Ferumoxtran-10-enhanced MRI for pre-operative metastatic lymph node detection in pancreatic, duodenal, or periampullary adenocarcinoma.

OBJECTIVES: To assess 3-Tesla (3-T) ultra-small superparamagnetic iron oxide (USPIO)-enhanced MRI in detecting lymph node (LN) metastases for resectable adenocarcinomas of the pancreas, duodenum, or periampullary region in a node-to-node validation against histopathology. METHODS: Twenty-seven consecutive patients with a resectable pancreatic, duodenal, or periampullary adenocarcinoma were enrolled in this prospective single expert centre study. Ferumoxtran-10-enhanced 3-T MRI was performed pre-surgery. LNs found on MRI were scored for suspicion of metastasis by two expert radiologists using a dedicated scoring system. Node-to-node matching from in vivo MRI to histopathology was performed using a post-operative ex vivo 7-T MRI of the resection specimen. Sensitivity and specificity were calculated using crosstabs. RESULTS: Eighteen out of 27 patients (median age 65 years, 11 men) were included in the final analysis (pre-surgery withdrawal n = 4, not resected because of unexpected metastases peroperatively n = 2, and excluded because of inadequate contrast-agent uptake n = 3). On MRI 453 LNs with a median size of 4.0 mm were detected, of which 58 (13%) were classified as suspicious. At histopathology 385 LNs with a median size of 5.0 mm were found, of which 45 (12%) were metastatic. For 55 LNs node-to-node matching was possible. Analysis of these 55 matched LNs, resulted in a sensitivity and specificity of 83% (95% CI: 36-100%) and 92% (95% CI: 80-98%), respectively. CONCLUSION: USPIO-enhanced MRI is a promising technique to preoperatively detect and localise LN metastases in patients with pancreatic, duodenal, or periampullary adenocarcinoma. CLINICAL RELEVANCE STATEMENT: Detection of (distant) LN metastases with USPIO-enhanced MRI could be used to determine a personalised treatment strategy that could involve neoadjuvant or palliative chemotherapy, guided resection of distant LNs, or targeted radiotherapy. REGISTRATION: The study was registered on clinicaltrials.gov NCT04311047. https://clinicaltrials.gov/ct2/show/NCT04311047?term=lymph+node&cond=Pancreatic+Cancer&cntry=NL&draw=2&rank=1 . KEY POINTS: LN metastases of pancreatic, duodenal, or periampullary adenocarcinoma cannot be reliably detected with current imaging. This technique detected LN metastases with a sensitivity and specificity of 83% and 92%, respectively. MRI with ferumoxtran-10 is a promising technique to improve preoperative staging in these cancers.

How to evaluate perfusion imaging in post-treatment glioma: a comparison of three different analysis methods.

INTRODUCTION: Dynamic susceptibility contrast (DSC) perfusion weighted (PW)-MRI can aid in differentiating treatment related abnormalities (TRA) from tumor progression (TP) in post-treatment glioma patients. Common methods, like the 'hot spot', or visual approach suffer from oversimplification and subjectivity. Using perfusion of the complete lesion potentially offers an objective and accurate alternative. This study aims to compare the diagnostic value and assess the subjectivity of these techniques. METHODS: 50 Glioma patients with enhancing lesions post-surgery and chemo-radiotherapy were retrospectively included. Outcome was determined by clinical/radiological follow-up or biopsy. Imaging analysis used the 'hot spot', volume of interest (VOI) and visual approach. Diagnostic accuracy was compared using receiving operator characteristics (ROC) curves for the VOI and 'hot spot' approach, visual assessment was analysed with contingency tables. Inter-operator agreement was determined with Cohens kappa and intra-class coefficient (ICC). RESULTS: 29 Patients suffered from TP, 21 had TRA. The visual assessment showed poor to substantial inter-operator agreement (κ = -0.72 - 0.68). Reliability of the 'hot spot' placement was excellent (ICC = 0.89), while reference placement was variable (ICC = 0.54). The area under the ROC (AUROC) of the mean- and maximum relative cerebral blood volume (rCBV) (VOI-analysis) were 0.82 and 0.72, while the rCBV-ratio ('hot spot' analysis) was 0.69. The VOI-analysis had a more balanced sensitivity and specificity compared to visual assessment. CONCLUSIONS: VOI analysis of DSC PW-MRI data holds greater diagnostic accuracy in single-moment differentiation of TP and TRA than 'hot spot' or visual analysis. This study underlines the subjectivity of visual placement and assessment.

