In Vivo Detection of Chronic Kidney Disease Using Tissue Deformation Fields From Dynamic MR Imaging.

OBJECTIVE: Chronic kidney disease (CKD) is a serious medical condition characterized by gradual loss of kidney function. Early detection and diagnosis is mandatory for adequate therapy and prognostic improvement. Hence, in the current pilot study we explore the use of image registration methods for detecting renal morphologic changes in patients with CKD. METHODS: Ten healthy volunteers and nine patients with presumed CKD underwent dynamic T1 weighted imaging without contrast agent. From real and simulated dynamic time series, kidney deformation fields were estimated using a poroelastic deformation model. From the deformation fields several quantitative parameters reflecting pressure gradients, and volumetric and shear deformations were computed. Eight of the patients also underwent a kidney biopsy as a gold standard. RESULTS: We found that the absolute deformation, normalized volume changes, as well as pressure gradients correlated significantly with arteriosclerosis from biopsy assessments. Furthermore, our results indicate that current image registration methodologies are lacking sensitivity to recover mild changes in tissue stiffness. CONCLUSION: Image registration applied to dynamic time series correlated with structural renal changes and should be further explored as a tool for invasive measurements of arteriosclerosis. SIGNIFICANCE: Under the assumption that the proposed framework can be further developed in terms of sensitivity and specificity, it can provide clinicians with a non-invasive tool of high spatial coverage available for characterization of arteriosclerosis and potentially other pathological changes observed in chronic kidney disease.

Magnetic resonance imaging biomarkers for chronic kidney disease: a position paper from the European Cooperation in Science and Technology Action PARENCHIMA.

Functional renal magnetic resonance imaging (MRI) has seen a number of recent advances, and techniques are now available that can generate quantitative imaging biomarkers with the potential to improve the management of kidney disease. Such biomarkers are sensitive to changes in renal blood flow, tissue perfusion, oxygenation and microstructure (including inflammation and fibrosis), processes that are important in a range of renal diseases including chronic kidney disease. However, several challenges remain to move these techniques towards clinical adoption, from technical validation through biological and clinical validation, to demonstration of cost-effectiveness and regulatory qualification. To address these challenges, the European Cooperation in Science and Technology Action PARENCHIMA was initiated in early 2017. PARENCHIMA is a multidisciplinary pan-European network with an overarching aim of eliminating the main barriers to the broader evaluation, commercial exploitation and clinical use of renal MRI biomarkers. This position paper lays out PARENCHIMA's vision on key clinical questions that MRI must address to become more widely used in patients with kidney disease, first within research settings and ultimately in clinical practice. We then present a series of practical recommendations to accelerate the study and translation of these techniques.

Uncertainty evaluation of image-based tumour control probability models in radiotherapy of prostate cancer using a visual analytic tool.

Functional imaging techniques provide radiobiological information that can be included into tumour control probability (TCP) models to enable individualized outcome predictions in radiotherapy. However, functional imaging and the derived radiobiological information are influenced by uncertainties, translating into variations in individual TCP predictions. In this study we applied a previously developed analytical tool to quantify dose and TCP uncertainty bands when initial cell density is estimated from MRI-based apparent diffusion coefficient maps of eleven patients. TCP uncertainty bands of 16% were observed at patient level, while dose variations bands up to 8 Gy were found at voxel level for an iso-TCP approach.

A biological modelling based comparison of radiotherapy plan robustness using photons vs protons for focal prostate boosting.

BACKGROUND AND PURPOSE: Focal tumour boosting is currently explored in radiotherapy of prostate cancer to increase tumour control. In this study we applied dose response models for both tumour control and normal tissue complications to explore the benefit of proton therapy (PT) combined with focal tumour boosting, also when accounting for inter-fractional motion. MATERIALS AND METHODS: CT scans of seven patients fused with MRI-based index volumes were used. Two volumetric modulated arc therapy (VMAT) plans were created for each patient; one with conventional dose (77 Gy) to the entire prostate, and one with an additional integrated boost (total dose of 95 Gy) to the index lesion. Two corresponding intensity modulated PT (IMPT) plans were created using two lateral opposing spot scanning beams. All plans were evaluated using an MRI-based tumour control probability (TCP) model and normal tissue complication probability (NTCP) models for the rectum and bladder. Plan robustness was evaluated using dose re-calculations on repeat cone-beam CTs. RESULTS: Across all plans, median TCP increased from 86% (range: 59-98%) without boost to 97% (range: 96-99%) with boost. IMPT plans had lower rectum NTCPs (e.g. 3% vs. 4% for boost plans) but higher bladder NTCPs (20% vs. 18% for boost plans), yet only the bladder NTCPs remained different in the cone beam CT-based re-calculations. CONCLUSIONS: Focal tumour boosting can be delivered with either VMAT or protons, and increases the predicted TCP. The small benefit of IMPT when assessing the planned dose distributions was lost when accounting for inter-fractional motion.

