Martijn Smeenge

Novel contrast-enhanced ultrasound imaging in prostate cancer

PurposeThe purposes of this paper were to present the current status of contrast-enhanced transrectal ultrasound imaging and to discuss the latest achievements and techniques now under preclinical testing.ObjectiveAlthough grayscale transrectal ultrasound is the standard method for prostate imaging, it lacks accuracy in the detection and localization of prostate cancer. With the introduction of contrast-enhanced ultrasound (CEUS), perfusion imaging of the microvascularization became available. By this, cancer-induced neovascularisation can be visualized with the potential to improve ultrasound imaging for prostate cancer detection and localization significantly. For example, several studies have shown that CEUS-guided biopsies have the same or higher PCa detection rate compared with systematic biopsies with less biopsies needed.Materials and methodsThis paper describes the current status of CEUS and discusses novel quantification techniques that can improve the accuracy even further. Furthermore, quantification might decrease the user-dependency, opening the door to use in the routine clinical environment. A new generation of targeted microbubbles is now under pre-clinical testing and showed avidly binding to VEGFR-2, a receptor up-regulated in prostate cancer due to angiogenesis. The first publications regarding a targeted microbubble ready for human use will be discussed.ConclusionUltrasound-assisted drug delivery gives rise to a whole new set of therapeutic options, also for prostate cancer. A major breakthrough in the future can be expected from the clinical use of targeted microbubbles for drug delivery for prostate cancer diagnosis as well as treatment.

Role of transrectal ultrasonography (TRUS) in focal therapy of prostate cancer: Report from a Consensus Panel

Whats known on the subject? and What does the study add?

Current status of transrectal ultrasound techniques in prostate cancer.

Purpose of review Present the current status of transrectal ultrasound imaging in prostate cancer (PCa) and discuss the latest techniques now under preclinical evaluation. Recent findings Three-dimensional ultrasound and quantification techniques are superior to two-dimensional ultrasound in visualizing PCa and can be beneficial in staging prior to operation. Doppler-guided biopsies are more likely to yield positive results, especially when high Gleason scores are present. Furthermore, Vardenafil usage strengthens Doppler enhancement and can help in increasing the diagnostic accuracy of Doppler. Multiple studies show elastography to be a promising new addition to the ultrasound investigations for detection of PCa. Especially the recently introduced Shear Wave Elastography shows decreased user dependency and increased PCa detection rates. MRI can also aid in the diagnostics of PCa. However, MRI-guided biopsies are more complicated compared to ultrasound guidance. MRI/ultrasound fusion combines best of both techniques and, although just recently emerged, the studies available show promising PCa detection rates. Summary Technical improvements in classical ultrasound modalities (2D/3D-greyscale, Doppler) and new modalities (elastography/MRI/ultrasound fusion) raised the accuracy of PCa detection. Especially latest elastography and MRI/ultrasound fusion are showing promising results in PCa visualization.

Effects of insulin on ketogenesis following fasting in lean and obese men.

The ketone bodies (KBs) D‐3‐hydroxybutyrate (D‐3HB) and acetoacetate (AcAc) play a role in starvation and have been associated with insulin resistance. The dose–response relationship between insulin and KBs was demonstrated to be shifted to the right in type 2 diabetes patients. However, KB levels have also been reported to be decreased in obesity. We investigated the metabolic adaptation to fasting with respect to glucose and KB metabolism in lean and obese men without type 2 diabetes using stable glucose and D‐3HB isotopes in a two‐step pancreatic clamp after 38 h of fasting. We found that D‐3HB fluxes in the basal state were higher in lean compared to obese men: 15.2 (10.7–27.1) vs. 7.0 (3.5–15.1) µmol/kg lean body mass (LBM)·min, respectively, P < 0.01. No differences were found in KB fluxes between lean and obese volunteers during the pancreatic clamp (step 1: 6.9 (1.8–12.0) vs. 7.4 (4.2–17.8) µmol/kg LBM·min, respectively; and step 2: 2.9 (0–7.2) vs. 3.4 (0.85–18.7) µmol/kg LBM·min, respectively), despite similar plasma insulin levels. Meanwhile, peripheral glucose uptake was higher in lean compared to obese men (step 1: 15.2 (12.3–25.6) vs. 14.7 (11.9–22.7) µmol/kg LBM·min, respectively, P ≤ 0.05; and step 2: 12.5 (7.0–17.3) vs. 10.8 (5.2–15.0) µmol/kg LBM·min, respectively, P ≤ 0.01). These data show that obese subjects who display insulin resistance on insulin‐mediated peripheral glucose uptake have the same sensitivity for the insulin‐mediated suppression of ketogenesis. This implies differential insulin sensitivity of intermediary metabolism in obesity.

4-D spatiotemporal analysis of ultrasound contrast agent dispersion for prostate cancer localization: a feasibility study

Currently, nonradical treatment for prostate cancer is hampered by the lack of reliable diagnostics. Contrastultrasound dispersion imaging (CUDI) has recently shown great potential as a prostate cancer imaging technique. CUDI estimates the local dispersion of intravenously injected contrast agents, imaged by transrectal dynamic contrast-enhanced ultrasound (DCE-US), to detect angiogenic processes related to tumor growth. The best CUDI results have so far been obtained by similarity analysis of the contrast kinetics in neighboring pixels. To date, CUDI has been investigated in 2-D only. In this paper, an implementation of 3-D CUDI based on spatiotemporal similarity analysis of 4-D DCE-US is described. Different from 2-D methods, 3-D CUDI permits analysis of the entire prostate using a single injection of contrast agent. To perform 3-D CUDI, a new strategy was designed to estimate the similarity in the contrast kinetics at each voxel, and data processing steps were adjusted to the characteristics of 4-D DCE-US images. The technical feasibility of 4-D DCE-US in 3-D CUDI was assessed and confirmed. Additionally, in a preliminary validation in two patients, dispersion maps by 3-D CUDI were quantitatively compared with those by 2-D CUDI and with 12-core systematic biopsies with promising results.