Quantification of perineural satellitosis in pretreatment glioblastoma with structural MRI and a diffusion tensor imaging template.

Background: Survival outcomes for glioblastoma (GBM) patients remain unfavorable, and tumor recurrence is often observed. Understanding the radiological growth patterns of GBM could aid in improving outcomes. This study aimed to examine the relationship between contrast-enhancing tumor growth direction and white matter, using an image registration and deformation strategy. Methods: In GBM patients 2 pretreatment scans (diagnostic and neuronavigation) were gathered retrospectively, and coregistered to a template and diffusion tensor imaging (DTI) atlas. The GBM lesions were segmented and coregistered to the same space. Growth vectors were derived and divided into vector populations parallel (Φ = 0-20°) and perpendicular (Φ = 70-90°) to white matter. To test for statistical significance between parallel and perpendicular groups, a paired samples Student's t-test was performed. O6-methylguanine-DNA methyltransferase (MGMT) methylation status and its correlation to growth rate were also tested using a one-way ANOVA test. Results: For 78 GBM patients (mean age 61 years ±â€…13 SD, 32 men), the included GBM lesions showed a predominant preference for perineural satellitosis (P < .001), with a mean percentile growth of 30.8% (95% CI: 29.6-32.0%) parallel (0°â€…< |Φ| < 20°) to white matter. Perpendicular tumor growth with respect to white matter microstructure (70°â€…< |Φ| < 90°) showed to be 22.7% (95% CI: 21.3-24.1%) of total tumor growth direction. Conclusions: The presented strategy showed that tumor growth direction in pretreatment GBM patients correlated with white matter architecture. Future studies with patient-specific DTI data are required to verify the accuracy of this method prospectively to identify its usefulness as a clinical metric in pre and posttreatment settings.

Prostate-Specific Membrane Antigen-Targeted Radioguided Pelvic Lymph Node Dissection in Newly Diagnosed Prostate Cancer Patients with a Suspicion of Locoregional Lymph Node Metastases: The DETECT Trial.

Prostate-specific membrane antigen (PSMA)-targeted radioguided surgery (RGS) aims to optimize the peroperative detection and removal of PSMA-avid lymph node (LN) metastases (LNMs) and has been described in patients with recurrent prostate cancer (PCa). In newly diagnosed PCa patients undergoing pelvic LN dissections, PSMA RGS could guide the urologist toward PSMA-expressing LNMs as identified on preoperative 18F-PSMA PET/CT imaging. The objective was to evaluate the safety and feasibility of 111In-PSMA RGS in primary PCa patients with one or more suggestive LNs on preoperative 18F-PSMA PET/CT. Methods: This prospective, phase I/II study included 20 newly diagnosed PCa patients with at least 1 suggestive LN on preoperative 18F-PSMA PET/CT. PSMA RGS was performed 24 h after 111In-PSMA-I&T administration, and postoperative 18F-PSMA PET/CT was performed to verify successful removal of the suggestive lesions. The primary endpoint was determination of the safety and feasibility of 111In-PSMA RGS. Safety was assessed by monitoring adverse events. Feasibility was described as the possibility to peroperatively detect suggestive LNs as identified on preoperative imaging. Secondary outcomes included the accuracy of 111In-PSMA RGS compared with histopathology, tumor- and lesion-to-background ratios, and biochemical recurrence. Results: No tracer-related adverse events were reported. In 20 patients, 43 of 49 (88%) 18F-PSMA PET-suggestive lesions were successfully removed. 111In-PSMA RGS facilitated peroperative identification and resection of 29 of 49 (59%) RGS-target lesions, of which 28 (97%) contained LNMs. Another 14 of 49 (29%) resected LNs were not detected with 111In-PSMA RGS, of which 2 contained metastases. Conclusion: 111In-PSMA RGS is a safe and feasible procedure that allows peroperative detection of 18F-PSMA PET/CT-suggestive lesions in newly diagnosed PCa patients. The use of a radioactive PSMA tracer and a detection device (γ-probe) during surgery helps in identifying LNs that were suggestive of PCa metastases on the 18F-PSMA PET/CT before surgery and thus may improve the peroperative identification and removal of these LNs.