Intensity-based volumetric registration of magnetic resonance images and whole-mount sections of the prostate.

OBJECTIVE: Magnetic Resonance Imaging (MRI) of the prostate provides useful in vivo diagnostic tissue information such as tumor location and aggressiveness, but ex vivo histopathology remains the ground truth. There are several challenges related to the registration of MRI to histopathology. We present a method for registration of standard clinical T2-weighted MRI (T2W-MRI) and transverse histopathology whole-mount (WM) sections of the prostate. METHODS: An isotropic volume stack was created from the WM sections using 2D rigid and deformable registration combined with linear interpolation. The prostate was segmented manually from the T2W-MRI volume and registered to the WM section volume using a combination of affine and deformable registration. The method was evaluated on a set of 12 patients who had undergone radical prostatectomy. Registration accuracy was assessed using volume overlap (Dice Coefficient, DC) and landmark distances. RESULTS: The DC was 0.94 for the whole prostate, 0.63 for the peripheral zone and 0.77 for the remaining gland. The landmark distances were on average 5.4 mm. CONCLUSION: The volume overlap for the whole prostate and remaining gland, as well as the landmark distances indicate good registration accuracy for the proposed method, and shows that it can be highly useful for registering clinical available MRI and WM sections of the prostate.

Optimising preoperative risk stratification tools for prostate cancer using mpMRI.

PURPOSE: To improve preoperative risk stratification for prostate cancer (PCa) by incorporating multiparametric MRI (mpMRI) features into risk stratification tools for PCa, CAPRA and D'Amico. METHODS: 807 consecutive patients operated on by robot-assisted radical prostatectomy at our institution during the period 2010-2015 were followed to identify biochemical recurrence (BCR). 591 patients were eligible for final analysis. We employed stepwise backward likelihood methodology and penalised Cox cross-validation to identify the most significant predictors of BCR including mpMRI features. mpMRI features were then integrated into image-adjusted (IA) risk prediction models and the two risk prediction tools were then evaluated both with and without image adjustment using receiver operating characteristics, survival and decision curve analyses. RESULTS: 37 patients suffered BCR. Apparent diffusion coefficient (ADC) and radiological extraprostatic extension (rEPE) from mpMRI were both significant predictors of BCR. Both IA prediction models reallocated more than 20% of intermediate-risk patients to the low-risk group, reducing their estimated cumulative BCR risk from approximately 5% to 1.1%. Both IA models showed improved prognostic performance with a better separation of the survival curves. CONCLUSION: Integrating ADC and rEPE from mpMRI of the prostate into risk stratification tools improves preoperative risk estimation for BCR. KEY POINTS: • MRI-derived features, ADC and EPE, improve risk stratification of biochemical recurrence. • Using mpMRI to stratify prostate cancer patients improves the differentiation between risk groups. • Using preoperative mpMRI will help urologists in selecting the most appropriate treatment.

Workflow sensitivity of post-processing methods in renal DCE-MRI.

OBJECTIVE: Estimation of renal filtration using dynamic contrast-enhanced imaging (DCE-MRI) requires a series of analysis steps. The possible number of distinct post-processing chains is large and grows rapidly with increasing number of processing steps or options. In this study we introduce a framework for systematic evaluation of the post-processing chains. The framework is later used to highlight the workflow processing chain sensitivity towards accuracy in estimation of glomerular filtration rate (GFR). METHODS: Twenty healthy volunteers underwent DCE-MRI examinations as well as iohexol clearance for reference GFR measurements. In total, 692 different combinations of post-processing steps were explored for analysis, including options for kidney segmentation, B1 inhomogeneity correction, placement of arterial input function, gadolinium concentration estimation as well as handling of motion-corrupted volumes and breathing motion. The evaluation of various processing chains is presented using a classification tree framework and random forest ensemble learning. RESULTS: Among the processing steps subject to testing, methods for calculating the gadolinium concentration as well as B1 inhomogeneity correction had the largest impact on accuracy of GFR estimations. Different segmentation methods did not play an important role in the post-processing of the MR data except from one processing chain where the automated segmentation outperformed the manual segmentation. CONCLUSION: The proposed classification trees were efficiently used as a statistical tool for visualization and communication of results to distinguish between important and less influential processing steps in renal DCE-MRI. We also identified several crucial factors in the processing chain.

