Optimizing carboplatin dosing by an improved prediction of carboplatin clearance using a CT-enhanced estimate of renal function.

AIMS: Carboplatin is generally dosed based on a modified Calvert formula, in which the Cockcroft-Gault-based creatinine clearance (CRCL) is used as proxy for the glomerular filtration rate (GFR). The Cockcroft-Gault formula (CG) overpredicts CRCL in patients with an aberrant body composition. The CT-enhanced estimate of RenAl FuncTion (CRAFT) was developed to compensate for this overprediction. We aimed to evaluate whether carboplatin clearance is better predicted by CRCL based on the CRAFT compared to the CG. METHODS: Data of four previously conducted trials was used. The CRAFT was divided by serum creatinine to derive CRCL. The difference between CRAFT- and CG-based CRCL was assessed by population pharmacokinetic modelling. Furthermore, the difference in calculated carboplatin dose was assessed in a heterogeneous dataset. RESULTS: In total, 108 patients were included in the analysis. Addition of the CRAFT- and CG-based CRCL as covariate on carboplatin clearance led, respectively, to an improved model fit with a 26-point drop in objective function value and a worsened model fit with an increase of 8 points. In 19 subjects with serum creatinine <50 µmol/L, the calculated carboplatin dose was 233 mg higher using the CG. CONCLUSIONS: Carboplatin clearance is better predicted by CRAFT vs. CG-based CRCL. In subjects with low serum creatinine, the calculated carboplatin dose using CG exceeds the dose using CRAFT, which might explain the need for dose capping when using the CG. Therefore, the CRAFT might be an alternative for dose capping while still dosing accurately.

3D-Reconstructed Contact Surface Area and Tumour Volume on Magnetic Resonance Imaging Improve the Prediction of Extraprostatic Extension of Prostate Cancer.

This study is to determine whether the volume and contact surface area (CSA) of a tumour with an adjacent prostate capsule on MRI in a three-dimensional (3D) model that can predict side-specific extraprostatic extension (EPE) at radical prostatectomy (RP). Patients with localised prostate cancer (PCa) who underwent robot-assisted RP between July 2015 and March 2021 were included in this retrospective study. MRI-based 3D prostate models incorporating the PCa volume and location were reconstructed. The tumour volume and surface variables were extracted. For the prostate-to-tumour and tumour-to-prostate CSAs, the areas in which the distances were ≤ 1, ≤ 2, ≤ 3, ≤ 4, and ≤ 5 mm were defined, and their surface (cm2) were determined. Differences in prostate sides with and without pathological EPE were analysed. Multivariable logistic regression analysis to find independent predictors of EPE. Overall, 75/302 (25%) prostate sides showed pathological EPE. Prostate sides with EPE had higher cT-stage, higher PSA density, higher percentage of positive biopsy cores, higher biopsy Gleason scores, higher radiological tumour stage, larger tumour volumes, larger prostate CSA, and larger tumour CSA (all p < 0.001). Multivariable logistic regression analysis showed that the radiological tumour stage (p = 0.001), tumour volume (p < 0.001), prostate CSA (p < 0.001), and tumour CSA (p ≤ 0.001) were independent predictors of pathological EPE. A 3D reconstruction of tumour locations in the prostate improves prediction of extraprostatic extension. Tumours with a higher 3D-reconstructed volume, a higher surface area of tumour in contact with the prostate capsule, and higher surface area of prostate capsule in contact with the tumour are at increased risk of side-specific extraprostatic extension.

The Impact of Peptide Amount on Tumor Uptake to Assess PSMA Receptor Saturation on 68Ga-PSMA-11 PET/CT in Patients with Primary Prostate Cancer.

