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In this study, the reproducibility of [ABSTRACT FROM AUTHOR]

Bone and soft tissue sarcomas are a group of rare malignant tumours with major histological and anatomical varieties. In a metastatic setting, sarcomas have a poor prognosis due to limited response rates to chemotherapy. Radioligand therapy targeting prostate-specific membrane antigen (PSMA) may offer a new perspective. PSMA is a type II transmembrane glycoprotein which is present in all prostatic tissue and overexpressed in prostate cancer. Despite the name, PSMA is not prostate-specific. PSMA expression is also found in a multitude of non-prostatic diseases including a subgroup of sarcomas, mostly in its neovascular endothelial cells. On PET/CT imaging, multiple sarcomas have also shown intense PSMA-tracer accumulation. PSMA expression and PSMA-tracer uptake seem to be highest in patients with aggressive and advanced sarcomas, who are also in highest need of new therapeutic options. Although these results provide a good rationale for the future use of PSMA-targeted radioligand therapy in a selection of sarcoma patients, more research is needed to gain insight into optimal patient selection methods, PSMA-targeting antibodies and tracers, administered doses of radioligand therapy, and their efficacy and tolerability. In this review, mRNA expression of the FOLH1 gene which encodes PSMA, PSMA immunohistochemistry, PSMA-targeted imaging and PSMA-targeted therapy in sarcomas will be discussed.

Current imaging modalities frequently misjudge disease stage in colorectal, gastric and pancreatic cancer. As treatment decisions are dependent on disease stage, incorrect staging has serious consequences. Previous preclinical research and case reports indicate that prostate-specific membrane antigen (PSMA)-targeted PET/CT imaging might provide a solution to some of these challenges. This prospective clinical study aims to assess the feasibility of [ 18 F]DCFPyL PET/CT imaging to target and visualize primary colon, gastric and pancreatic cancer. In this prospective clinical trial, patients with colon, gastric and pancreatic cancer were included and underwent both [ 18 F]DCFPyL and [ 18 F]FDG PET/CT scans prior to surgical resection or (for gastric cancer) neoadjuvant therapy. Semiquantitative analysis of immunohistochemical PSMA staining was performed on the surgical resection specimens, and the results were correlated to imaging parameters. The results of this study demonstrate detection of the primary tumor by [ 18 F]DCFPyL PET/CT in 7 out of 10 patients with colon, gastric and pancreatic cancer, with a mean tumor-to-blood pool ratio (TBR) of 3.3 and mean SUV max of 3.6. However, due to the high surrounding uptake, visual distinction of these tumors was difficult, and the SUV max and TBR on [ 18 F]FDG PET/CT were significantly higher than on [ 18 F]DCFPyL PET/CT. In addition, no correlation between PSMA expression in the resection specimen and SUV max on [ 18 F]DCFPyL PET/CT was found. In conclusion, the detection of several gastrointestinal cancers using [ 18 F]DCFPyL PET/CT is feasible. However, low tumor expression and high uptake physiologically in organs/background hamper the clear distinction of the tumor. As a result, [ 18 F]FDG PET/CT was superior in detecting colon, gastric and pancreatic cancers.

Poor responses to iodine-131 (I-131) therapy can relate to either low iodine uptake and retention in thyroid cancer cells or to increased radioresistance. Both mechanisms are currently termed radioactive iodine (RAI)-refractory (RAI-R) thyroid cancer but the first reflects unsuitability for I-131 therapy that can be evaluated in advance of treatment, whereas the other can only be identified post hoc. Management of both represents a considerable challenge in clinical practice as failure of I-131 therapy, the most effective treatment of metastatic thyroid cancer, is associated with a poor overall prognosis. The development of targeted therapies has shown substantial promise in the treatment of RAI-R thyroid cancer in progressive patients. Recent studies show that selective tyrosine kinase inhibitors (TKIs) targeting B-type rapidly accelerated fibrosarcoma kinase (BRAF) and mitogen-activated protein kinase (MEK) can be used as redifferentiation agents to re-induce RAI uptake, thereby (re)enabling I-131 therapy. The use of dosimetry prior- and post-TKI treatment can assist in quantifying RAI uptake and improve identification of patients that will benefit from I-131 therapy. It also potentially offers the prospect of calculating individualized therapeutic administered activities to enhance efficacy and limit toxicity. In this review, we present an overview of the regulation of RAI uptake and clinically investigated redifferentiation agents, both reimbursed and in experimental setting, that induce renewed RAI uptake. We describe the role of dosimetry in redifferentiation and subsequent I-131 therapy in RAI-R thyroid cancer, explain different dosimetry approaches and discuss limitations and considerations in the field.