Dynamic contrast-enhanced ultrasound parametric imaging for the detection of prostate cancer

To investigate the value of dynamic contrast‐enhanced (DCE)‐ultrasonography (US) and software‐generated parametric maps in predicting biopsy outcome and their potential to reduce the amount of negative biopsy cores.

3D surface-based registration of ultrasound and histology in prostate cancer imaging

Several transrectal ultrasound (TRUS)-based techniques aiming at accurate localization of prostate cancer are emerging to improve diagnostics or to assist with focal therapy. However, precise validation prior to introduction into clinical practice is required. Histopathology after radical prostatectomy provides an excellent ground truth, but needs accurate registration with imaging. In this work, a 3D, surface-based, elastic registration method was developed to fuse TRUS images with histopathologic results. To maximize the applicability in clinical practice, no auxiliary sensors or dedicated hardware were used for the registration. The mean registration errors, measured in vitro and in vivo, were 1.5±0.2 and 2.1±0.5mm, respectively.

3D contrast ultrasound dispersion imaging by mutual information for prostate cancer localization

Prostate cancer (PCa) is the most occurring type of cancer in the Western World. Yet, the most common diagnostic tool, systematic biopsy, is invasive and has low sensitivity. Recently, contrast-ultrasound dispersion imaging (CUDI) by spatiotemporal similarity analysis on contrast-enhanced ultrasound (CEUS) has been proposed as a promising, non-invasive alternative for PCa localization. It was shown that increased mutual information (MutI) between the indicator dilution curves in a block kernel and its central pixel relates to the presence of PCa. However, until now CUDI by MutI has been investigated in 2-D only, requiring a separate contrast injection for each imaging plane. Moreover, out-of-plane contrast flow could not be taken into account. In this work, we implemented CUDI by MutI using 4-D CEUS to overcome the aforementioned issues. We tested its feasibility to perform 3-D CUDI by comparison with 12-core systematic biopsies in 3 patients. The mean MutI for the patient with only one positive biopsy sample was significantly lower than that for the other two patients with more than 6 positive samples. This result encourages refinement and validation of the presented method in a larger patient group.

Transabdominal Contrast-Enhanced Ultrasound Imaging of the Prostate

Numerous age-related pathologies affect the prostate gland, the most menacing of which is prostate cancer (PCa). The diagnostic tools for prostate investigation are invasive, requiring biopsies when PCa is suspected. Novel dynamic contrast-enhanced ultrasound (DCE-US) imaging approaches have been proposed recently and appear promising for minimally invasive localization of PCa. Ultrasound imaging of the prostate is traditionally performed with a transrectal probe because the location of the prostate allows for high-resolution images using high-frequency transducers. However, DCE-US imaging requires lower frequencies to induce bubble resonance and, thus, improve contrast-to-tissue ratio. For this reason, in this study we investigate the feasibility of quantitative DCE-US imaging of the prostate via the abdomen. The study included 10 patients (age = 60.7 ± 5.7 y) referred for a needle biopsy study. After having given informed consent, patients underwent DCE-US with both transabdominal and transrectal probes. Time-intensity contrast curves were derived using both approaches and their model-fit quality was compared. Although further improvements are expected by optimization of the transabdominal settings, the results of transabdominal and transrectal DCE-US are closely comparable, confirming the feasibility of transabdominal DCE-US; transabdominal curve fitting revealed an average determination coefficient r(2) = 0.91 (r(2) > 0.75 for 78.6% of all prostate pixels) compared with r(2) = 0.91 (r(2) > 0.75 for 81.6% of all prostate pixels) by the transrectal approach. Replacing the transrectal approach with more acceptable transabdominal scanning for prostate investigation is feasible. This approach would improve patient comfort and represent a useful option for PCa localization and monitoring.

Three-dimensional contrast-ultrasound dispersion imaging for prostate cancer localization, a feasibility study

Prostate cancer (PCa) is the type of cancer with the highest incidence in men in Western countries. To date, reliable tools for PCa localization are lacking. Recently, contrast-ultrasound dispersion imaging (CUDI) by spatiotemporal analysis performed on transrectal dynamic contrast-enhanced ultrasound (DCE-US) has been proposed as a promising option for PCa localization. This technique evaluates the spatial similarity between indicator dilution curves in a ring-shaped kernel and its center pixel. Until now, CUDI has been performed in 2D only. Hence, each imaged plane requires a separate bolus injection of contrast agent, motion compensation is limited, and out-of-plane contrast flow cannot be observed. 3D DCE-US can potentially solve the aforementioned issues, permitting the analysis of the entire prostate with a single bolus injection. In this work, we implemented a full 4D spatiotemporal similarity analysis. Its feasibility to localize PCa was evaluated in 2 patients by qualitatively comparing similarity maps obtained by 3D CUDI with those obtained by 2D CUDI in the corresponding planes and with histopathologic results from 12-core systematic biopsies. All results showed good agreement, confirming the feasibility of 3D CUDI for PCa localization and encouraging extension of the study to a larger dataset. Additionally, the characteristics - and in particular the spatial and temporal resolution - of 3D DCE-US were analyzed with respect to the requirements for CUDI. Both the spatial and temporal resolution were considered to be sufficient for CUDI.