Multivariable prognostic modelling to improve prediction of colorectal cancer recurrence: the PROSPeCT trial.

OBJECTIVE: Improving prognostication to direct personalised therapy remains an unmet need. This study prospectively investigated promising CT, genetic, and immunohistochemical markers to improve the prediction of colorectal cancer recurrence. MATERIAL AND METHODS: This multicentre trial (ISRCTN 95037515) recruited patients with primary colorectal cancer undergoing CT staging from 13 hospitals. Follow-up identified cancer recurrence and death. A baseline model for cancer recurrence at 3 years was developed from pre-specified clinicopathological variables (age, sex, tumour-node stage, tumour size, location, extramural venous invasion, and treatment). Then, CT perfusion (blood flow, blood volume, transit time and permeability), genetic (RAS, RAF, and DNA mismatch repair), and immunohistochemical markers of angiogenesis and hypoxia (CD105, vascular endothelial growth factor, glucose transporter protein, and hypoxia-inducible factor) were added to assess whether prediction improved over tumour-node staging alone as the main outcome measure. RESULTS: Three hundred twenty-six of 448 participants formed the final cohort (226 male; mean 66 ± 10 years. 227 (70%) had ≥ T3 stage cancers; 151 (46%) were node-positive; 81 (25%) developed subsequent recurrence. The sensitivity and specificity of staging alone for recurrence were 0.56 [95% CI: 0.44, 0.67] and 0.58 [0.51, 0.64], respectively. The baseline clinicopathologic model improved specificity (0.74 [0.68, 0.79], with equivalent sensitivity of 0.57 [0.45, 0.68] for high vs medium/low-risk participants. The addition of prespecified CT perfusion, genetic, and immunohistochemical markers did not improve prediction over and above the clinicopathologic model (sensitivity, 0.58-0.68; specificity, 0.75-0.76). CONCLUSION: A multivariable clinicopathological model outperformed staging in identifying patients at high risk of recurrence. Promising CT, genetic, and immunohistochemical markers investigated did not further improve prognostication in rigorous prospective evaluation. CLINICAL RELEVANCE STATEMENT: A prognostic model based on clinicopathological variables including age, sex, tumour-node stage, size, location, and extramural venous invasion better identifies colorectal cancer patients at high risk of recurrence for neoadjuvant/adjuvant therapy than stage alone. KEY POINTS: Identification of colorectal cancer patients at high risk of recurrence is an unmet need for treatment personalisation. This model for recurrence, incorporating many patient variables, had higher specificity than staging alone. Continued optimisation of risk stratification schema will help individualise treatment plans and follow-up schedules.

Diffusion-weighted imaging complements T2-weighted MRI for tumour response assessment in squamous anal carcinoma.

OBJECTIVES: A published tumour regression grade (TRG) score for squamous anal carcinoma treated with definitive chemoradiotherapy based on T2-weighted MRI yields a high proportion of indeterminate responses (TRG-3). We investigate whether the addition of diffusion-weighted imaging (DWI) improves tumour response assessment in the early post treatment period. MATERIALS AND METHODS: This retrospective observational study included squamous anal carcinoma patients undergoing MRI before and within 3 months of completing chemoradiotherapy from 2009 to 2020. Four independent radiologists (1-20 years' experience) scored MRI studies using a 5-point TRG system (1 = complete response; 5 = no response) based on T2-weighted sequences alone, and then after a 12-week washout period, using a 5-point DWI-TRG system based on T2-weighted and DWI. Scoring confidence was recorded on a 5-point scale (1 = low; 5 = high) for each reading and compared using the Wilcoxon test. Indeterminate scores (TRG-3) from each reading session were compared using the McNemar test. Interobserver agreement was assessed using kappa statistics. RESULTS: Eighty-five patients were included (mean age, 59 years ± 12 [SD]; 55 women). T2-weighted TRG-3 scores from all readers combined halved from 24% (82/340) to 12% (41/340) with DWI (p < 0.001). TRG-3 scores changed most frequently (41%, 34/82) to DWI-TRG-2 (excellent response). Complete tumour response was recorded clinically in 77/85 patients (91%). Scoring confidence increased using DWI (p < 0.001), with scores of 4 or 5 in 84% (287/340). Interobserver agreement remained fair to moderate (kappa range, 0.28-0.58). CONCLUSION: DWI complements T2-weighted MRI by reducing the number of indeterminate tumour responses (TRG-3). DWI increases radiologist's scoring confidence. CLINICAL RELEVANCE STATEMENT: Diffusion-weighted imaging improves T2-weighted tumour response assessment in squamous anal cancer, halving the number of indeterminate responses in the early post treatment period, and increases radiologists' confidence. KEY POINTS: Tumour response based on T2-weighted MRI is often indeterminate in squamous anal carcinoma. Diffusion-weighted imaging alongside T2-weighted MRI halved indeterminate tumour regression grade scores assigned by four radiologists from 24 to 12%. Scoring confidence of expert and non-expert radiologists increased with the inclusion of diffusion-weighted imaging.

