parameters with MRI variables. RESULTS: According to mRECIST, 14 patients (14/22; 64%) were non-responders and 8 (8/22; 36%) were responders. Four radiomics parameters (long run emphasis, minor axis length, surface area, and gray level non-uniformity on arterial phase images) were the only predictors of early response. ROC curve analysis showed that long run emphasis was the best parameter for predicting early response, with 100% sensitivity (95% CI: 68-100) and 100% specificity (95% CI: 78-100). EASL morphologic criteria yielded 75% sensitivity (95% CI: 41-96%) and 93% specificity (95% CI: 69-100%). CONCLUSION: Radiomics allows identify marked differences between responders and non-responders, and could aid in the prediction of early treatment response following TARE in patients with HCC.

Ion fluxes, transmembrane potential, and osmotic stabilization: a new dynamic electrophysiological model for eukaryotic cells.

Survival of mammalian cells is achieved by tight control of cell volume, while transmembrane potential has been known to control many cellular functions since the seminal work of Hodgkin and Huxley. Regulation of cell volume and transmembrane potential have a wide range of implications in physiology, from neurological and cardiac disorders to cancer and muscle fatigue. Therefore, understanding the relationship between transmembrane potential, ion fluxes, and cell volume regulation has become of great interest. In this paper we derive a system of differential equations that links transmembrane potential, ionic concentrations, and cell volume. In particular, we describe the dynamics of the cell within a few seconds after an osmotic stress, which cannot be done by the previous models in which either cell volume was constant or osmotic regulation instantaneous. This new model demonstrates that both membrane potential and cell volume stabilization occur within tens of seconds of changes in extracellular osmotic pressure. When the extracellular osmotic pressure is constant, the cell volume varies as a function of transmembrane potential and ion fluxes, thus providing an implicit link between transmembrane potential and cell volume. Experimental data provide results that corroborate the numerical simulations of the model in terms of time-related changes in cell volume and dynamics of the phenomena. This paper can be seen as a generalization of previous electrophysiological results, since under restrictive conditions they can be derived from our model.

Spatial mechanistic modeling for prediction of the growth of asymptomatic meningiomas.

BACKGROUND AND OBJECTIVE: Mathematical modeling of tumor growth draws interest from the medical community as they have the potential to improve patients' care and the use of public health resources. The main objectives of this work are to model the growth of meningiomas - slow-growing benign tumors requiring extended imaging follow-up - and to predict tumor volume and shape at a later desired time using only two times examinations. METHODS: We develop two variants of a 3D partial differential system of equations (PDE) which yield after a spatial integration systems of ordinary differential equations (ODE) that relate tumor volume with time. Estimation of models parameters is a crucial step to obtain a personalized model for a patient that can be used for descriptive or predictive purposes. As PDE and ODE systems share the same parameters, they are both estimated by fitting the ODE systems to the tumor volumes obtained from MRI examinations acquired at different times. A population approach allows to compensate for sparse sampling times and measurement uncertainties by constraining the variability of the parameters in the population. RESULTS: Description capabilities of the models are investigated in 39 patients with benign asymptomatic meningiomas who had had at least three surveillance MRI examinations. The two models can fit to the data accurately and more realistically than a naive linear regression. Prediction performances are validated for 33 patients using a population approach. Mean relative errors in volume predictions are less than 10% with ODE systems versus 12.5% with the naive linear model using only two times examinations. Concerning the shape, the mean Sørensen-Dice coefficients are 85% with the PDE systems in a subset of 10 representative patients. CONCLUSIONS: Our strategy - based on personalization of mathematical model - provides a good insight on meningioma growth and may help decide whether to extend the follow-up or to treat the tumor.

Improved 18-FDG PET/CT diagnosis of multiple myeloma diffuse disease by radiomics analysis.

OBJECTIVES: In multiple myeloma, the diagnosis of diffuse bone marrow infiltration on 18-FDG PET/CT can be challenging. We aimed to develop a PET/CT radiomics-based model that could improve the diagnosis of multiple myeloma diffuse disease on 18-FDG PET/CT. METHODS: We prospectively performed PET/CT and whole-body diffusion-weighted MRI in 30 newly diagnosed multiple myeloma. MRI was the reference standard for diffuse disease assessment. Twenty patients were randomly assigned to a training set and 10 to an independent test set. Visual analysis of PET/CT was performed by two nuclear medicine physicians. Spine volumes were automatically segmented, and a total of 174 Imaging Biomarker Standardisation Initiative-compliant radiomics features were extracted from PET and CT. Selection of best features was performed with random forest features importance and correlation analysis. Machine-learning algorithms were trained on the selected features with cross-validation and evaluated on the independent test set. RESULTS: Out of the 30 patients, 18 had established diffuse disease on MRI. The sensitivity, specificity and accuracy of visual analysis were 67, 75 and 70%, respectively, with a moderate kappa coefficient of agreement of 0.6. Five radiomics features were selected. On the training set, random forest classifier reached a sensitivity, specificity and accuracy of 93, 86 and 91%, respectively, with an area under the curve of 0.90 (95% confidence interval, 0.89-0.91). On the independent test set, the model achieved an accuracy of 80%. CONCLUSIONS: Radiomics analysis of 18-FDG PET/CT images with machine-learning overcame the limitations of visual analysis, providing a highly accurate and more reliable diagnosis of diffuse bone marrow infiltration in multiple myeloma patients.