A multivariate curve resolution analysis of multicenter proton spectroscopic imaging of the prostate for cancer localization and assessment of aggressiveness.

In this study, we investigated the potential of the multivariate curve resolution alternating least squares (MCR-ALS) algorithm for analyzing three-dimensional (3D) 1 H-MRSI data of the prostate in prostate cancer (PCa) patients. MCR-ALS generates relative intensities of components representing spectral profiles derived from a large training set of patients, providing an interpretable model. Our objectives were to classify magnetic resonance (MR) spectra, differentiating tumor lesions from benign tissue, and to assess PCa aggressiveness. We included multicenter 3D 1 H-MRSI data from 106 PCa patients across eight centers. The patient cohort was divided into a training set (N = 63) and an independent test set (N = 43). Singular value decomposition determined that MR spectra were optimally represented by five components. The profiles of these components were extracted from the training set by MCR-ALS and assigned to specific tissue types. Using these components, MCR-ALS was applied to the test set for a quantitative analysis to discriminate tumor lesions from benign tissue and to assess tumor aggressiveness. Relative intensity maps of the components were reconstructed and compared with histopathology reports. The quantitative analysis demonstrated a significant separation between tumor and benign voxels (t-test, p < 0.001). This result was achieved including voxels with low-quality MR spectra. A receiver operating characteristic analysis of the relative intensity of the tumor component revealed that low- and high-risk tumor lesions could be distinguished with an area under the curve of 0.88. Maps of this component properly identified the extent of tumor lesions. Our study demonstrated that MCR-ALS analysis of 1 H-MRSI of the prostate can reliably identify tumor lesions and assess their aggressiveness. It handled multicenter data with minimal preprocessing and without using prior knowledge or quality control. These findings indicate that MCR-ALS can serve as an automated tool to assess the presence, extent, and aggressiveness of tumor lesions in the prostate, enhancing diagnostic capabilities and treatment planning of PCa patients.

The Potential of Iron Oxide Nanoparticle-Enhanced MRI at 7 T Compared With 3 T for Detecting Small Suspicious Lymph Nodes in Patients With Prostate Cancer.

BACKGROUND: Accurate detection of lymph node (LN) metastases in prostate cancer (PCa) is a challenging but crucial step for disease staging. Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) enables distinction between healthy LNs and nodes suspicious for harboring metastases. When combined with MRI at an ultra-high magnetic field, an unprecedented spatial resolution can be exploited to visualize these LNs. PURPOSE: The aim of this study was to explore USPIO-enhanced MRI at 7 T in comparison to 3 T for the detection of small suspicious LNs in the same cohort of patients with PCa. MATERIALS AND METHODS: Twenty PCa patients with high-risk primary or recurrent disease were referred to our hospital for an investigational USPIO-enhanced 3 T MRI examination with ferumoxtran-10. With consent, they underwent a 7 T MRI on the same day. Three-dimensional anatomical and T2*-weighted images of both examinations were evaluated blinded, with an interval, by 2 readers who annotated LNs suspicious for metastases. Number, size, and level of suspicion (LoS) of LNs were paired within patients and compared between field strengths. RESULTS: At 7 T, both readers annotated significantly more LNs compared with 3 T (474 and 284 vs 344 and 162), with 116 suspicious LNs on 7 T (range, 1-34 per patient) and 79 suspicious LNs on 3 T (range, 1-14 per patient) in 17 patients. For suspicious LNs, the median short axis diameter was 2.6 mm on 7 T (1.3-9.5 mm) and 2.8 mm for 3 T (1.7-10.4 mm, P = 0.05), with large overlap in short axis of annotated LNs between LoS groups. At 7 T, significantly more suspicious LNs had a short axis <2.5 mm compared with 3 T (44% vs 27%). Magnetic resonance imaging at 7 T provided better image quality and structure delineation and a higher LoS score for suspicious nodes. CONCLUSIONS: In the same cohort of patients with PCa, more and more small LNs were detected on 7 T USPIO-enhanced MRI compared with 3 T MRI. Suspicious LNs are generally very small, and increased nodal size was not a good indication of suspicion for the presence of metastases. The high spatial resolution of USPIO-enhanced MRI at 7 T improves structure delineation and the visibility of very small suspicious LNs, potentially expanding the in vivo detection limits of pelvic LN metastases in PCa patients.