Bladder paragangliomas: a pictorial review.

Bladder paragangliomas (bPGL) are rare neuroendocrine tumors arising from the sympathetic paraganglia present in the bladder wall. Bladder PGLs are typically submucosal or intramural but when subserosal may not be readily visible at cystoscopy. The average size at presentation is 3.9 cm (range 1.0-9.1 cm). When small, bPGL are usually spherical, well-marginated and homogeneous. Larger bPGL are typically more complex with peri- and intra-tumoral neovascularity and central necrosis. On ultrasound, increased color Doppler signal is typical. The increased soft tissue resolution of MRI enables localization of bPGL within the bladder wall more accurately than CT. Restricted diffusion and avid contrast enhancement help differentiate small bPGLs from leiomyomas, which have similar appearances on ultrasound and CT. Nuclear medicine techniques identify bPGLs and their metastases with high specificity, 68Ga-DOTATATE PET/CT having largely replaced 123I-mIBG SPECT/CT as the first line functional investigation. Imaging is essential to aid surgical planning, as endoscopic resection is often not possible or incomplete due to tumor location. For patients with advanced disease, 68Ga-DOTATATE PET/CT and 123I-mIBG SPECT/CT assess suitability for peptide receptor radionuclide therapy. Up to 63% of bPGL patients have a germline mutation, most commonly in the SDHB subunit gene, increasing their risk of developing pheochromocytomas and further paragangliomas; lifelong annual biochemical and periodic imaging screening from skull base to pelvis is therefore recommended.

Multimodality Assessment of Cystic Renal Masses.

Renal cysts are a common imaging finding, often incidental. Ultrasound, CT and MRI are the main modalities responsible for renal cyst detection and characterization. These modalities often play a complementary role in modern radiological practice, each of them with strengths and limitations. In view of a recently proposed 'multimodality' update to the historical Bosniak classification, this article provides a general overview of the current imaging approach to renal cysts, and outlines some of the diverse pathologic entities responsible for renal cyst formation.

Multiparametric Ultrasound of Nonpalpable Focal Testicular Lesions.

Indeterminate nonpalpable focal testicular lesions have emerged as a clinical problem with the increasing use of scrotal ultrasound, particularly in the context of infertility. Conventional morphological ultrasound and color Doppler have been unreliable at differentiating benign from malignant lesions. Multiparametric ultrasound (mpUS) comprises real-time elastography and contrast-enhanced ultrasound as adjunctive tools, and is ready for use in most state-of-the-art ultrasound systems. Initial experience with mpUS from selected specialist centers shows promise for lesion characterization, and potential for affecting management and improving outcomes. This article provides a summary of the existing literature on testicular mpUS, and outlines the clinical context from a urological and histopathological perspective.

Accelerated 3D T2 w-imaging of the prostate with 1-millimeter isotropic resolution in less than 3 minutes.