Purpose: To evaluate whether PET/CT could be used to assess the extent of colorectal peritoneal metastases., Methods: All patients who underwent a PET/CT scan before a CRS-HIPEC procedure between January 1, 2010 and December 31, 2013 were retrospectively included (n = 35). Two nuclear medicine physicians (observer 1 and observer 2) separately reviewed the scans on intraperitoneal abnormalities. A simplified PCI was used to compare the extent of rPCI versus sPCI., Results: Included patients had a median age of 60.6 years. Histology of primary tumors were 51.5% adenocarcinomas, 37.1% mucinous adenocarcinoma, and 11.4% SRCC. Median sPCI was 9.5 (5.0-11.8) and median rPCI was 5.0 (3.0-7.0) for observer 1 and 4.0 (3.0-6.0) for observer 2 (p = 0.02 and p = 0.01, respectively). When compared to the surgical data, PET/CT showed a poor correlation for assessing the extent of PC for both adenocarcinoma (observer 1 rho - 0.17, p = 0.51 and observer 2 rho 0.13, p = 0.61) as well as mucinous carcinoma or SRCC (observer 1 rho 0.44, p = 0.08 and observer 2 rho 0.38, p = 0.14)., Conclusion: PET/CT underestimates the extent of PC during surgery in both mucinous and non-mucinous CRC and is not recommended for intraperitoneal tumor scoring.

Purpose: A relatively high signal for choline-containing compounds (total choline, tCho) is commonly found in 1 H MR spectra of malignant tumors, but it is unclear if this also occurs in tumors in the liver. We evaluated the potential of the tCho signal in single voxel 1 H MR spectra of the human liver to assess metastases of colorectal cancers., Experiment: MR spectra of an 8 cm 3 PRESS-localized voxel were obtained at 3 T from the livers of 12 healthy volunteers and from metastatic lesions in 20 patients in two different sessions. To correct for motion artifacts, sequentially recorded spectra were individually phased and frequency aligned before averaging. Spectra were analyzed using LCModel and tissue levels estimated by water referencing. Repeatability was assessed with Bland-Altman analyses. To estimate tumor necrosis, diffusion-weighted imaging of the liver was performed. High resolution magic angle spinning (HRMAS) spectra of tumor and normal liver samples were obtained at 11.7 T., Results: With increasing tumor volumes, tCho levels decreased, indicating a partial volume effect. Mean tCho content in tumors larger than the PRESS voxel (>8 cm 3 ) was significantly lower (p < 0.01) than for normal liver: 1.6 (range 0.0-3.4) versus 6.9 (range 4.9-11.1) mmol/kg wet weight, while it was comparable for tumors smaller than 8 cm 3 : 7.0 (range 3.8-9.3) mmol/kg. The higher 90th percentile apparent diffusion coefficient value in the larger lesions indicates more necrosis. Measurement repeatability was average in normal livers and poor in tumors. HRMAS did not show substantial differences in choline-containing compounds between normal liver and metastasis., Conclusion: An increased tCho content was not observed in 1 H MR spectra of liver metastasis of colorectal cancer, compared with normal liver. This may be due to the background of a high tCho signal in spectra of normal liver or to an intrinsic lower tCho content in these tumors, but is most likely the result of necrosis in metastatic tumor tissue., (© 2018 John Wiley & Sons, Ltd.)