MRI-Based Radiomics Input for Prediction of 2-Year Disease Recurrence in Anal Squamous Cell Carcinoma.

PURPOSE: Chemo-radiotherapy (CRT) is the standard treatment for non-metastatic anal squamous cell carcinomas (ASCC). Despite excellent results for T1-2 stages, relapses still occur in around 35% of locally advanced tumors. Recent strategies focus on treatment intensification, but could benefit from a better patient selection. Our goal was to assess the prognostic value of pre-therapeutic MRI radiomics on 2-year disease control (DC). METHODS: We retrospectively selected patients with non-metastatic ASCC treated at the CHU Bordeaux and in the French FFCD0904 multicentric trial. Radiomic features were extracted from T2-weighted pre-therapeutic MRI delineated sequences. After random division between training and testing sets on a 2:1 ratio, univariate and multivariate analysis were performed on the training cohort to select optimal features. The correlation with 2-year DC was assessed using logistic regression models, with AUC and accuracy as performance gauges, and the prediction of disease-free survival using Cox regression and Kaplan-Meier analysis. RESULTS: A total of 82 patients were randomized in the training (n = 54) and testing sets (n = 28). At 2 years, 24 patients (29%) presented relapse. In the training set, two clinical (tumor size and CRT length) and two radiomic features (FirstOrder_Entropy and GLCM_JointEnergy) were associated with disease control in univariate analysis and included in the model. The clinical model was outperformed by the mixed (clinical and radiomic) model in both the training (AUC 0.758 versus 0.825, accuracy of 75.9% versus 87%) and testing (AUC 0.714 versus 0.898, accuracy of 78.6% versus 85.7%) sets, which led to distinctive high and low risk of disease relapse groups (HR 8.60, p = 0.005). CONCLUSION: A mixed model with two clinical and two radiomic features was predictive of 2-year disease control after CRT and could contribute to identify high risk patients amenable to treatment intensification with view of personalized medicine.

Systematic review of sarcomas radiomics studies: Bridging the gap between concepts and clinical applications?

OBJECTIVES: Sarcomas are a model for intra- and inter-tumoral heterogeneities making them particularly suitable for radiomics analyses. Our purposes were to review the aims, methods and results of radiomics studies involving sarcomas METHODS: Pubmed and Web of Sciences databases were searched for radiomics or textural studies involving bone, soft-tissues and visceral sarcomas until June 2020. Two radiologists evaluated their objectives, results and quality of their methods, imaging pre-processing and machine-learning workflow helped by the items of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2), Image Biomarker Standardization Initiative (IBSI) and 'Radiomics Quality Score' (RQS). Statistical analyses included inter-reader agreements, correlations between methodological assessments, scientometrics indices, and their changes over years, and between RQS, number of patients and models performance. RESULTS: Fifty-two studies were included involving: soft-tissue sarcomas (29/52, 55.8 %), bone sarcomas (15/52, 28.8 %), gynecological sarcomas (6/52, 11.5 %) and mixed sarcomas (2/52, 3.8 %), mostly imaged with MRI (36/52, 69.2 %), for a total of distinct patients. Median RQS was 4.5 (28.4 % of the maximum, range: -7 - 17). Performances of predictive models and number of patients negatively correlated (p = 0.027). None of the studies detailed all the items from the IBSI guidelines. There was a significant increase in studies' impact factors since the establishing of the RQS in 2017 (p = 0.038). CONCLUSION: Although showing promising results, further efforts are needed to make sarcoma radiomics studies reproducible with an acceptable level of evidence. A better knowledge of the RQS and IBSI reporting guidelines could improve the quality of sarcoma radiomics studies and accelerate clinical applications.

Machine Learning and Mechanistic Modeling for Prediction of Metastatic Relapse in Early-Stage Breast Cancer.

PURPOSE: For patients with early-stage breast cancer, predicting the risk of metastatic relapse is of crucial importance. Existing predictive models rely on agnostic survival analysis statistical tools (eg, Cox regression). Here we define and evaluate the predictive ability of a mechanistic model for time to distant metastatic relapse. METHODS: The data we used for our model consisted of 642 patients with 21 clinicopathologic variables. A mechanistic model was developed on the basis of two intrinsic mechanisms of metastatic progression: growth (parameter α) and dissemination (parameter µ). Population statistical distributions of the parameters were inferred using mixed-effects modeling. A random survival forest analysis was used to select a minimal set of five covariates with the best predictive power. These were further considered to individually predict the model parameters by using a backward selection approach. Predictive performances were compared with classic Cox regression and machine learning algorithms. RESULTS: The mechanistic model was able to accurately fit the data. Covariate analysis revealed statistically significant association of Ki67 expression with α (P = .001) and EGFR expression with µ (P = .009). The model achieved a c-index of 0.65 (95% CI, 0.60 to 0.71) in cross-validation and had predictive performance similar to that of random survival forest (95% CI, 0.66 to 0.69) and Cox regression (95% CI, 0.62 to 0.67) as well as machine learning classification algorithms. CONCLUSION: By providing informative estimates of the invisible metastatic burden at the time of diagnosis and forward simulations of metastatic growth, the proposed model could be used as a personalized prediction tool for routine management of patients with breast cancer.