Dynamic contrast-enhanced MRI measurement of renal function in healthy participants.

Background High repeatability, accuracy, and precision for renal function measurements need to be achieved to establish renal dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as a clinically useful diagnostic tool. Purpose To investigate the repeatability, accuracy, and precision of DCE-MRI measured renal perfusion and glomerular filtration rate (GFR) using iohexol-GFR as the reference method. Material and Methods Twenty healthy non-smoking volunteers underwent repeated DCE-MRI and an iohexol-GFR within a period of 10 days. Single-kidney (SK) MRI measurements of perfusion (blood flow, Fb) and filtration (GFR) were derived from parenchymal intensity time curves fitted to a two-compartment filtration model. The repeatability of the SK-MRI measurements was assessed using coefficient of variation (CV). Using iohexol-GFR as reference method, the accuracy of total MR-GFR was determined by mean difference (MD) and precision by limits of agreement (LoA). Results SK-Fb (MR1, 345 ± 84; MR2, 371 ± 103 mL/100 mL/min) and SK-GFR (MR1, 52 ± 14; MR2, 54 ± 10 mL/min/1.73 m2) measurements achieved a repeatability (CV) in the range of 15-22%. With reference to iohexol-GFR, MR-GFR was determined with a low mean difference but high LoA (MR1, MD 1.5 mL/min/1.73 m2, LoA [-42, 45]; MR2, MD 6.1 mL/min/1.73 m2, LoA [-26, 38]). Eighty percent and 90% of MR-GFR measurements were determined within ± 30% of the iohexol-GFR for MR1 and MR2, respectively. Conclusion Good repeatability of SK-MRI measurements and good agreement between MR-GFR and iohexol-GFR provide a high clinical potential of DCE-MRI for renal function assessment. A moderate precision in MR-derived estimates indicates that the method cannot yet be used in clinical routine.

Quantification of Single-Kidney Function and Volume in Living Kidney Donors Using Dynamic Contrast-Enhanced MRI.

OBJECTIVE: The objective of our study was to investigate whether dynamic contrast-enhanced MRI (DCE-MRI) can detect differences and potential adaption in single-kidney parenchymal volume, blood flow, glomerular filtration rate (GFR), and filtration fraction in the remaining kidney of healthy donors compared with nondonors. Further, we evaluated the agreement in donor GFRs measured using DCE-MRI versus serum clearance of iohexol. SUBJECTS AND METHODS: Twenty living kidney donors and 20 healthy control subjects underwent DCE-MRI and iohexol GFR. Renal parenchymal volume was assessed from maximum-signal-intensity maps. Single-kidney MRI measurements of blood flow and GFR were derived from parenchymal signal intensity-time curves fitted to a two-compartment filtration model. The Student t test, Pearson correlation coefficient, mean differences, and limits of agreement were applied to analyze MRI measurements between groups and agreement with iohexol GFR. RESULTS: MRI findings showed significantly higher blood flow (difference in mean values of donors vs control subjects, 54%; p = 0.001), GFR (78%, p < 0.0001), and renal parenchymal volume (65%, p < 0.0001) in the single kidney of donors compared with the single kidney of healthy control subjects. In the donors, a proportional increase in blood flow and GFR resulted in a comparable filtration fraction, as was observed in the control subjects. Significant correlations were found between MRI-derived GFR and parenchymal volume (p < 0.0016) as well as with iohexol GFR (p < 0.0001). The mean difference between MRI-derived GFR and iohexol GFR was 14.0 mL/min, and the limits of agreement between MRI-derived GFR and iohexol GFR were -24.1 and 52.1 mL/min. CONCLUSION: DCE-MRI-derived values for single-kidney function and volume in kidney donors were significantly higher than those in control subjects and suggest a future potential benefit of DCE-MRI for diagnostic and prognostic structural and functional assessments in living kidney donors.

A tumour control probability model for radiotherapy of prostate cancer using magnetic resonance imaging-based apparent diffusion coefficient maps.