Subnodal Correspondence of PSMA Expression and USPIO-MRI in Metastatic Pelvic Lymph Nodes in Prostate Cancer.

OBJECTIVES: Two advanced imaging modalities used to detect lymph node (LN) metastases in prostate cancer patients are prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography and ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI). As these modalities use different targets, a subnodal comparison is needed to interpret both their correspondence and their differences. The aim of this explorative study was to compare ex vivo 111In-PSMA µSPECT images with high-resolution 7 T USPIO µMR images and histopathology of resected LN specimens from prostate cancer patients to assess the degree of correspondence at subnodal level. MATERIALS AND METHODS: Twenty primary prostate cancer patients who underwent pelvic LN dissection were included and received USPIO contrast and 111In-PSMA. A total of 41 LNs of interest (LNOIs) were selected for ex vivo imaging based on γ-probe detection or palpation. µSPECT and µMRI acquisition were performed immediately after resection. Overlay of µSPECT images on MR images was performed, and the level of correspondence (LoC) between µSPECT and µMR findings was assessed according to a 4-point Likert classification scheme. RESULTS: Forty-one LNOIs could be matched to an LN on ex vivo µMRI. Coregistration of µSPECT and USPIO-enhanced water-selective multigradient echo MR images was successful for all 41 LNOIs. Ninety percent of the lesions showed excellent correspondence regarding the presence of metastatic tissue and affected subnodal site (LoC 4; 37/41). In only 1 of 41 LNOIs, a small metastasis was misclassified by both techniques. Three LNOIs were classified as LoC 3 (7%) and 1 LNOI as LoC 2. All LoC 2 and LoC 3 lesions had PSMA-expressing metastases on final histopathology. CONCLUSIONS: Coregistration of µSPECT and USPIO-µMRI showed excellent subnodal correspondence in the majority (90%) of LNs. Ex vivo imaging may thus help localize small cancer deposits within resected LNs and could contribute to improved interpretation of in vivo imaging of LNs.

Apparent Diffusion Coefficient Metrics to Differentiate between Treatment-Related Abnormalities and Tumor Progression in Post-Treatment Glioblastoma Patients: A Retrospective Study.

Distinguishing treatment-related abnormalities (TRA) from tumor progression (TP) in glioblastoma patients is a diagnostic imaging challenge due to the identical morphology of conventional MR imaging sequences. Diffusion-weighted imaging (DWI) and its derived images of the apparent diffusion coefficient (ADC) have been suggested as diagnostic tools for this problem. The aim of this study is to determine the diagnostic accuracy of different cut-off values of the ADC to differentiate between TP and TRA. In total, 76 post-treatment glioblastoma patients with new contrast-enhancing lesions were selected. Lesions were segmented using a T1-weighted, contrast-enhanced scan. The mean ADC values of the segmentations were compared between TRA and TP groups. Diagnostic accuracy was compared by use of the area under the curve (AUC) and the derived sensitivity and specificity values from cutoff points. Although ADC values in TP (mean = 1.32 × 10-3 mm2/s; SD = 0.31 × 10-3 mm2/s) were significantly different compared to TRA (mean = 1.53 × 10-3 mm2/s; SD = 0.28 × 10-3 mm2/s) (p = 0.003), considerable overlap in their distributions exists. The AUC of ADC values to distinguish TP from TRA was 0.71, with a sensitivity and specificity of 65% and 70%, respectively, at an ADC value of 1.47 × 10-3 mm2/s. These findings therefore indicate that ADC maps should not be used in discerning between TP and TRA at a certain timepoint without information on temporal evolution.

Performance of a Nonlinear Magnetic Handheld Probe for Intraoperative Sentinel Lymph Node Detection: A Phantom Study.