Intensity harmonization techniques influence radiomics features and radiomics-based predictions in sarcoma patients.

Intensity harmonization techniques (IHT) are mandatory to homogenize multicentric MRIs before any quantitative analysis because signal intensities (SI) do not have standardized units. Radiomics combine quantification of tumors' radiological phenotype with machine-learning to improve predictive models, such as metastastic-relapse-free survival (MFS) for sarcoma patients. We post-processed the initial T2-weighted-imaging of 70 sarcoma patients by using 5 IHTs and extracting 45 radiomics features (RFs), namely: classical standardization (IHTstd), standardization per adipose tissue SIs (IHTfat), histogram-matching with a patient histogram (IHTHM.1), with the average histogram of the population (IHTHM.All) and plus ComBat method (IHTHM.All.C), which provided 5 radiomics datasets in addition to the original radiomics dataset without IHT (No-IHT). We found that using IHTs significantly influenced all RFs values (p-values: < 0.0001-0.02). Unsupervised clustering performed on each radiomics dataset showed that only clusters from the No-IHT, IHTstd, IHTHM.All, and IHTHM.All.C datasets significantly correlated with MFS in multivariate Cox models (p = 0.02, 0.007, 0.004 and 0.02, respectively). We built radiomics-based supervised models to predict metastatic relapse at 2-years with a training set of 50 patients. The models performances varied markedly depending on the IHT in the validation set (range of AUROC from 0.688 with IHTstd to 0.823 with IHTHM.1). Hence, the use of intensity harmonization and the related technique should be carefully detailed in radiomics post-processing pipelines as it can profoundly affect the reproducibility of analyses.

Interval between planning and frameless stereotactic radiosurgery for brain metastases: are our margins still accurate?

BACKGROUND: Advances in intracranial stereotactic radiosurgery (SRS) have led to dramatically reduced planning target volume (PTV) margins. However, tumor growth between planning and treatment may lead to treatment failure. Our purpose was to assess the kinetics of tumor growth before SRS for brain metastases. METHODS: This retrospective, monocentric study included all consecutive patients (pts) treated for brain metastases secondary to melanoma (ML) and non-small cell lung cancer (NSCLC) between June 2015 and May 2016. All pts underwent diagnostic brain imaging and a radiosurgery planning MRI, during which gross tumor volume (GTV) was delineated. Linear and exponential models were used to extrapolate a theoretical GTV at first day of treatment, and theoretical time to outgrow the PTV margins. RESULTS: Twenty-three ML and 31 NSCLC brain metastases (42 pts, 84 brain imaging scans) were analyzed. Comparison of GTV at diagnosis and planning showed increased tumor volume for 20 ML pts (96%) and 22 NSCLC pts (71%). The shortest time to outgrow a 1 mm margin was 6 days and 3 days for ML and 14 and 8 days for NSCLC with linear and exponential models, respectively. CONCLUSIONS: Physicians should bear in mind the interval between SRS planning and treatment. A mathematical model could screen rapidly progressing tumors.

A pharmacologically based multiscale mathematical model of angiogenesis and its use in investigating the efficacy of a new cancer treatment strategy.

Tumor angiogenesis is the process by which new blood vessels are formed and enhance the oxygenation and growth of tumors. As angiogenesis is recognized as being a critical event in cancer development, considerable efforts have been made to identify inhibitors of this process. Cytostatic treatments that target the molecular events of the angiogenesis process have been developed, and have met with some success. However, it is usually difficult to preclinically assess the effectiveness of targeted therapies, and apparently promising compounds sometimes fail in clinical trials. We have developed a multiscale mathematical model of angiogenesis and tumor growth. At the molecular level, the model focuses on molecular competition between pro- and anti-angiogenic substances modeled on the basis of pharmacological laws. At the tissue scale, the model uses partial differential equations to describe the spatio-temporal changes in cancer cells during three stages of the cell cycle, as well as those of the endothelial cells that constitute the blood vessel walls. This model is used to qualitatively assess how efficient endostatin gene therapy is. Endostatin is an anti-angiogenic endogenous substance. The gene therapy entails overexpressing endostatin in the tumor and in the surrounding tissue. Simulations show that there is a critical treatment dose below which increasing the duration of treatment leads to a loss of efficacy. This theoretical model may be useful to evaluate the efficacy of therapies targeting angiogenesis, and could therefore contribute to designing prospective clinical trials.