BACKGROUND AND PURPOSE: Standard tumour control probability (TCP) models assume uniform tumour cell density across the tumour. The aim of this study was to develop an individualised TCP model by including index-tumour regions extracted form multi-parametric magnetic resonance imaging (MRI) and apparent diffusion coefficient (ADC) maps-based cell density distributions. MATERIALS AND METHODS: ADC maps in a series of 20 prostate cancer patients were applied to estimate the initial number of cells within each voxel, using three different approaches for the relation between ADC values and cell density: a linear, a binary and a sigmoid relation. All TCP models were based on linear-quadratic cell survival curves assuming α/ß=1.93Gy (consistent with a recent meta-analysis) and α set to obtain a 70% of TCP when 77Gy was delivered to the entire prostate in 35 fractions (α=0.18Gy(-1)). RESULTS: Overall, TCP curves based on ADC maps showed larger differences between individuals than those assuming uniform cell densities. The range of the dose required to reach 50% TCP across the patient cohort was 20.1Gy, 18.7Gy and 13.2Gy using an MRI-based voxel density (linear, binary and sigmoid approach, respectively), compared to 4.1Gy using a constant density. CONCLUSIONS: Inclusion of tumour-index information together with ADC maps-based cell density increases inter-patient tumour response differentiation for use in prostate cancer RT, resulting in TCP curves with a larger range in D50% across the cohort compared with those based on uniform cell densities.

Trends in stage-specific incidence of prostate cancer in Norway, 1980-2010: a population-based study.

OBJECTIVE: To estimate changes in the stage distribution of prostate cancer during the time period where opportunistic prostate-specific antigen (PSA) testing was introduced. PATIENTS AND METHODS: Cancer stage, age, and year of diagnosis were obtained for all men aged >50 years diagnosed with prostate cancer in Norway during the period 1980-2010. Three calendar-time periods (1980-1989, 1990-2000, and 2001-2010) and three age groups (50-65, 66-74, and ≥75 years) were defined. Birth cohorts were categorised into four intervals: ≤1915, 1916-1925, 1926-1940 and ≥1941. We used Poisson regressions to conduct both a time period and cohort-based analysis of trends in the incidence of localised, regional, and distant cancer for each combination of age groups and calendar-time periods or birth cohorts, respectively. Additionally, we explored the effect of cohorts on the stage-specific incidence graphically with a Poisson regression using 5-year age groups, and by estimating cumulative incidence rates for each birth cohort. RESULTS: The annual incidence of localised cancers among men aged 50-65 and 66-74 years rose from 41.4 and 255.2 per 100 000, respectively, before the introduction of PSA testing to 137.9 and 418.7 in 2001-2010 afterwards, corresponding to 3.3 [95% confidence interval (CI) 3.1-3.5] and 1.6 (95% CI 1.6-1.7) fold increases. The incidence of regional cancers increased by a factor seven among men aged <75 years. The incidence of distant cancers in men aged ≥75 years decreased by 29% (95% CI 25-33%). These findings were confirmed in the cohort-based approach. CONCLUSION: Opportunistic PSA testing substantially increased the incidence of localised and regional prostate cancers among men aged 50-74 years, which was not fully compensated by the 30% decrease in incidence of distant prostate cancers in older men.

Use of 3D DCE-MRI for the estimation of renal perfusion and glomerular filtration rate: an intrasubject comparison of FLASH and KWIC with a comprehensive framework for evaluation.

OBJECTIVE. The purpose of this article is to compare two 3D dynamic contrast-enhanced (DCE) MRI measurement techniques for MR renography, a radial k-space weighted image contrast (KWIC) sequence and a cartesian FLASH sequence, in terms of intrasubject differences in estimates of renal functional parameters and image quality characteristics. SUBJECTS AND METHODS. Ten healthy volunteers underwent repeated breath-hold KWIC and FLASH sequence examinations with temporal resolutions of 2.5 and 2.8 seconds, respectively. A two-compartment model was used to estimate MRI-derived perfusion parameters and glomerular filtration rate (GFR). The latter was compared with the iohexol GFR and the estimated GFR. Image quality was assessed using a visual grading characteristic analysis of relevant image quality criteria and signal-to-noise ratio calculations. RESULTS. Perfusion estimates from FLASH were closer to literature reference values than were the KWIC sequences. In relation to the iohexol GFR (mean [± SD], 103 ± 11 mL/min/1.73 m(2)), KWIC produced significant underestimations and larger bias in GFR values (mean, 70 ± 30 mL/min/1.73 m(2); bias = -33.2 mL/min/1.73 m(2)) compared with the FLASH GFR (110 ± 29 mL/min/1.73 m(2); bias = 6.4 mL/min/1.73 m(2)). KWIC was statistically significantly (p < 0.005) more impaired by artifacts than was FLASH (AUC = 0.18). The average signal-enhancement ratio (delta ratio) in the cortex was significantly lower for KWIC (delta ratio = 0.99) than for FLASH (delta ratio = 1.40). Other visually graded image quality characteristics and signal-to-noise ratio measurements were not statistically significantly different. CONCLUSION. Using the same postprocessing scheme and pharmacokinetic model, FLASH produced more accurate perfusion and filtration parameters than did KWIC compared with clinical reference methods. Our data suggest an apparent relationship between image quality characteristics and the degree of stability in the numeric model-based renal function estimates.

