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Background: This study addresses the technical gap between clinical radiation therapy (RT) and preclinical small‐animal RT, hindering the comprehensive validation of innovative clinical RT approaches in small‐animal models of cancer and the translation of preclinical RT studies into clinical practices. Purpose: The main aim was to explore the feasibility of biologically guided RT implemented within a small‐animal radiation therapy (SART) platform, with integrated quad‐modal on‐board positron emission tomography (PET), single‐photon emission computed tomography, photon‐counting spectral CT, and cone‐beam CT (CBCT) imaging, in a Monte Carlo model as a proof‐of‐concept. Methods: We developed a SART workflow employing quad‐modal imaging guidance, integrating multimodal image‐guided RT and emission‐guided RT (EGRT). The EGRT algorithm was outlined using positron signals from a PET radiotracer, enabling near real‐time adjustments to radiation treatment beams for precise targeting in the presence of a 2‐mm setup error. Molecular image‐guided RT, incorporating a dose escalation/de‐escalation scheme, was demonstrated using a simulated phantom with a dose painting plan. The plan involved delivering a low dose to the CBCT‐delineated planning target volume (PTV) and a high dose boosted to the highly active biological target volume (hBTV) identified by the 18F‐PET image. Additionally, the Bayesian eigentissue decomposition method illustrated the quantitative decomposition of radiotherapy‐related parameters, specifically iodine uptake fraction and virtual noncontrast (VNC) electron density, using a simulated phantom with Kidney1 and Liver2 inserts mixed with an iodine contrast agent at electron fractions of 0.01–0.02. Results: EGRT simulations generated over 4,000 beamlet responses in dose slice deliveries and illustrated superior dose coverage and distribution with significantly lower doses delivered to normal tissues, even with a 2‐mm setup error introduced, demonstrating the robustness of the novel EGRT scheme compared to conventional image‐guided RT. In the dose‐painting plan, doubling the dose to the hBTV while maintaining a low dose for the PTV resulted in an organ‐at‐risk (OAR) dose comparable to the low‐dose treatment for the PTV alone. Furthermore, the decomposition of radiotherapy‐related parameters in Kidney1 and Liver2 inserts, including iodine uptake fractions and VNC electron densities, exhibited average relative errors of less than 1.0% and 2.5%, respectively. Conclusions: The results demonstrated the successful implementation of biologically guided RT within the proposed quad‐model image‐guided SART platform, with potential applications in preclinical RT and adaptive RT studies. [ABSTRACT FROM AUTHOR]

Background: In spite of the tremendous potential of game‐changing biological image‐ and/or biologically guided radiation therapy (RT) and adaptive radiation therapy for cancer treatment, existing limited strategies for integrating molecular imaging and/or biological information with RT have impeded the translation of preclinical research findings to clinical applications. Additionally, there is an urgent need for a highly integrated small‐animal radiation therapy (SART) platform that can seamlessly combine therapeutic and diagnostic capabilities to comprehensively enhance RT for cancer treatment. Purpose: We investigated a highly integrated quad‐modal on‐board imaging configuration combining positron emission tomography (PET), single‐photon emission computed tomography (SPECT), photon‐counting spectral CT, and cone‐beam computed tomography (CBCT) in a SART platform using a Monte Carlo model as a proof‐of‐concept. Methods: The quad‐modal on‐board imaging configuration of the SART platform was designed and evaluated by using the GATE Monte Carlo code. A partial‐ring on‐board PET imaging subsystem, utilizing advanced semiconductor thallium bromide detector technology, was designed to achieve high sensitivity and spatial resolution. On‐board SPECT, photon‐counting spectral‐CT, and CBCT imaging were performed using a single cadmium zinc telluride flat detector panel. The absolute peak sensitivity and scatter fraction of the PET subsystem were estimated by using simulated phantoms described in the NEMA NU‐4 standard. The spatial resolution of the PET image of the platform was evaluated by imaging a simulated micro‐Derenzo hot‐rod phantom. To evaluate the quantitative imaging capability of the system's spectral CT, the Bayesian eigentissue decomposition (ETD) method was utilized to quantitatively decompose the virtual noncontrast (VNC) electron densities and iodine contrast agent fractions in the Kidney1 inserts mixed with the iodine contrast agent within the simulated phantoms. The performance of the proposed quad‐model imaging in the platform was validated by imaging a simulated phantom with multiple imaging probes, including an iodine contrast agent and radioisotopes of 18F and 99mTc. Results: The PET subsystem demonstrated an absolute peak sensitivity of 18.5% at the scanner center, with an energy window of 175–560 KeV, and a scatter fraction of only 3.5% for the mouse phantom, with a default energy window of 480–540 KeV. The spatial resolution of PET on‐board imaging exceeded 1.2 mm. All imaging probes were identified clearly within the phantom. The PET and SPECT images agreed well with the actual spatial distributions of the tracers within the phantom. Average relative errors on electron density and iodine contrast agent fraction in the Kidney1 inserts were less than 3%. High‐quality PET images, SPECT images, spectral‐CT images (including iodine contrast agent fraction images and VNC electron density images), and CBCT images of the simulated phantom demonstrated the comprehensive multimodal imaging capability of the system. Conclusions: The results demonstrated the feasibility of the proposed quad‐modal imaging configuration in a SART platform. The design incorporates anatomical, molecular, and functional information about tumors, thereby facilitating successful translation of preclinical studies into clinical practices. [ABSTRACT FROM AUTHOR]

