Imaging features of the evolving patterns of metastatic prostate cancer.

The pattern of metastases in prostate cancer (PC) is evolving. Increased use of imaging, newer imaging techniques with higher sensitivity for disease detection and patients receiving multiple lines of novel therapies with increased life expectancy are likely to be contributory. Awareness of metastatic disease patterns improves early diagnosis, accurate staging, and initiation of appropriate therapy, and can inform prognostic information and anticipate potential disease complications. The aim of this review is to document the spectrum of metastases in PC including emerging and unusual patterns, and to highlight the role of novel imaging including prostate-specific membrane antigen (PSMA)-positron-emission tomography (PET) and whole-body magnetic resonance imaging (WB-MRI) to improve diagnostic and response assessment accuracy.

Introduction to the National Cancer Imaging Translational Accelerator (NCITA): a UK-wide infrastructure for multicentre clinical translation of cancer imaging biomarkers.

The National Cancer Imaging Translational Accelerator (NCITA) is creating a UK national coordinated infrastructure for accelerated translation of imaging biomarkers for clinical use. Through the development of standardised protocols, data integration tools and ongoing training programmes, NCITA provides a unique scalable infrastructure for imaging biomarker qualification using multicentre clinical studies.

Whole-body MRI: a practical guide for imaging patients with malignant bone disease.

Whole-body magnetic resonance imaging (MRI) is now a crucial tool for the assessment of the extent of systemic malignant bone disease and response to treatment, and forms part of national and international recommendations for imaging patients with myeloma or metastatic prostate cancer. Recent developments in scanners have enabled acquisition of good-quality whole-body MRI data within 45 minutes on modern MRI systems from all main manufacturers. This provides complimentary morphological and functional whole-body imaging; however, lack of prior experience and acquisition times required can act as a barrier to adoption in busy radiology departments. This article aims to tackle the former by reviewing the indications and providing guidance for technical delivery and clinical interpretation of whole-body MRI for patients with malignant bone disease.

First MRI application of an active breathing coordinator.

A commercial active breathing coordinator (ABC) device, employed to hold respiration at a specific level for a predefined duration, was successfully adapted for magnetic resonance imaging (MRI) use for the first time. Potential effects of the necessary modifications were assessed and taken into account. Automatic MR acquisition during ABC breath holding was achieved. The feasibility of MR-ABC thoracic and abdominal examinations together with the advantages of imaging in repeated ABC-controlled breath holds were demonstrated on healthy volunteers. Five lung cancer patients were imaged under MR-ABC, visually confirming the very good intra-session reproducibility of organ position in images acquired with the same patient positioning as used for computed tomography (CT). Using identical ABC settings, good MR-CT inter-modality registration was achieved. This demonstrates the value of ABC, since application of T1, T2 and diffusion weighted MR sequences provides a wider range of contrast mechanisms and additional diagnostic information compared to CT, thus improving radiotherapy treatment planning and assessment.

Dichloroacetate induces autophagy in colorectal cancer cells and tumours.

BACKGROUND: Dichloroacetate (DCA) has been found to have antitumour properties. METHODS: We investigated the cellular and metabolic responses to DCA treatment and recovery in human colorectal (HT29, HCT116 WT and HCT116 Bax-ko), prostate carcinoma cells (PC3) and HT29 xenografts by flow cytometry, western blotting, electron microscopy, (1)H and hyperpolarised (13)C-magnetic resonance spectroscopy. RESULTS: Increased expression of the autophagy markers LC3B II was observed following DCA treatment both in vitro and in vivo. We observed increased production of reactive oxygen species (ROS) and mTOR inhibition (decreased pS6 ribosomal protein and p4E-BP1 expression) as well as increased expression of MCT1 following DCA treatment. Steady-state lactate excretion and the apparent hyperpolarised [1-(13)C] pyruvate-to-lactate exchange rate (k(PL)) were decreased in DCA-treated cells, along with increased NAD(+)/NADH ratios and NAD(+). Steady-state lactate excretion and k(PL) returned to, or exceeded, control levels in cells recovered from DCA treatment, accompanied by increased NAD(+) and NADH. Reduced k(PL) with DCA treatment was found in HT29 tumour xenografts in vivo. CONCLUSIONS: DCA induces autophagy in cancer cells accompanied by ROS production and mTOR inhibition, reduced lactate excretion, reduced k(PL) and increased NAD(+)/NADH ratio. The observed cellular and metabolic changes recover on cessation of treatment.

Imaging hypoxia in tumours with advanced MRI.