1.5-T multiparametric MRI using PI-RADS: a region by region analysis to localize the index-tumor of prostate cancer in patients undergoing prostatectomy.

BACKGROUND: The use of multiparametric magnetic resonance imaging (mpMRI) to detect and localize prostate cancer has increased in recent years. In 2010, the European Society of Urogenital Radiology (ESUR) published guidelines for mpMRI and introduced the Prostate Imaging Reporting and Data System (PI-RADS) for scoring the different parameters. PURPOSE: To evaluate the reliability and diagnostic performance of endorectal 1.5-T mpMRI using the PI-RADS to localize the index tumor of prostate cancer in patients undergoing prostatectomy. MATERIAL AND METHODS: This institutional review board IRB-approved, retrospective study included 63 patients (mean age, 60.7 years, median PSA, 8.0). Three observers read mpMRI parameters (T2W, DWI, and DCE) using the PI-RADS, which were compared with the results from whole-mount histopathology that analyzed 27 regions of interest. Inter-observer agreement was calculated as well as sensitivity, specificity, positive predictive value (PPV), and negative predicted value (NPV) by dichotomizing the PI-RADS criteria scores ≥3. A receiver-operating curve (ROC) analysis was performed for the different MR parameters and overall score. RESULTS: Inter-observer agreement on the overall score was 0.41. The overall score in the peripheral zone achieved sensitivities of 0.41, 0.60, and 0.55 with an NPV of 0.80, 0.84, and 0.83, and in the transitional zone, sensitivities of 0.26, 0.15, and 0.19 with an NPV of 0.92, 0.91, and 0.92 for Observers 1, 2, and 3, respectively. The ROC analysis showed a significantly increased area under the curve (AUC) for the overall score when compared to T2W alone for two of the three observers. CONCLUSION: 1.5 T mpMRI using the PI-RADS to localize the index tumor achieved moderate reliability and diagnostic performance.

Normalized gradient fields for nonlinear motion correction of DCE-MRI time series.

Dynamic MR image recordings (DCE-MRI) of moving organs using bolus injections create two different types of dynamics in the images: (i) spatial motion artifacts due to patient movements, breathing and physiological pulsations that we want to counteract and (ii) signal intensity changes during contrast agent wash-in and wash-out that we want to preserve. Proper image registration is needed to counteract the motion artifacts and for a reliable assessment of physiological parameters. In this work we present a partial differential equation-based method for deformable multimodal image registration using normalized gradients and the Fourier transform to solve the Euler-Lagrange equations in a multilevel hierarchy. This approach is particularly well suited to handle the motion challenges in DCE-MRI time series, being validated on ten DCE-MRI datasets from the moving kidney. We found that both normalized gradients and mutual information work as high-performing cost functionals for motion correction of this type of data. Furthermore, we demonstrated that normalized gradients have improved performance compared to mutual information as assessed by several performance measures. We conclude that normalized gradients can be a viable alternative to mutual information regarding registration accuracy, and with promising clinical applications to DCE-MRI recordings from moving organs.

A variational approach to image registration in dynamic contrast-enhanced MRI of the human kidney.