PURPOSE: To achieve 3D T2 w imaging of the prostate with 1-mm isotropic resolution in less than 3 min. METHODS: We devised and implemented a 3D T2 -prepared multishot balanced steady state free precession (T2 prep-bSSFP) acquisition sequence with a variable density undersampled trajectory combined with a total variation regularized iterative SENSE (TV-SENSE) reconstruction. Prospectively undersampled images of the prostate (acceleration factor R = 3) were acquired in 11 healthy subjects in an institutional review board-approved study. Image quality metrics (subjective signal-to-noise ratio, contrast, sharpness, and overall prostate image quality) were evaluated by 2 radiologists. Scores of the proposed accelerated sequence were compared using the Wilcoxon signed-rank and Kruskal-Wallis non-parametric tests to prostate images acquired using a fully sampled 3D T2 prep-bSSFP acquisition, and with clinical standard 2D and 3D turbo spin echo (TSE) T2 w acquisitions. A P-value < 0.05 was considered significant. RESULTS: The 3× accelerated 3D T2 prep-bSSFP images required a scan time (min:s) of 2:45, while the fully sampled 3D T2 prep-bSSFP and clinical standard 3D TSE images were acquired in 8:23 and 7:29, respectively. Image quality scores (contrast, sharpness, and overall prostate image quality) of the accelerated 3D T2 prep-bSSFP, fully sampled T2 prep-bSSFP, and clinical standard 3D TSE acquisitions along all 3 spatial dimensions were not significantly different (P > 0.05). CONCLUSION: 3D T2 w images of the prostate with 1-mm isotropic resolution can be acquired in less than 3 min, with image quality that is comparable to a clinical standard 3D TSE sequence but only takes a third of the acquisition time.

MRI heterogeneity analysis for prediction of recurrence and disease free survival in anal cancer.

BACKGROUND: The aim of this study was to evaluate the role of image heterogeneity analysis of standard care magnetic resonance imaging (MRI) in patients with anal squamous cell carcinoma (ASCC) to predict chemoradiotherapy (CRT) outcome. The ability to predict disease recurrence following CRT has the potential to inform personalized radiotherapy approaches currently being explored in novel clinical trials. METHODS: An IRB waiver was obtained for retrospective analysis of standard care MRIs from ASCC patients presenting between 2010 and 2014. Whole tumor 3D volume-of-interest (VOI) was outlined on T2-weighted (T2w) and diffusion weighted imaging (DWI) of the pre- and post-treatment scans. Independent imaging features most predictive of disease recurrence were added to the baseline clinico-pathological model and the predictive value of respective extended models was calculated using net reclassification improvement (NRI) algorithm. Cross-validation analysis was carried out to determine percentage error reduction with inclusion of imaging features to the baseline model for both endpoints. RESULTS: Forty patients who underwent 1.5 T pelvic MRI at baseline and following completion of CRT were included. A combination of two baseline MR heterogeneity features (baseline T2w energy and DWI coefficient of variation) was most predictive of disease recurrence resulting in significant NRI (p = 0 < 0.001). This was confirmed in cross-validation analysis with 34.8% percentage error reduction for the primary endpoint and 18.1% reduction for the secondary endpoint with addition of imaging variables to baseline model. CONCLUSION: MRI heterogeneity analysis offers complementary information, in addition to clinical staging, in predicting outcome of CRT in anal SCC, warranting validation in larger datasets.

Adaptive statistical iterative reconstruction (ASIR) affects CT radiomics quantification in primary colorectal cancer.