Tumour hypoxia results in biological alterations that leads to a more aggressive disease phenotype and is associated with resistance to treatment. In this review, we discuss current magnetic resonance imaging techniques, which can be applied to evaluate tumour hypoxia, highlighting the principles of each technique, their pre-clinical and clinical deployment, as well as their strengths and limitations. The potential to combine these techniques, and also with other imaging modalities (e.g., PET imaging) using a multiparametric approach, may further improve our understanding of the complex interaction of vascular supply, oxygen diffusion and tissue metabolism in pathogenesis of tumour hypoxia; and its reversal with treatment.

The role of pre-treatment diffusion-weighted MRI in predicting long-term outcome of colorectal liver metastasis.

OBJECTIVE: To determine the prognostic value of pre-treatment apparent diffusion coefficient (ADC) of colorectal liver metastases in predicting disease response, progression-free survival (PFS) and overall survival (OS). METHODS: We retrospectively reviewed 102 patients who underwent pre-treatment diffusion-weighted MRI using a breath-hold (b=0, 150, 500) or a free-breathing (b=0, 50, 100, 250, 500, 750) technique. The mean ADC (b=0-500) and mean flow-insensitive ADC (ADChigh) values (breath-hold: b=150 and 500; free-breathing: b=100 and 500) of up to three hepatic lesions were evaluated in each patient. Clinical and laboratory parameters were recorded. Tumour response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria at 12 weeks after treatment. Associations between tumour response, ADC values and clinical/laboratory parameters were examined by one-way analysis of variance. The relationship of ADC with PFS and OS was determined by Kaplan-Meier analysis. RESULTS: 62 patients responded to chemotherapy at 12 weeks. The pre-treatment mean ADC and mean ADChigh were higher in the non-responding group than in the responding group (1.55 vs 1.36, p=0.033; 1.40 vs 1.16, p=0.024). However, the PFS and OS of the two groups of patients stratified by the median of mean ADC values or threshold derived by receiver operating characteristic analysis were not statistically significant. By multivariate Cox regression analysis, patients with ≤2 metastases and response to chemotherapy showed better PFS; white cell count ≤10 and surgical treatment were associated with better OS. CONCLUSION: Colorectal liver metastasis with higher pre-treatment mean ADC and mean ADChigh was associated with poorer response to chemotherapy. However, ADC and ADChigh values did not predict the patient outcome in this study cohort. ADVANCES IN KNOWLEDGE: High mean ADC values of colorectal liver metastases on pre-treatment diffusion-weighted MRI is associated with poorer response to chemotherapy.

Diffusion-weighted imaging of the liver: an update.

Diffusion-weighted magnetic resonance imaging (DW-MRI) is now widely used as a standard imaging sequence for evaluation of the liver. The technique is easy to implement across different MRI platforms, and results in enhanced disease detection and characterization. With careful implementation, the quantitative apparent diffusion coefficient derived shows good measurement reproducibility, which can be applied for tissue characterization, the assessment of tumour response and disease prognostication. There is now a body of evidence that highlights the relative strengths and limitations of the technique for the assessment of liver diseases. The potential for more sophisticated analysis of DW-MRI data is currently being widely investigated.

Measurement reproducibility of perfusion fraction and pseudodiffusion coefficient derived by intravoxel incoherent motion diffusion-weighted MR imaging in normal liver and metastases.

OBJECTIVE: To determine the measurement reproducibility of perfusion fraction f, pseudodiffusion coefficient D and diffusion coefficient D in colorectal liver metastases and normal liver. METHODS: Fourteen patients with known colorectal liver metastases were examined twice using respiratory-triggered echo-planar DW-MRI with eight b values (0 to 900 s/mm(2)) 1 h apart. Regions of interests were drawn around target metastasis and normal liver in each patient to derive ADC (all b values), ADC(high) (b values ≥ 100 s/mm(2)) and intravoxel incoherent motion (IVIM) parameters f, D and D by least squares data fitting. Short-term measurement reproducibility of median ADC, ADC(high), f, D and D values were derived from Bland-Altman analysis. RESULTS: The measurement reproducibility for ADC, ADC(high) and D was worst in colorectal liver metastases (-21 % to +25 %) compared with liver parenchyma (-6 % to +8 %). Poor measurement reproducibility was observed for the perfusion-sensitive parameters of f (-75 % to +241 %) and D (-89 % to +2,120 %) in metastases, and to a lesser extent the f (-24 % to +25 %) and D (-31 % to +59 %) of liver. CONCLUSIONS: Estimates of f and D derived from the widely used least squares IVIM fitting showed poor measurement reproducibility. Efforts should be made to improve the measurement reproducibility of perfusion-sensitive IVIM parameters.