Background: Developments in image reconstruction techniques for planar imaging, also known as enhanced planar processing (EPP), enable the possibility to reconstruct planar scintigraphic images with low count statistics, providing the opportunity to reduce image acquisition time. In this study, the performance of EPP for oncologic half-time bone scintigraphy images was evaluated., Methods: The EPP software was evaluated for different imaging conditions using standardized phantom experiments. Additionally, 51 patients with prostate and breast cancer were prospectively included and underwent bone scintigraphy using a standard and half-time protocol. Independent reading was performed on three image types (standard, half-time non-processed, and half-time EPP) by three observers, scoring the number and anatomical location of lesions, image quality, and diagnostic confidence by which the definitive diagnosis was made., Results: EPP images had improved contrast and lower noise levels compared to the non-processed half-time images. It was determined that EPP images acquired at double scan speed had similar image quality to the standard non-processed images. There was substantial agreement with respect to diagnosis and diagnostic confidence based on all three image types between the observers. Image quality in the EPP images was higher with respect to the non-processed half-time images, and was comparable to the standard images., Conclusions: Diagnostic confidence was not affected by reduction in image acquisition time. There was substantial agreement between all three observers with respect to the diagnosis provided in all three image types. Subjective and objective image quality improved when half-time images were processed with EPP software.

Driven by the continuous improvement in the accuracy of cross-sectional imaging, image-guided minimally invasive local ablative therapies have received incremental interest over the past few years. In this article, we systematically review the currently available literature on 18 F-FDG PET/CT to monitor the efficacy of these local ablative therapies. By including all local ablative treatment modalities, tumor types, and organ sites, we provide a comprehensive overview of the current status, identify general patterns across studies, and provide recommendations for future studies and clinical practice. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS) criteria were used to assess the quality of the reported diagnostic accuracy of the retrieved studies. Data in the literature suggest that 18 F-FDG PET/CT is a highly accurate tool to assess the technical success of local treatment, to identify residual or recurrent tumor early after intervention, and to provide prognostic and predictive information. However, prospective interventional studies based on 18 F-FDG PET/CT findings of disease activity are mandatory to develop uniform and quantitative criteria for PET evaluation. Moreover, the optimal timing of 18 F-FDG PET/CT after treatment may vary according to the location of the disease, with very early imaging being possible in solid organs such as the liver but posttreatment imaging being challenging for 3 mo in a location such as the lung parenchyma., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: The aim of the study was to investigate the potential of diffusion-weighted magnetic resonance imaging (DW-MRI) and 3'-dexoy-3'-[ 18 F]fluorothymidine ([ 18 F]FLT) positron emission tomography (PET) as early biomarkers of treatment response of 5-fluorouracil (5-FU) in a syngeneic rat model of colorectal cancer liver metastases., Procedures: Wag/Rij rats with intrahepatic syngeneic CC531 tumors were treated with 5-FU (15, 30, or 60 mg/kg in weekly intervals). Before treatment and at days 1, 3, 7, and 14 after treatment rats underwent DW-MRI and [ 18 F]FLT PET. Tumors were analyzed immunohistochemically for Ki67, TK1, and ENT1 expression., Results: 5-FU inhibited the growth of CC531 tumors in a dose-dependent manner. Immunohistochemical analysis did not show significant changes in Ki67, TK1, and ENT1 expression. However, [ 18 F]FLT SUV mean and SUV max were significantly increased at days 4 and 7 after treatment with 5-FU (60 mg/kg) and returned to baseline at day 14 (SUV max at days -1, 4, 7, and 14 was 1.1 ± 0.1, 2.3 ± 0.5, 2.3 ± 0.6, and 1.5 ± 0.4, respectively). No changes in [ 18 F]FLT uptake were observed in the nontreated animals. Furthermore, the apparent diffusion coefficient (ADC mean ) did not change in 5-FU-treated rats compared to untreated rats., Conclusion: This study suggests that 5-FU treatment induces a flare in [ 18 F]FLT uptake of responsive CC531 tumors in the liver, while the ADC mean did not change significantly. Future studies in larger groups are warranted to further investigate whether [ 18 F]FLT PET can discriminate between disease progression and treatment response.