OBJECTIVES: To investigate whether adaptive statistical iterative reconstruction (ASIR), a hybrid iterative CT image reconstruction algorithm, affects radiomics feature quantification in primary colorectal cancer compared to filtered back projection. Additionally, to establish whether radiomics from single-slice analysis undergo greater change than those from multi-slice analysis. METHODS: Following review board approval, contrast-enhanced CT studies from 32 prospective primary colorectal cancer patients were reconstructed with 20% ASIR level increments, from 0 to 100%. Radiomics analysis was applied to single-slice and multi-slice regions of interest outlining the tumour: 70 features, including statistical (first-, second- and high-order) and fractal radiomics, were generated per dataset. The effect of ASIR was calculated by means of multilevel linear regression. RESULTS: Twenty-eight CT datasets were suitable for analysis. Incremental ASIR levels determined a significant change (p < 0.001) in most statistical radiomics features, best described by a simple linear relationship. First-order statistical features, including mean, standard deviation, skewness, kurtosis, energy and entropy, underwent a relatively small change in both single-slice and multi-slice analysis (median standardised effect size B = 0.08). Second-order statistical features, including grey-level co-occurrence and difference matrices, underwent a greater change in single-slice analysis (median B = 0.36) than in multi-slice analysis (median B = 0.13). Fractal features underwent a significant change only in single-slice analysis (median B = 0.49). CONCLUSIONS: Incremental levels of ASIR affect significantly CT radiomics quantification in primary colorectal cancer. Second-order statistical and fractal features derived from single-slice analysis undergo greater change than those from multi-slice analysis. KEY POINTS: • Incremental levels of ASIR determine a significant change in most statistical (first-, second- and high-order) CT radiomics features measured in primary colorectal cancer, best described by a linear relationship. • First-order statistical features undergo a small change, both from single-slice and multi-slice radiomics analyses. • Most second-order statistical features undergo a greater change in single-slice analysis than in multi-slice analysis. Fractal features are only affected in single-slice analysis.

Imaging biomarkers in oncology: Basics and application to MRI.

Cancer remains a global killer alongside cardiovascular disease. A better understanding of cancer biology has transformed its management with an increasing emphasis on a personalized approach, so-called "precision cancer medicine." Imaging has a key role to play in the management of cancer patients. Imaging biomarkers that objectively inform on tumor biology, the tumor environment, and tumor changes in response to an intervention complement genomic and molecular diagnostics. In this review we describe the key principles for imaging biomarker development and discuss the current status with respect to magnetic resonance imaging (MRI). LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 5 J. Magn. Reson. Imaging 2018;48:13-26.

Imaging for the diagnosis and response assessment of renal tumours.

PURPOSE: Imaging plays a key role throughout the renal cell carcinoma (RCC) patient pathway, from diagnosis and staging of the disease, to the assessment of response to therapy. This review aims to summarise current knowledge with regard to imaging in the RCC patient pathway, highlighting recent advances and challenges. METHODS: A literature review was performed using Medline. Particular focus was paid to RCC imaging in the diagnosis, staging and response assessment following therapy. RESULTS: Characterisation of small renal masses (SRM) remains a diagnostic conundrum. Contrast-enhanced ultrasound (CEUS) has been increasingly applied in this field, as have emerging technologies such as multiparametric MRI, radiomics and molecular imaging with 99mtechnetium-sestamibi single photon emission computed tomography/CT. CT remains the first-line modality for staging of locoregional and suspected metastatic disease. Although the staging accuracy of CT is good, limitations in determining nodal status persist. Response assessment following ablative therapies remains challenging, as reduction in tumour size may not occur. The pattern of enhancement on CT may be a more reliable indicator of treatment success. CEUS may also have a role in monitoring response following ablation. Response assessments following anti-angiogenic and immunotherapies in advanced RCC is an evolving field, with a number of alternative response criteria being proposed. Tumour response patterns may vary between different immunotherapy agents and tumour types; thus, future response criteria modifications may be inevitable. CONCLUSION: The diagnosis and characterisation of SRM and response assessment following targeted therapy for advanced RCC are key challenges which warrant further research.

Characterization of Small Renal Tumors With Magnetic Resonance Elastography: A Feasibility Study.