OBJECTIVE: This study investigates the performance of the DiffMag handheld probe (nonlinear magnetometry), to be used for sentinel lymph node detection. Furthermore, the performance of DiffMag is compared with a gamma probe and a first-order magnetometer (Sentimag®, linear magnetometry). METHODS: The performance of all three probes was evaluated based on longitudinal distance, transverse distance, and resolving power for two tracer volumes. A phantom was developed to investigate the performance of the probes for a clinically relevant situation in the floor of the mouth (FOM). RESULTS: Considering the longitudinal distance, both DiffMag handheld and Sentimag® probe had comparable performance, while the gamma probe was able to detect at least a factor of 10 deeper. Transverse distances of 13, 11, and 51 mm were measured for the small tracer volume by the DiffMag handheld, Sentimag®, and the gamma probe, respectively. For the large tracer volume this was 21, 18, and 55 mm, respectively. The full width at half maximum, at 7 mm probe height from the phantom surface, was 14, 12, and 18 mm for the small tracer volume and 15, 18, and 25 mm for the large tracer volume with the DiffMag handheld, Sentimag®, and gamma probe, respectively. CONCLUSIONS: With a high resolving power but limited longitudinal distance, the DiffMag handheld probe seems suitable for detecting SLNs which are in close proximity to the primary tumor. In this study, comparable results were shown using linear magnetometry. The gamma probe reached 10 times deeper, but has a lower resolving power compared with the DiffMag handheld probe.

Post-acquisition water-signal removal in 3D water-unsuppressed 1 H-MR spectroscopic imaging of the prostate.

PURPOSE: To develop a robust processing procedure of raw signals from water-unsuppressed MRSI of the prostate for the mapping of absolute tissue concentrations of metabolites. METHODS: Water-unsuppressed 3D MRSI data were acquired from a phantom, from healthy volunteers, and a patient with prostate cancer. Signal processing included sequential computation of the modulus of the FID to remove water sidebands, a Hilbert transformation, and k-space Hamming filtering. For the removal of the water signal, we compared Löwner tensor-based blind source separation (BSS) and Hankel Lanczos singular value decomposition techniques. Absolute metabolite levels were quantified with LCModel and the results were statistically analyzed to compare the water removal methods and conventional water-suppressed MRSI. RESULTS: The post-processing algorithms successfully removed the water signal and its sidebands without affecting metabolite signals. The best water removal performance was achieved by Löwner tensor-based BSS. Absolute tissue concentrations of citrate in the peripheral zone derived from water-suppressed and unsuppressed 1 H MRSI were the same and as expected from the known physiology of the healthy prostate. Maps for citrate and choline from water-unsuppressed 3D 1 H-MRSI of the prostate showed expected spatial variations in metabolite levels. CONCLUSION: We developed a robust relatively simple post-processing method of water-unsuppressed MRSI of the prostate to remove the water signal. Absolute quantification using the water signal, originating from the same location as the metabolite signals, avoids the acquisition of additional reference data.

Diffusion imaging could aid to differentiate between glioma progression and treatment-related abnormalities: a meta-analysis.

BACKGROUND: In a considerable subgroup of glioma patients treated with (chemo) radiation new lesions develop either representing tumor progression (TP) or treatment-related abnormalities (TRA). Quantitative diffusion imaging metrics such as the Apparent Diffusion Coefficient (ADC) and Fractional Anisotropy (FA) have been reported as potential metrics to noninvasively differentiate between these two phenomena. Variability in performance scores of these metrics and absence of a critical overview of the literature contribute to the lack of clinical implementation. This meta-analysis therefore critically reviewed the literature and meta-analyzed the performance scores. METHODS: Systematic searching was carried out in PubMed, EMBASE and The Cochrane Library. Using predefined criteria, papers were reviewed. Diagnostic accuracy values of suitable papers were meta-analyzed quantitatively. RESULTS: Of 1252 identified papers, 10 ADC papers, totaling 414 patients, and 4 FA papers, with 154 patients were eligible for meta-analysis. Mean ADC values of the patients in the TP/TRA groups were 1.13 × 10-3mm2/s (95% CI 0.912 × 10-3-1.32 × 10-3mm2/s) and 1.38 × 10-3mm2/s (95% CI 1.33 × 10-3-1.45 × 10-3mm2/s, respectively. Mean FA values of TP/TRA was 0.19 (95% CI 0.189-0.194) and 0.14 (95% CI 0.137-0.143) respectively. A significant mean difference between ADC and FA values in TP versus TRA was observed (p = 0.005). CONCLUSIONS: Quantitative ADC and FA values could be useful for distinguishing TP from TRA on a meta-level. Further studies using serial imaging of individual patients are warranted to determine the role of diffusion imaging in glioma patients.