The purpose of this work was to improve dynamic contrast enhanced MRI (DCE-MRI) of liver lesions by removing motion corrupted images as identified by a structural similarity (SSIM) algorithm, and to assess the effect of this correction on the pharmacokinetic parameter K trans using automatically determined arterial input functions (AIFs). Fifteen patients with colorectal liver metastases were measured twice with a T 1 weighted multislice 2D FLASH sequence for DCE-MRI (time resolution 1.2 s). AIFs were automatically derived from contrast inflow in the aorta of each patient. Thereafter, SSIM identified motion corrupted images of the liver were removed from the DCE dataset. From this corrected data set K trans and its reproducibility were determined. Using the SSIM algorithm a median fraction of 46% (range 37-50%) of the liver images in DCE time series was labeled as motion distorted. Rejection of these images resulted in a significantly lower median K trans (p < 0.05) and lower coefficient of repeatability of K trans in liver metastases compared with an analysis without correction. SSIM correction improves the reproducibility of the DCE-MRI parameter K trans in liver metastasis and reduces contamination of K trans values of lesions by that of surrounding normal liver tissue., (Copyright © 2016 John Wiley & Sons, Ltd.)

Aim: Aim of this study was to investigate the potential of 18F-FDG PET, diffusion weighted imaging (DWI) and susceptibility-weighted (T2*) MRI to predict response to systemic treatment in patients with colorectal liver metastases. The predictive values of pretreatment measurements and of early changes one week after start of therapy, were evaluated., Methods: Imaging was performed prior to and one week after start of first line chemotherapy in 39 patients with colorectal liver metastases. 18F-FDG PET scans were performed on a PET/CT scanner and DWI and T2* were performed on a 1.5T MR scanner. The maximum standardized uptake values (SUV), total lesion glycolysis (TLG), apparent diffusion coefficient (ADC) and T2* value were assessed in the same lesions. Up to 5 liver metastases per patient were analyzed. Outcome measures were progression free survival (PFS), overall survival (OS) and size response., Results: Pretreatment, high SUVmax, high TLG, low ADC and high T2* were associated with a shorter OS. Low pretreatment ADC value was associated with shorter PFS. After 1 week a significant drop in SUVmax and rise in ADC were observed. The drop in SUV was correlated with the rise in ADC (r=-0.58, p=0.002). Neither change in ADC nor in SUV was predictive of PFS or OS. T2* did not significantly change after start of treatment., Conclusion: Pretreatment SUVmax, TLG, ADC, and T2* values in colorectal liver metastases are predictive of patient outcome. Despite sensitivity of DWI and 18F-FDG PET for early treatment effects, change in these parameters was not predictive of long term outcome.

Background: The use of therapeutic monoclonal antibodies for clinical purposes has significantly increased in recent years, and so has the need to monitor antibody concentrations. This may be achieved using the well-established enzyme linked immunoassay (ELISA) methods; however, these assays are subject to a variety of interferences., Methods: In the present study, the authors have tested the ELISA methods for quantifying bevacizumab (BVZ) to investigate this interference. Three different ELISA methods were used and exhibited similar characteristics., Results: The detection limits of the ELISA methods varied from 0.05 to 0.07 ng/mL. To monitor assay performance, BVZ was measured in a control sample during each run. The BVZ concentration in the control sample was 15.4 μg/mL, the within-run imprecision (CV) and between-run CV were 4.3% and 10.4% (direct ELISA), 5.2% and 12.9% (indirect/Rabbit ELISA), and 3.9% and 9.1% (indirect/Chicken ELISA). The assays exhibited good precision and parallelism in serial dilutions of samples and a mean recovery of 98% (range, 78%-118%)., Conclusions: The authors show that the degree of interference by using direct and indirect target immobilization depends heavily on the method of target immobilization on the surface of the ELISA plate, and is patient-specific. The results highlight pitfalls of potential relevance to sandwich-type assays, and an approach to rectify such problems. This approach will yield a valid assay protocol for the measurement of monoclonal therapeutic antibodies in case no target is available for direct immobilization.