Kidney function can be accessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measurements which yield spatially resolved maps of physiological parameters like perfusion or filtration. The motion of the kidneys during the scan is a dominant limitation of the measurement quality, and image registration is necessary for accurate quantification. We analyzed the feasibility of applying an algorithm, originally developed for multimodal registration, to kidney perfusion time series. The algorithm uses a variational calculation scheme to align the images. In four out of five data sets, kidney motion could be reduced to below the spatial resolution of the images of 1.6mm while preserving the enhancement pattern of kidney perfusion. Fitting a pharmacokinetic model to the data showed an average reduction of the Akaike fit error of 10% for the registered data, suggesting more stable parameters. We conclude that this image registration algorithm is feasible for correcting kidney motion in renal DCE-MRI.

Assessment of kidney volumes from MRI: acquisition and segmentation techniques.

OBJECTIVE: The prevalence of chronic kidney disease (CKD) is increasing worldwide. In Europe alone, at least 8% of the population currently has some degree of CKD. CKD is associated with serious comorbidity, reduced life expectancy, and high economic costs; hence, early detection and adequate treatment of kidney disease are important. CONCLUSION: We review state-of-the-art MRI acquisition techniques for CKD, with a special focus on image segmentation methods used for the estimation of kidney volume.

Standard 1.5-T MRI of endometrial carcinomas: modest agreement between radiologists.

OBJECTIVES: To evaluate pelvic magnetic resonance imaging (MRI) interobserver agreement for the detection of deep myometrial invasion, cervical stroma invasion and lymph node metastases in endometrial carcinoma patients in relation to surgical staging. METHODS: Fifty-seven patients with histologically confirmed endometrial carcinoma were prospectively included in a study of preoperative 1.5-T MRI. Four radiologists, blinded to patient data, independently reviewed the images for the presence of deep myometrial invasion, cervical stroma invasion and lymph node metastases. Kappa coefficients for interobserver agreement and diagnostic performances for each observer were calculated using final surgical staging results (FIGO 09) as reference standard. RESULTS: Overall agreement among all observers was moderate for cervical stroma invasion (κ = 0.50 [95% CI 0.27-0.73]) and lymph node metastases (κ = 0.56 [0.09-0.80]) and fair for deep myometrial invasion (κ = 0.39 [0.26-0.55]). Sensitivity (specificity) values for the four observers were 72-92% (44-63%) for deep myometrial invasion, 38-63% (82-94%) for cervical stroma invasion and 25-38% (90-100%) for lymph node metastases. CONCLUSIONS: Conventional MRI showed only modest interobserver agreement and diagnostic accuracy for detection of deep myometrial invasion, cervical stroma invasion and lymph node metastases. Improved methods are needed for preoperative imaging in the staging of endometrial carcinomas. KEY POINTS: MRI is an important tool for preoperative endometrial cancer staging. • Staging agreement based on pelvic MRI was modest among different observers. • Preoperative MRI alone was suboptimal in identifying high-risk patients. • Improved imaging and biomarkers may refine preoperative risk stratification in endometrial cancer.

High frequency of adrenal myelolipomas and testicular adrenal rest tumours in adult Norwegian patients with classical congenital adrenal hyperplasia because of 21-hydroxylase deficiency.

BACKGROUND: Increased frequencies of adrenal tumours and testicular adrenal rest tumours (TART) have been reported in patients with 21-hydroxylase deficiency (21OHD). OBJECTIVE: Patients, methods and design From a cross-sectional population-based study of 101 adult Norwegian patients with 21OHD, sixty-two participated in this study (23 men, 39 women; age range 18-75); thirty-two were salt wasting (SW) and 30 simple virilizing (SV); they were assessed with adrenal computed tomography (CT), testicular ultrasound and hormone measurement in the morning after overnight medication fast. RESULTS: Nine adrenal tumours were detected in seven (11%) patients (bilateral in 2); four were myelolipomas and one a phaeochromocytoma. Seventeen (27%) had normal adrenal size, whereas 36 (58%) had persisting hyperplasia, and seven (11%) adrenal hypoplasia. Abnormal adrenals were more common in SW than in SV. TART occurred exclusively in SW and was present in seven (57%) of these men. Testicular volumes were small compared with normative data. Morning ACTH and 17-hydroxyprogesterone levels correlated positively with adrenal dimensions and frequency of TART. CONCLUSION: In this unselected population of patients with classical 21OHD, we found high frequencies of adrenal tumours, particularly myelolipomas, and of hyperplasia and hypoplasia, and TART in SW. It is important that physicians are aware that benign adrenal and testicular tumours occur frequently in 21OHD. Furthermore, these findings may reflect inappropriate glucocorticoid therapy, making a case for the advancement of novel physiological treatment modalities.