68Ga-labeled prostate-specific membrane antigen (PSMA) is often produced on-site, where usually a fixed amount of peptide is conjugated to the generator eluate. However, fluctuations in specific activity might influence tracer distribution and tumor accumulation. Therefore, our aim was to investigate the potential effect of varying the administered peptide amount on 68Ga-PSMA-11 uptake in tumors using PET/CT in patients with primary prostate cancer (PCa). Additionally, the impact of tumor volume on this potential effect and on accumulation in reference organs was assessed. Methods: The imaging data of 362 men with primary PCa who underwent 68Ga-PSMA-11 PET/CT were retrospectively included. Scans were quantified for normal tissue and primary tumors. Patients were divided into 3 groups based on their tumor volume. Correlation and multivariable linear regression analyses were performed. Results: The median index lesion volume was 9.50 cm3 (range, 0.064-174 cm3). Groups were based on quartiles of prostatic lesion volume: ≤4.11 cm3 (group 1), 4.11-20.6 cm3 (group 2), and ≥20.6 cm3 (group 3). No correlation was found between administered peptide amount and tumor uptake (SUVmean or SUVpeak) for any group, except for a significant correlation for SUVmean in the first group (P = 0.008). Linear regression analysis supported these findings. Conclusion: The amount of administered peptide had no evident effect on 68Ga-PSMA-11 uptake in tumors, except for a significant positive correlation between administered peptide amount and tumor SUVmean for group 1. The findings imply that no receptor saturation occurs in men with primary PCa at peptide levels of about 2.5 µg.

A workflow for automated segmentation of the liver surface, hepatic vasculature and biliary tree anatomy from multiphase MR images.

Accurate assessment of 3D models of patient-specific anatomy of the liver, including underlying hepatic and biliary tree, is critical for preparation and safe execution of complex liver resections, especially due to high variability of biliary and hepatic artery anatomies. Dynamic MRI with hepatospecific contrast agents is currently the only type of diagnostic imaging that provides all anatomical information required for generation of such a model, yet there is no information in the literature on how the complete 3D model can be generated automatically. In this work, a new automated segmentation workflow for extraction of patient-specific 3D model of the liver, hepatovascular and biliary anatomy from a single multiphase MRI acquisition is developed and quantitatively evaluated. The workflow incorporates course 4D k-means clustering estimation and geodesic active contour refinement of the liver boundary, based on organ's characteristic uptake of gadolinium contrast agents overtime. Subsequently, hepatic vasculature and biliary ducts segmentations are performed using multiscale vesselness filters. The algorithm was evaluated using 15 test datasets of patients with liver malignancies of various histopathological types. It showed good correlation with expert manual segmentation, resulting in an average of 1.76 ± 2.44 mm Hausdorff distance for the liver boundary, and 0.58 ± 0.72 and 1.16 ± 1.98 mm between centrelines of biliary ducts and liver veins, respectively. A workflow for automatic segmentation of the liver, hepatic vasculature and biliary anatomy from a single diagnostic MRI acquisition was developed. This enables automated extraction of 3D models of patient-specific liver anatomy, and may facilitating better perception of organ's anatomy during preparation and execution of liver surgeries. Additionally, it may help to reduce the incidence of intraoperative biliary duct damage due to an unanticipated variation in the anatomy.

Clinical Implementation of In-House Developed MR-Based Patient-Specific 3D Models of Liver Anatomy.

Knowledge of patient-specific liver anatomy is key to patient safety during major hepatobiliary surgery. Three-dimensional (3D) models of patient-specific liver anatomy based on diagnostic MRI images can provide essential vascular and biliary anatomical insight during surgery. However, a method for generating these is not yet publicly available. This paper describes how these 3D models of the liver can be generated using open source software, and then subsequently integrated into a sterile surgical environment. The most common image quality aspects that degrade the quality of the 3D models as well possible ways of eliminating these are also discussed. Per patient, a single diagnostic multiphase MRI scan with hepatospecific contrast agent was used for automated segmentation of liver contour, arterial, portal, and venous anatomy, and the biliary tree. Subsequently, lesions were delineated manually. The resulting interactive 3D model could be accessed during surgery on a sterile covered tablet. Up to now, such models have been used in 335 surgical procedures. Their use simplified the surgical treatment of patients with a high number of liver metastases and contributed to the localization of vanished lesions in cases of a radiological complete response to neoadjuvant treatment. They facilitated perioperative verification of the relationship of tumors and the surrounding vascular and biliary anatomy, and eased decision-making before and during surgery.