Imaging vascular function for early stage clinical trials using dynamic contrast-enhanced magnetic resonance imaging.

Many therapeutic approaches to cancer affect the tumour vasculature, either indirectly or as a direct target. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has become an important means of investigating this action, both pre-clinically and in early stage clinical trials. For such trials, it is essential that the measurement process (i.e. image acquisition and analysis) can be performed effectively and with consistency among contributing centres. As the technique continues to develop in order to provide potential improvements in sensitivity and physiological relevance, there is considerable scope for between-centre variation in techniques. A workshop was convened by the Imaging Committee of the Experimental Cancer Medicine Centres (ECMC) to review the current status of DCE-MRI and to provide recommendations on how the technique can best be used for early stage trials. This review and the consequent recommendations are summarised here. Key Points • Tumour vascular function is key to tumour development and treatment • Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumour vascular function • Thus DCE-MRI with pharmacokinetic models can assess novel treatments • Many recent developments are advancing the accuracy of and information from DCE-MRI • Establishing common methodology across multiple centres is challenging and requires accepted guidelines.

Bone metastases from prostate, breast and multiple myeloma: differences in lesion conspicuity at short-tau inversion recovery and diffusion-weighted MRI.

OBJECTIVES: The objective of this study was to compare the relative conspicuity of bone metastases on short-tau inversion recovery (STIR) and diffusion-weighted MRI (DWI) whole-body MR sequences for breast, prostate and myeloma malignancies. METHODS: 44 whole-body MRI scans were reviewed retrospectively (coronal T(1) weighted, STIR and DWI with b=800). On each scan, up to four of the largest bone lesions were identified on T(1) weighting, and the region of interest signal intensity was measured on STIR and DWI, as well as the background signal intensity. The mean lesion signal to background ratio was calculated for each patient and then for each malignancy group. RESULTS: In prostate cancer patients, the DWI signal/background ratio was greater than that of STIR in 22 out of 24 patients (mean DWI lesion/background ratio 3.91, mean STIR lesion/background ratio 2.31; p=0.0001). In multiple myeloma, the DWI ratio was higher in 6/7 patients (DWI group mean ratio 7.59, STIR group mean ratio 3.7; p=0.0366). In 13 breast cancer patients, mean STIR and DWI signal/background were similar (DWI group mean ratio 4.13, group mean STIR ratio 4.26; p=0.8587). CONCLUSION: Bone lesion conspicuity measured by lesion/background signal intensity was higher on DWI b=800 than on STIR in patients with prostate cancer and multiple myeloma. DWI should be used in whole-body MR oncology protocols in these conditions to maximise lesion detection.

Combining diffusion-weighted MRI with Gd-EOB-DTPA-enhanced MRI improves the detection of colorectal liver metastases.

OBJECTIVES: To compare the diagnostic accuracy of gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced MRI, diffusion-weighted MRI (DW-MRI) and a combination of both techniques for the detection of colorectal hepatic metastases. METHODS: 72 patients with suspected colorectal liver metastases underwent Gd-EOB-DTPA MRI and DW-MRI. Images were retrospectively reviewed with unenhanced T(1) and T(2) weighted images as Gd-EOB-DTPA image set, DW-MRI image set and combined image set by two independent radiologists. Each lesion detected was scored for size, location and likelihood of metastasis, and compared with surgery and follow-up imaging. Diagnostic accuracy was compared using receiver operating characteristics and interobserver agreement by kappa statistics. RESULTS: 417 lesions (310 metastases, 107 benign) were found in 72 patients. For both readers, diagnostic accuracy using the combined image set was higher [area under the curve (Az)=0.96, 0.97] than Gd-EOB-DTPA image set (Az=0.86, 0.89) or DW-MRI image set (Az=0.93, 0.92). Using combined image set improved identification of liver metastases compared with Gd-EOB-DTPA image set (p<0.001) or DW-MRI image set (p<0.001). There was very good interobserver agreement for lesion classification (κ=0.81-0.88). CONCLUSIONS: Combining DW-MRI with Gd-EOB-DTPA-enhanced T(1) weighted MRI significantly improved the detection of colorectal liver metastases.

Segmental liver hyperintensity in malignant biliary obstruction on diffusion weighted MRI: associated MRI findings and relationship with serum alanine aminotransferase levels.