OBJECTIVES: The aim of this study was to explore the feasibility of magnetic resonance elastography (MRE) for characterizing indeterminate small renal tumors (SRTs) as part of a multiparametric magnetic resonance (MR) imaging protocol. MATERIALS AND METHODS: After institutional review board approval and informed consent were obtained, 21 prospective adults (15 men; median age, 55 years; age range, 25-72 years) with SRT were enrolled. Tumors (2-5 cm Ø) were imaged using 3-directional, gradient echo MRE. Viscoelastic parametric maps (shear wave velocity [c] and attenuation [α]) were analyzed by 2 independent radiologists. Interobserver agreement (Bland-Altman statistics and intraclass correlation coefficients) was assessed. Anatomical T2-weighted, dynamic contrast-enhanced (DCE) and diffusion sequences completed the acquisition protocol. Imaging parameters were compared between groups (Mann-Whitney U test). RESULTS: Quality of MRE was good in 18 cases (mean nonlinearity <50%), including 1 papillary renal cell carcinoma and 1 metanephric adenoma. A cohort of 5 oncocytomas and 11 clear-cell renal cell carcinomas (ccRCCs) was analyzed for statistical differences. The MRE viscoelastic parameters were the strongest imaging discriminators: oncocytomas displayed significantly lower shear velocity c (median, 0.77 m/s; interquartile range [IQR], 0.76-0.79) (P = 0.007) and higher shear attenuation α (median, 0.087 mm; IQR, 0.082-0.087) (P = 0.008) than ccRCC (medians, 0.92 m/s and 0.066 mm; IQR, 0.84-0.97 and 0.054-0.074, respectively). T2 signal intensity ratio (tumor/renal cortex) was lower in oncocytomas (P = 0.02). The DCE and diffusion MR parameters overlapped substantially (P ≥ 0.1). Oncocytomas displayed a consistent MRE viscoelastic profile, corresponding to data point clustering in a bidimensional scatter plot. Values for MRE intraclass correlation coefficient were 0.982 for c and 0.984 for α, indicating excellent interobserver agreement. CONCLUSIONS: Magnetic resonance elastography is feasible for SRT characterization; MRE viscoelastic parameters were stronger discriminators between oncocytoma and ccRCC than anatomical, DCE and diffusion MR imaging parameters.

The impact of MRI sequence on tumour staging and gross tumour volume delineation in squamous cell carcinoma of the anal canal.

OBJECTIVES: To compare maximum tumour diameter (MTD) and gross tumour volume (GTV) measurements between T2-weighted (T2-w) and diffusion-weighted (DWI) MRI in squamous cell carcinoma of the anal canal (SCCA) and assess sequence impact on tumour (T) staging. Second, to evaluate interobserver agreement and reader delineation confidence. METHODS: The staging MRI scans of 45 SCCA patients (25 females) were assessed retrospectively by two independent radiologists (0 and 5 years' experience of anal cancer MRI). MTD and GTV were delineated on both T2-w and high-b-value DWI images and compared between sequences; T staging was derived from MTD. Interobserver agreement was assessed and delineation confidence scored (1 to 5) by each observer. RESULTS: GTV and MTD were significantly and systematically lower on DWI versus T2-w sequences by 14.80%/9.98% (MTD) and 29.70%/12.25% (GTV) for each reader, respectively, causing T staging discordances in approximately a quarter of cases. Bland-Altman limits of agreement were narrower and intraclass correlation coefficients higher for DWI. Delineation confidence was greater on DWI: 40/42 cases were scored confidently (4 or 5) by each reader, respectively, versus 31/36 cases based on T2-w images. CONCLUSIONS: Sequence selection affects SCCA measurements and T stage. DWI yields higher interobserver agreement and greater tumour delineation confidence. KEY POINTS: • MTD and GTV measurements are significantly lower on DWI than on T 2 -w MRI. • Such differences cause T staging discordances in up to a quarter of cases. • DWI results in higher agreement between inexperienced and experienced observers. • DWI offers greater tumour delineation confidence to inexperienced readers.

Primary Rectal Cancer: Repeatability of Global and Local-Regional MR Imaging Texture Features.