The accuracy of ultrashort echo time MRI sequences for medical additive manufacturing.

OBJECTIVES: Additively manufactured bone models, implants and drill guides are becoming increasingly popular amongst maxillofacial surgeons and dentists. To date, such constructs are commonly manufactured using CT technology that induces ionizing radiation. Recently, ultrashort echo time (UTE) MRI sequences have been developed that allow radiation-free imaging of facial bones. The aim of the present study was to assess the feasibility of UTE MRI sequences for medical additive manufacturing (AM). METHODS: Three morphologically different dry human mandibles were scanned using a CT and MRI scanner. Additionally, optical scans of all three mandibles were made to acquire a "gold standard". All CT and MRI scans were converted into Standard Tessellation Language (STL) models and geometrically compared with the gold standard. To quantify the accuracy of the AM process, the CT, MRI and gold-standard STL models of one of the mandibles were additively manufactured, optically scanned and compared with the original gold-standard STL model. RESULTS: Geometric differences between all three CT-derived STL models and the gold standard were <1.0 mm. All three MRI-derived STL models generally presented deviations <1.5 mm in the symphyseal and mandibular area. The AM process introduced minor deviations of <0.5 mm. CONCLUSIONS: This study demonstrates that MRI using UTE sequences is a feasible alternative to CT in generating STL models of the mandible and would therefore be suitable for surgical planning and AM. Further in vivo studies are necessary to assess the usability of UTE MRI sequences in clinical settings.

A novel Bayesian respiratory motion model to estimate and resolve uncertainty in image-guided cardiac interventions.

In image-guided cardiac interventions, respiratory motion causes misalignments between the pre-procedure roadmap of the heart used for guidance and the intra-procedure position of the heart, reducing the accuracy of the guidance information and leading to potentially dangerous consequences. We propose a novel technique for motion-correcting the pre-procedural information that combines a probabilistic MRI-derived affine motion model with intra-procedure real-time 3D echocardiography (echo) images in a Bayesian framework. The probabilistic model incorporates a measure of confidence in its motion estimates which enables resolution of the potentially conflicting information supplied by the model and the echo data. Unlike models proposed so far, our method allows the final motion estimate to deviate from the model-produced estimate according to the information provided by the echo images, so adapting to the complex variability of respiratory motion. The proposed method is evaluated using gold-standard MRI-derived motion fields and simulated 3D echo data for nine volunteers and real 3D live echo images for four volunteers. The Bayesian method is compared to 5 other motion estimation techniques and results show mean/max improvements in estimation accuracy of 10.6%/18.9% for simulated echo images and 20.8%/41.5% for real 3D live echo data, over the best comparative estimation method.

Manifold learning for image-based breathing gating in ultrasound and MRI.

Respiratory motion is a challenging factor for image acquisition and image-guided procedures in the abdominal and thoracic region. In order to address the issues arising from respiratory motion, it is often necessary to detect the respiratory signal. In this article, we propose a novel, purely image-based retrospective respiratory gating method for ultrasound and MRI. Further, we apply this technique to acquire breathing-affected 4D ultrasound with a wobbler probe and, similarly, to create 4D MR with a slice stacking approach. We achieve the gating with Laplacian eigenmaps, a manifold learning technique, to determine the low-dimensional manifold embedded in the high-dimensional image space. Since Laplacian eigenmaps assign to each image frame a coordinate in low-dimensional space by respecting the neighborhood relationship, they are well suited for analyzing the breathing cycle. We perform the image-based gating on several 2D and 3D ultrasound datasets over time, and quantify its very good performance by comparing it to measurements from an external gating system. For MRI, we perform the manifold learning on several datasets for various orientations and positions. We achieve very high correlations by a comparison to an alternative gating with diaphragm tracking.

Effects of respiratory liver motion on heating for gated and model-based motion-compensated high-intensity focused ultrasound ablation.