High-Accuracy Nodal Staging of Head and Neck Cancer With USPIO-Enhanced MRI: A New Reading Algorithm Based on Node-to-Node Matched Histopathology.

OBJECTIVES: Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) is a potential diagnostic tool for lymph node assessment in patients with head and neck cancer. Validation by radiologic-pathologic correlation is essential before the method is evaluated in clinical studies. In this study, MRI signal intensity patterns of lymph nodes are correlated to their histopathology to develop a new USPIO-enhanced MRI reading algorithm that can be used for nodal assessment in head and neck cancer patients. MATERIALS AND METHODS: Ten head and neck cancer patients underwent in vivo USPIO-enhanced MRI before neck dissection. An ex vivo MRI of the neck dissection specimen was performed for precise coregistration of in vivo MRI with histopathology. Normal clinical histopathological workup was extended with meticulous matching of all lymph nodes regarded as potentially metastatic based on their in vivo MRI signal intensity pattern. On the basis of histopathology of resected nodes, in vivo MRI signal characteristics were defined separating benign from malignant lymph nodes. RESULTS: Fifteen of 34 node-to-node correlated lymph nodes with remaining signal intensity on T2*-weighted MRI were histopathologically metastatic and 19 were benign. Radiological analysis revealed that metastatic lymph nodes showed equal or higher MRI signal intensity when compared with lipid tissue on T2*-weighted MGRE sequence (15/16 lymph nodes; 94%), whereas healthy lymph nodes showed lower (17/19 lymph nodes; 89%) or complete attenuation of signal intensity (273/279; 98%) when compared with lipid tissue on T2*-weighted MGRE. Histopathology of all resected specimens identified 392 lymph nodes. Six lymph nodes with (micro)metastases were missed with in vivo MRI. Whether these 6 lymph nodes were correlated to a nonmalignant lymph node on in vivo MRI or could not be detected at all is unclear. CONCLUSIONS: We developed a new reading algorithm to differentiate benign from malignant lymph nodes in head and neck cancer patients on the basis of their appearance on high-resolution T2*-weighted USPIO-enhanced MRI. Next steps involve validation of our reading algorithm to further improve the accuracy of neck lymph node staging with USPIO-enhanced MRI in prospective clinical studies with larger number of patients.

Ultra-high-field MR in Prostate cancer: Feasibility and Potential.

Multiparametric MRI of the prostate at clinical magnetic field strengths (1.5/3 Tesla) has emerged as a reliable noninvasive imaging modality for identifying clinically significant cancer, enabling selective sampling of high-risk regions with MRI-targeted biopsies, and enabling minimally invasive focal treatment options. With increased sensitivity and spectral resolution, ultra-high-field (UHF) MRI (≥ 7 Tesla) holds the promise of imaging and spectroscopy of the prostate with unprecedented detail. However, exploiting the advantages of ultra-high magnetic field is challenging due to inhomogeneity of the radiofrequency field and high local specific absorption rates, raising local heating in the body as a safety concern. In this work, we review various coil designs and acquisition strategies to overcome these challenges and demonstrate the potential of UHF MRI in anatomical, functional and metabolic imaging of the prostate and pelvic lymph nodes. When difficulties with power deposition of many refocusing pulses are overcome and the full potential of metabolic spectroscopic imaging is used, UHF MR(S)I may aid in a better understanding of the development and progression of local prostate cancer. Together with large field-of-view and low-flip-angle anatomical 3D imaging, 7 T MRI can be used in its full strength to characterize different tumor stages and help explain the onset and spatial distribution of metastatic spread.

Developments in proton MR spectroscopic imaging of prostate cancer.

In this paper, we review the developments of 1H-MR spectroscopic imaging (MRSI) methods designed to investigate prostate cancer, covering key aspects such as specific hardware, dedicated pulse sequences for data acquisition and data processing and quantification techniques. Emphasis is given to recent advancements in MRSI methodologies, as well as future developments, which can lead to overcome difficulties associated with commonly employed MRSI approaches applied in clinical routine. This includes the replacement of standard PRESS sequences for volume selection, which we identified as inadequate for clinical applications, by sLASER sequences and implementation of 1H MRSI without water signal suppression. These may enable a new evaluation of the complementary role and significance of MRSI in prostate cancer management.