The purpose of this study was to assess the effect of bevacizumab on vasculature and hypoxia in a colorectal tumor model. Nude mice with subcutaneous LS174T tumors were treated with bevacizumab or saline. To assess tumor properties, separate groups of mice were imaged using (18) F-Fluoromisonidazole (FMISO) and (18) F-Fluorodeoxyglucose (FDG) positron emission tomography or magnetic resonance imaging before and 2, 6 and 10 days after the start of treatment. Tumors were harvested after imaging to determine hypoxia and vascular density immunohistochemically. The T2 * time increased significantly less in the bevacizumab group. FMISO uptake increased more over time in the control group. Vessel density significantly decreased in the bevacizumab-treated group. The Carbonic anhydrase 9 (CAIX) and glucose uptake transporter 1 (GLUT1) fractions were higher in bevacizumab-treated tumors. However, the hypoxic fraction showed no significant difference. Bevacizumab led to shorter T2 * times and higher GLUT1 and CAIX expression, suggesting an increase in hypoxia and a higher glycolytic rate. This could be a mechanism of resistance to bevacizumab. The increase in hypoxia, however, could not be demonstrated by pimonidazole/FMISO, possibly because distribution of these tracers is hampered by bevacizumab-induced effects on vascular permeability and perfusion., (Copyright © 2014 John Wiley & Sons, Ltd.)

Objectives: Before diffusion-weighted imaging (DWI) can be implemented in standard clinical practice for response monitoring, data on reproducibility are needed to assess which differences outside the range of normal variation can be detected in an individual patient. In this study we assessed the reproducibility of the apparent diffusion coefficient (ADC) values in colorectal liver metastases. To provide a biological basis for these values, their relation with histopathology was assessed., Methods: DWI was performed twice in 1 week in patients scheduled for metastasectomy of colorectal liver metastases. Correlation between ADC values and apoptosis marker p53, anti-apoptotic protein BCL-2, proliferation marker Ki67 and serum vascular endothelial growth factor (VEGF) concentration were assessed., Results: A good reproducibility coefficient of the mean ADC (coefficient of reproducibility 0.20 × 10(-3) mm(2)/s) was observed in colorectal liver metastases (n = 21). The ADC value was related to the proliferation index and BCL-2 expression of the metastases. Furthermore, in metastases recently treated with systemic therapy, the ADC was significantly higher (1.27 × 10(-3) mm(2)/s vs 1.05 × 10(-3) mm(2)/s, P = 0.02)., Conclusions: The good reproducibility, correlation with histopathology and implied sensitivity for systemic treatment-induced anti-tumour effects suggest that DWI might be an excellent tool to monitor response in metastatic colorectal cancer.

Purpose: Several studies showed potential for monitoring response to systemic therapy in metastatic colorectal cancer patients with (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Before (18)F-FDG PET can be implemented for response evaluation the repeatability should be known. This study was performed to assess the magnitude of the changes in standardized uptake value (SUV), volume and total lesion glycolysis (TLG) in colorectal liver metastases and validate the biological basis of (18)F-FDG PET in colorectal liver metastases., Methods: Twenty patients scheduled for liver metastasectomy underwent two (18)F-FDG PET scans within 1 week. Bland-Altman analysis was performed to assess repeatability of SUV(max), SUV(mean), volume and TLG. Tumours were delineated using an adaptive threshold method (PET(SBR)) and a semiautomatic fuzzy locally adaptive Bayesian (FLAB) delineation method., Results: Coefficient of repeatability of SUV(max) and SUV(mean) were ∼39 and ∼31 %, respectively, independent of the delineation method used and image reconstruction parameters. However, repeatability was worse in recently treated patients. The FLAB delineation method improved the repeatability of the volume and TLG measurements compared to PET(SBR), from coefficients of repeatability of over 85 % to 45 % and 57 % for volume and TLG, respectively. Glucose transporter 1 (GLUT1) expression correlated to the SUV(mean). Vascularity (CD34 expression) and tumour hypoxia (carbonic anhydrase IX expression) did not correlate with (18)F-FDG PET parameters., Conclusion: In conclusion, repeatability of SUV(mean) and SUV(max) was mainly affected by preceding systemic therapy. The repeatability of tumour volume and TLG could be improved using more advanced and robust delineation approaches such as FLAB, which is recommended when (18)F-FDG PET is utilized for volume or TLG measurements. Improvement of repeatability of PET measurements, for instance by dynamic PET scanning protocols, is probably necessary to effectively use PET for early response monitoring.