PURPOSE: To quantify the effects of respiratory motion on high-intensity focused ultrasound heating of liver tissue by comparing the simulated ablation using a conventional respiratory gating versus a MR-model-based motion compensation approach. METHODS: To measure liver motion, dynamic free-breathing abdominal MR scans were acquired for five volunteers. Deformable registration was used to calculate continuous motion models, and tissue heating at a moving single focus was computed in 3-D by solving the bioheat equation. Ablated volume ratios with respect to the static case, V(ab), were determined for a range of exposure times t(exp) and heating rates r. RESULTS: To achieve V(ab) > 90% required t(exp) < 0.5s and r > 120 degrees C/s when gating, whereas t(exp) < 1s and r > 60 degrees C/s for motion-compensation. CONCLUSIONS: Accurate compensation for respiratory motion is important for efficient tissue ablation. Model-based motion compensation allows substantially lower heating rates than gating, reducing the risk of skin burns and focal boiling.

Strategies for online organ motion correction for intensity-modulated radiotherapy of prostate cancer: prostate, rectum, and bladder dose effects.

PURPOSE: To quantify and evaluate the accumulated prostate, rectum, and bladder dose for several strategies including rotational organ motion correction for intensity-modulated radiotherapy (IMRT) of prostate cancer using realistic organ motion data. METHODS AND MATERIALS: Repeat computed tomography (CT) scans of 19 prostate patients were used. Per patient, two IMRT plans with different uniform margins were created. To quantify prostate and seminal vesicle motion, repeat CT clinical target volumes (CTVs) were matched onto the planning CTV using deformable registration. Four different strategies, from online setup to full motion correction, were simulated. Rotations were corrected for using gantry and collimator angle adjustments. Prostate, rectum, and bladder doses were accumulated for each patient, plan, and strategy. Minimum CTV dose (D(min)), rectum equivalent uniform dose (EUD, n = 0.13), and bladder surface receiving >or=78 Gy (S78), were calculated. RESULTS: With online CTV translation correction, a 7-mm margin was sufficient (i.e., D(min) >or= 95% of the prescribed dose for all patients). A 4-mm margin required additional rotational correction. Margin reduction lowered the rectum EUD(n = 0.13) by approximately 2.6 Gy, and the bladder S78 by approximately 1.9%. CONCLUSIONS: With online correction of both translations and rotations, a 4-mm margin was sufficient for 15 of 19 patients, whereas the remaining four patients had an underdosed CTV volume <1%. Margin reduction combined with online corrections resulted in a similar or lower dose to the rectum and bladder. The more advanced the correction strategy, the better the planned and accumulated dose agreed.

Strategy for online correction of rotational organ motion for intensity-modulated radiotherapy of prostate cancer.

PURPOSE: To develop and evaluate a correction strategy for prostate rotation using gantry and collimator angle adjustments. METHODS AND MATERIALS: Gantry and collimator angle adjustments were used to correct for prostate rotation without rotating the table. A formula to partially correct for left-right (LR) rotations was derived through geometric analysis of rotation-induced clinical target volume (CTV) beam's-eye-view shape changes. For 10 prostate patients, intensity-modulated radiotherapy (IMRT) plans with different margins were created. Simulating CTV LR rotation and correcting each beam by a collimator rotation, the corrected CTV dose was compared with the original and uncorrected dose. Effects of residual geometric uncertainties were assessed using a Monte Carlo technique. A large number of treatments representative for prostate patients were simulated. Dose probability histograms of the minimum CTV dose (D min) were derived, with and without online correction, resulting in a more realistic margin estimate. RESULTS: Dosimetric analysis of all IMRT plans showed that, with rotational correction and a 2-mm margin, D min was constant to within 3% for LR rotations up to +/-15 degrees . The Monte Carlo dose probability histograms showed that, with correction, a margin of 4 mm ensured that 90% of patients received a D min >or=95% of the prescribed dose. Without correction a margin of 6 mm was required. CONCLUSIONS: We developed and tested a practical method for (online) correction of prostate rotation, allowing safe and straightforward implementation of margin reduction and dose escalation.