OBJECTIVES: Segmental liver hyperintensity can be observed in malignant biliary obstruction on diffusion weighted MRI (DW-MRI). We describe MRI findings associated with this sign and evaluate whether DW-MRI segmental hyperintensity has any relationship with serum alanine aminotransferase (ALT) levels. METHODS: The DW-MRI T(1) weighted, T(2) weighted and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced T(1) weighted images obtained in 21 patients with hepatic malignancy, who demonstrated biliary obstruction and segmental hyperintensity on DW-MRI (b=0-750 s mm(-2)), were retrospectively reviewed by 2 readers blinded to clinical results. DW-MRI hyperintense liver segments were recorded as hypointense, isointense or hyperintense relative to normal liver on T(1)/T(2) weighted imaging. It was also noted whether contrast enhancement was similar to that observed in normal liver or diminished in the hepatocellular phase. The mean apparent diffusion coefficient (ADC) value (×10(-3) s mm(-2)) of DW-MRI hyperintense segments, normal liver and tumour were compared using Student's t-test. The frequency of MRI findings was corroborated with serum ALT levels, which reflect hepatocyte injury. RESULTS: DW-MRI hyperintense segments frequently showed T(1) hyperintensity (10/21), T(2) hyperintensity (19/21) and/or diminished contrast enhancement (15/21). Tumours showed significantly lower mean ADC values than liver (1.23 ± 0.08 vs 1.43 ± 0.05; p=0.013). Segments showing concomitant T(1) hyperintensity had lower mean ADC values than liver (1.30 ± 0.05 vs 1.43 ± 0.05; p=0.023). The patients (8/10) with concomitant T(1) and DW-MRI segmental hyperintensity showed elevated ALT levels (p=0.030, Fisher's exact test). CONCLUSION: Concomitantly high T(1) weighted and DW-MRI signal in liver segments was associated with lower ADC values and abnormal liver function tests, which could reflect underlying cellular swelling and damage.

Appearances of colorectal hepatic metastases at diffusion-weighted MRI compared with histopathology: initial observations.

OBJECTIVE: To describe the appearances of colorectal liver metastases on diffusion-weighted MRI (DW-MRI) and to compare these appearances with histopathology. METHODS: 43 patients with colorectal liver metastases were evaluated using breath-hold DW-MRI (b-values 0, 150 and 500 s mm(-2)). The b=500 s mm(-2) DW-MRI were reviewed consensually for lesion size and appearance by two readers. 18/43 patients underwent surgery allowing radiological-pathological comparison. Tissue sections were reviewed by a pathologist, who classified metastases histologically as cellular, fibrotic, necrotic or mixed. The frequency of DW-MRI findings and histological features were compared using the χ(2) test. RESULTS: 84 metastases were found in 43 patients. On b=500 s mm(-2) DW-MRI, metastases showed three high signal intensity patterns: rim (55/84), uniform (23/84) and variegate (6/84). Of the 55 metastases showing rim pattern, 54 were >1 cm in diameter (p<0.01, χ(2) test). 25/84 metastases were surgically resected. Of these, 11/22 metastases >1 cm in diameter showed rim pattern and demonstrated central necrosis at histopathology (p=0.04, χ(2) test). No definite relationship was found between uniform and variegate patterns with histology. CONCLUSION: Rim high signal intensity was the most common appearance of colorectal liver metastases >1 cm diameter on DW-MRI at b-values of 500 s mm(-2), a finding attributable to central necrosis.

Assessment of colorectal hepatic metastases by quantitative T2 relaxation time.

AIM: To determine the T(2) relaxation time of colorectal hepatic metastases and changes in T(2) relaxation times following chemotherapy. MATERIALS AND METHODS: 42 patients with 96 hepatic colorectal metastases underwent baseline MRI. Axial T(1), T(2) and multi-echo GRASE sequences were acquired. ROIs were drawn on T(2) relaxation maps, obtained from GRASE images, encompassing metastasis and normal liver to record T(2) relaxation time values. In 11 patients with 28 metastases, MRI was repeated using same protocol at 6 weeks following chemotherapy. The median pre-treatment T(2) values of metastases and normal liver were compared using the Mann-Whitney test. The pre- and post-treatment median T(2) values of metastases were compared using the Wilcoxon-Rank test for responding (n=16) and non-responding (n=12) lesions defined by RECIST criteria. The change in T(2) values (ΔT(2)) were compared and correlated with percentage change in lesion size. RESULTS: There was no difference in the pre-treatment median T(2) of metastases between responding (67.3±8.6) and non-responding metastases (71.4±16.5). At the end of chemotherapy, there was a decrease in the median T(2) of responding lesions (61.6±12.6) p=0.83, and increase in non-responding lesions (76.2±18.4) p=0.03, but these were not significantly different from the pre-treatment values. There was no significant difference in ΔT(2) of responding and non-responding lesions (p=0.18) and no correlation was seen between size change and ΔT(2) (coefficient=0.3). CONCLUSION: T(2) relaxation time does not appear to predict response of colorectal liver metastasis to chemotherapy.