Purpose To assess the day-to-day repeatability of global and local-regional magnetic resonance (MR) imaging texture features derived from primary rectal cancer. Materials and Methods After ethical approval and patient informed consent were obtained, two pretreatment T2-weighted axial MR imaging studies performed prospectively with the same imaging unit on 2 consecutive days in 14 patients with rectal cancer (11 men [mean age, 61.7 years], three women [mean age, 70.0 years]) were analyzed to extract (a) global first-order statistical histogram and model-based fractal features reflecting the whole-tumor voxel intensity histogram distribution and repeating patterns, respectively, without spatial information and (b) local-regional second-order and high-order statistical texture features reflecting the intensity and spatial interrelationships between adjacent in-plane or multiplanar voxels or regions, respectively. Repeatability was assessed for 46 texture features, and mean difference, 95% limits of agreement, within-subject coefficient of variation (wCV), and repeatability coefficient (r) were recorded. Results Repeatability was better for global parameters than for most local-regional parameters. In particular, histogram mean, median, and entropy, fractal dimension mean and standard deviation, and second-order entropy, homogeneity, difference entropy, and inverse difference moment demonstrated good repeatability, with narrow limits of agreement and wCVs of 10% or lower. Repeatability was poorest for the following high-order gray-level run-length (GLRL) gray-level zone size matrix (GLZSM) and neighborhood gray-tone difference matrix (NGTDM) parameters: GLRL intensity variability, GLZSM short-zone emphasis, GLZSM intensity nonuniformity, GLZSM intensity variability, GLZSM size zone variability, and NGTDM complexity, demonstrating wider agreement limits and wCVs of 50% or greater. Conclusion MR imaging repeatability is better for global texture parameters than for local-regional texture parameters, indicating that global texture parameters should be sufficiently robust for clinical practice. Online supplemental material is available for this article.

Positron Emission Tomography/Magnetic Resonance Imaging of Gastrointestinal Cancers.

As an integrated system, hybrid positron emission tomography/magnetic resonance imaging (PET/MRI) is able to provide simultaneously complementary high-resolution anatomic, molecular, and functional information, allowing comprehensive cancer phenotyping in a single imaging examination. In addition to an improved patient experience by combining 2 separate imaging examinations and streamlining the patient pathway, the superior soft tissue contrast resolution of MRI and the ability to acquire multiparametric MRI data is advantageous over computed tomography. For gastrointestinal cancers, this would improve tumor staging, assessment of neoadjuvant response, and of the likelihood of a complete (R0) resection in comparison with positron emission tomography or computed tomography.

Monitoring Crohn's disease during anti-TNF-α therapy: validation of the magnetic resonance enterography global score (MEGS) against a combined clinical reference standard.

OBJECTIVES: To assess the ability of magnetic resonance enterography global score (MEGS) to characterise Crohn's disease (CD) response to anti-TNF-α therapy. METHODS: Thirty-six CD patients (median age 26 years, 20 males) commencing anti-TNF-α therapy with concomitant baseline MRI enterography (MRE) were identified retrospectively. Patients' clinical course was followed and correlated with subsequent MREs. Scan order was randomised and MEGS (a global activity score) was applied by two blinded radiologists. A physician's global assessment of the disease activity (remission, mild, moderate or severe) at the time of MRE was assigned. The cohort was divided into clinical responders and non-responders and MEGS compared according to activity status and treatment response. Interobserver agreement was assessed. RESULTS: Median MEGS decreased significantly between baseline and first follow-up in responders (28 versus 6, P < 0.001) but was unchanged in non-responders (26 versus 18, P = 0.28). The median MEGS was significantly lower in clinical remission (9) than in moderate (14) or severe (29) activity (P < 0.001). MEGS correlated significantly with clinical activity (r = 0.53; P < 0.001). Interobserver Bland-Altman limits of agreement (BA LoA) were -19.7 to 18.5. CONCLUSIONS: MEGS decreases significantly in clinical responders to anti-TNF-α therapy but not in non-responders, demonstrates good interobserver agreement and moderate correlation with clinical disease activity. KEY POINTS: • MRI scores of Crohn's activity are used increasingly in clinical practice and therapeutic trials. • Such scores have been advocated as biomarkers of therapeutic response. • MEGS reflects clinical response to anti-TNF-α therapy and the clinical classification of disease activity. • MEGS demonstrates good interobserver agreement.