Validation of In Vivo Nodal Assessment of Solid Malignancies with USPIO-Enhanced MRI: A Workflow Protocol.

BACKGROUND: In various cancer types, the first step towards extended metastatic disease is the presence of lymph node metastases. Imaging methods with sufficient diagnostic accuracy are required to personalize treatment. Lymph node metastases can be detected with ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI), but this method needs validation. Here, a workflow is presented, which is designed to compare MRI-visible lymph nodes on a node-to-node basis with histopathology. METHODS: In patients with prostate, rectal, periampullary, esophageal, and head-and-neck cancer, in vivo USPIO-enhanced MRI was performed to detect lymph nodes suspicious of harboring metastases. After lymphadenectomy, but before histopathological assessment, a 7 Tesla preclinical ex vivo MRI of the surgical specimen was performed, and in vivo MR images were radiologically matched to ex vivo MR images. Lymph nodes were annotated on the ex vivo MRI for an MR-guided pathological examination of the specimens. RESULTS: Matching lymph nodes of ex vivo MRI to pathology was feasible in all cancer types. The annotated ex vivo MR images enabled a comparison between USPIO-enhanced in vivo MRI and histopathology, which allowed for analyses on a nodal, or at least on a nodal station, basis. CONCLUSIONS: A workflow was developed to validate in vivo USPIO-enhanced MRI with histopathology. Guiding the pathologist towards lymph nodes in the resection specimens during histopathological work-up allowed for the analysis at a nodal basis, or at least nodal station basis, of in vivo suspicious lymph nodes with corresponding histopathology, providing direct information for validation of in vivo USPIO-enhanced, MRI-detected lymph nodes.

A Comprehensive Grading System for a Magnetic Sentinel Lymph Node Biopsy Procedure in Head and Neck Cancer Patients.

A magnetic sentinel lymph node biopsy ((SLN)B) procedure has recently been shown feasible in oral cancer patients. However, a grading system is absent for proper identification and classification, and thus for clinical reporting. Based on data from eight complete magnetic SLNB procedures, we propose a provisional grading system. This grading system includes: (1) a qualitative five-point grading scale for MRI evaluation to describe iron uptake by LNs; (2) an ex vivo count of resected SLN with a magnetic probe to quantify iron amount; and (3) a qualitative five-point grading scale for histopathologic examination of excised magnetic SLNs. Most SLNs with iron uptake were identified and detected in level II. In this level, most variance in grading was seen for MRI and histopathology; MRI and medullar sinus were especially highly graded, and cortical sinus was mainly low graded. On average 82 ± 58 µg iron accumulated in harvested SLNs, and there were no significant differences in injected tracer dose (22.4 mg or 11.2 mg iron). In conclusion, a first step was taken in defining a comprehensive grading system to gain more insight into the lymphatic draining system during a magnetic SLNB procedure.

Update to a randomized controlled trial of lutetium-177-PSMA in Oligo-metastatic hormone-sensitive prostate cancer: the BULLSEYE trial.

BACKGROUND: The BULLSEYE trial is a multicenter, open-label, randomized controlled trial to test the hypothesis if 177Lu-PSMA is an effective treatment in oligometastatic hormone-sensitive prostate cancer (oHSPC) to prolong the progression-free survival (PFS) and postpone the need for androgen deprivation therapy (ADT). The original study protocol was published in 2020. Here, we report amendments that have been made to the study protocol since the commencement of the trial. CHANGES IN METHODS AND MATERIALS: Two important changes were made to the original protocol: (1) the study will now use 177Lu-PSMA-617 instead of 177Lu-PSMA-I&T and (2) responding patients with residual disease on 18F-PSMA PET after the first two cycles are eligible to receive additional two cycles of 7.4 GBq 177Lu-PSMA in weeks 12 and 18, summing up to a maximum of 4 cycles if indicated. Therefore, patients receiving 177Lu-PSMA-617 will also receive an interim 18F-PSMA PET scan in week 4 after cycle 2. The title of this study was modified to; "Lutetium-177-PSMA in Oligo-metastatic Hormone Sensitive Prostate Cancer" and is now partly supported by Advanced Accelerator Applications, a Novartis Company. CONCLUSIONS: We present an update of the original study protocol prior to the completion of the study. Treatment arm patients that were included and received 177Lu-PSMA-I&T under the previous protocol will be replaced. TRIAL REGISTRATION: ClinicalTrials.gov NCT04443062 . First posted: June 23, 2020.