Dynamic contrast-enhanced MRI of neuroendocrine hepatic metastases: A feasibility study using a dual-input two-compartment model.

Neuroendocrine hepatic metastases exhibit various contrast uptake enhancement patterns in dynamic contrast-enhanced MRI. Using a dual-input two-compartment distributed parameter model, we analyzed the dynamic contrast-enhanced MRI datasets of seven patient study cases with the aim to relate the tumor contrast uptake patterns to parameters of tumor microvasculature. Simulation studies were also performed to provide further insights into the effects of individual microcirculatory parameter on the tumor concentration-time curves. Although the tumor contrast uptake patterns can be influenced by many parameters, initial results indicate that hepatic blood flow and the ratio of fractional vascular volume to fractional interstitial volume may potentially distinguish between the patterns of neuroendocrine hepatic metastases.

Diffusion-weighted magnetic resonance imaging for tumour response assessment: why, when and how?

Diffusion-weighted magnetic resonance imaging (DWI) is increasingly being used to assess tumour response to a variety of anticancer treatments. The technique is quick to perform without the need for administration of exogenous contrast medium, and enables the apparent diffusion coefficient (ADC) of tissues to be quantified. Studies have shown that ADC increases in response to a variety of treatments including chemotherapy, radiotherapy, minimally invasive therapies and novel therapeutics. In this article, we review the rationale of applying DWI for tumour assessment, the evidence for ADC measurements in relation to specific treatments and some of the practical considerations for using ADC to evaluate treatment response.

Imaging in clinical trials.

Drug development continues to face challenges to successfully progress the most promising drug candidates through the stages of clinical trials. Given the increasing cost to develop a drug, methods are required to characterise early drug efficacy and safety. Imaging techniques are increasingly used in oncological clinical trials to provide evidence for decision making. With the application of conventional morphological imaging techniques and standardised response criteria based on tumour size measurements, imaging continues to be used to define key study end points. However, functional imaging techniques are likely to play an important role in the evaluation of novel therapeutics, although how these methods are to be optimally applied has yet to be clearly established. The specific challenges of standardising multi-centre imaging in the context of clinical trials are highlighted, including the processes for image acquisition, data analysis and radiological review.

Fusion of high b-value diffusion-weighted and T2-weighted MR images improves identification of lymph nodes in the pelvis.

Accurate identification of lymph nodes facilitates nodal assessment by size, morphological or MR lymphographic criteria. We compared the MR detection of lymph nodes in patients with pelvic cancers using T2-weighted imaging, and fusion of diffusion-weighted imaging (DWI) and T2-weighted imaging. Twenty patients with pelvic tumours underwent 5-mm axial T2-weighted and DWI (b-values 0-750 s/mm(2)) on a 1.5T system. Fusion images of b = 750 s/mm(2) diffusion-weighted MR and T2-weighted images were created. Two radiologists evaluated in consensus the T2-weighted images and fusion images independently. For each image set, the location and diameter of pelvic nodes were recorded, and nodal visibility was scored using a 4-point scale (0-3). Nodal visualisation was compared using Relative to an Identified Distribution (RIDIT) analysis. The mean RIDIT score describes the probability that a randomly selected node will be better visualised relative to the other image set. One hundred fourteen pelvic nodes (mean 5.9 mm; 2-10 mm) were identified on T2-weighted images and 161 nodes (mean 4.3 mm; 2-10 mm) on fusion images. Using fusion images, 47 additional nodes were detected compared with T2-weighted images alone (eight external iliac, 24 inguinal, 12 obturator, two peri-rectal, one presacral). Nodes detected only on fusion images were 2-9 mm (mean 3.7 mm). Nodal visualisation was better using fusion images compared with T2-weighted images (mean RIDIT score 0.689 vs 0.302). Fusion of diffusion-weighted MR with T2-weighted images improves identification of pelvic lymph nodes compared with T2-weighted images alone. The improved nodal identification may aid treatment planning and further nodal characterisation.