In Vivo PET Imaging of Monocytes Labeled with [89Zr]Zr-PLGA-NH2 Nanoparticles in Tumor and Staphylococcus aureus Infection Models.

The exponential growth of research on cell-based therapy is in major need of reliable and sensitive tracking of a small number of therapeutic cells to improve our understanding of the in vivo cell-targeting properties. 111In-labeled poly(lactic-co-glycolic acid) with a primary amine endcap nanoparticles ([111In]In-PLGA-NH2 NPs) were previously used for cell labeling and in vivo tracking, using SPECT/CT imaging. However, to detect a low number of cells, a higher sensitivity of PET is preferred. Therefore, we developed 89Zr-labeled NPs for ex vivo cell labeling and in vivo cell tracking, using PET/MRI. We intrinsically and efficiently labeled PLGA-NH2 NPs with [89Zr]ZrCl4. In vitro, [89Zr]Zr-PLGA-NH2 NPs retained the radionuclide over a period of 2 weeks in PBS and human serum. THP-1 (human monocyte cell line) cells could be labeled with the NPs and retained the radionuclide over a period of 2 days, with no negative effect on cell viability (specific activity 279 ± 10 kBq/106 cells). PET/MRI imaging could detect low numbers of [89Zr]Zr-THP-1 cells (10,000 and 100,000 cells) injected subcutaneously in Matrigel. Last, in vivo tracking of the [89Zr]Zr-THP-1 cells upon intravenous injection showed specific accumulation in local intramuscular Staphylococcus aureus infection and infiltration into MDA-MB-231 tumors. In conclusion, we showed that [89Zr]Zr-PLGA-NH2 NPs can be used for immune-cell labeling and subsequent in vivo tracking of a small number of cells in different disease models.

Lutetium-177-PSMA-617 in Low-Volume Hormone-Sensitive Metastatic Prostate Cancer: A Prospective Pilot Study.

PURPOSE: [177Lu]Lu-PSMA-617 radioligand therapy (177Lu-PSMA) is a novel treatment for metastatic castration-resistant prostate cancer (mCRPC), which could also be applied to patients with metastatic hormone-sensitive prostate cancer (mHSPC) with PSMA expression. In this prospective study (NCT03828838), we analyzed toxicity, radiation doses, and treatment effect of 177Lu-PSMA in pateints with low-volume mHSPC. PATIENTS AND METHODS: Ten progressive patients with mHSPC following local treatment, with a maximum of ten metastatic lesions on [68Ga]Ga-PSMA-11 PET/diagnostic-CT imaging (PSMA-PET) and serum PSA doubling time <6 months received two cycles of 177Lu-PSMA. Whole-body single-photon emission CT/CT (SPECT/CT) and blood dosimetry was performed to calculate doses to the tumors and organs at risk (OAR). Adverse events (AE), laboratory values (monitoring response and toxicity), and quality of life were monitored until week 24 after cycle 2, the end of study (EOS). All patients underwent PSMA-PET at screening, 8 weeks after cycle 1, 12 weeks after cycle 2, and at EOS. RESULTS: All patients received two cycles of 177Lu-PSMA without complications. No treatment-related grade III-IV adverse events were observed. According to dosimetry, none of the OAR reached threshold doses for radiation-related toxicity. Moreover, all target lesions received a higher radiation dose than the OAR. All 10 patients showed altered PSA kinetics, postponed androgen deprivation therapy, and maintained good quality of life. Half of the patients showed a PSA response of more than 50%. One patient had a complete response on PSMA-PET imaging until EOS and two others had only minimal residual disease. CONCLUSIONS: 177Lu-PSMA appeared to be a feasible and safe treatment modality in patients with low-volume mHSPC.