Purpose: [18F]fluorocholine PET/CT can detect hepatocellular carcinoma (HCC) based on imaging the initial steps of phosphatidylcholine synthesis. To relate the diagnostic performance of [18F]fluorocholine positron emission tomography (PET)/x-ray computed tomography (CT) to the phospholipid composition of liver tumors, radiopathologic correspondence was performed in patients with early-stage liver cancer who had undergone [18F]fluorocholine PET/CT before tumor resection.Procedures: Tumor and adjacent liver were profiled by liquid chromatography mass spectrometry, quantifying phosphatidylcholine species by mass-to-charge ratio. For clinical-radiopathologic correlation, HCC profiles were reduced to two orthogonal principal component factors (PCF1 and PCF2) accounting for 80 % of total profile variation.Results: Tissues from 31 HCC patients and 4 intrahepatic cholangiocarcinoma (ICC) patients were analyzed, revealing significantly higher levels of phosphocholine, CDP-choline, and highly saturated phosphatidylcholine species in HCC tumors relative to adjacent liver and ICC tumors. Significant loading values for PCF1 corresponded to phosphatidylcholines containing poly-unsaturated fatty acids while PCF2 corresponded only to highly saturated phosphatidylcholines. Only PCF2 correlated significantly with HCC tumor-to-liver [18F]fluorocholine uptake ratio (ρ = 0.59, p < 0.0005). Sensitivity for all tumors based on an abnormal [18F]fluorocholine uptake ratio was 93 % while sensitivity for HCC based on increased tumor [18F]fluorocholine uptake was 84 %, with lower levels of highly saturated phosphatidylcholines in tumors showing low [18F]fluorocholine uptake.Conclusion: Most HCC tumors contain high levels of saturated phosphatidylcholines, supporting their dependence on de novo fatty acid metabolism for phospholipid membrane synthesis. While [18F]fluorocholine PET/CT can serve to identify these lipogenic tumors, its imperfect diagnostic sensitivity implies metabolic heterogeneity across HCC and a weaker lipogenic phenotype in some tumors. [ABSTRACT FROM AUTHOR]

Purpose This study evaluated expected tumor control and normal tissue toxicity for prostate volumetric modulated arc therapy (VMAT) with and without radiation boosts to an intraprostatically dominant lesion (IDL), defined by 18 F-choline positron emission tomography/computed tomography (PET/CT). Methods and Materials Thirty patients with localized prostate cancer underwent 18 F-choline PET/CT before treatment. Two VMAT plans, plan 79 Gy and plan 100-105 Gy , were compared for each patient. The whole-prostate planning target volume (PTV prostate ) prescription was 79 Gy in both plans, but plan 100-105 Gy added simultaneous boost doses of 100 Gy and 105 Gy to the IDL, defined by 60% and 70% of maximum prostatic uptake on 18 F-choline PET (IDL suv60% and IDL suv70% , respectively, with IDL suv70% nested inside IDL suv60% to potentially enhance tumor specificity of the maximum point dose). Plan evaluations included histopathological correspondence, isodose distributions, dose-volume histograms, tumor control probability (TCP), and normal tissue complication probability (NTCP). Results Planning objectives and dose constraints proved feasible in 30 of 30 cases. Prostate sextant histopathology was available for 28 cases, confirming that IDL suv60% adequately covered all tumor-bearing prostate sextants in 27 cases and provided partial coverage in 1 case. Plan 100-105 Gy had significantly higher TCP than plan 79 Gy across all prostate regions for α/β ratios ranging from 1.5 Gy to 10 Gy ( P <.001 for each case). There were no significant differences in bladder and femoral head NTCP between plans and slightly lower rectal NTCP (endpoint: grade ≥ 2 late toxicity or rectal bleeding) was found for plan 100-105 Gy . Conclusions VMAT can potentially increase the likelihood of tumor control in primary prostate cancer while observing normal tissue tolerances through simultaneous delivery of a steep radiation boost to a 18 F-choline PET-defined IDL. [ABSTRACT FROM AUTHOR]

Purpose: Radiolabeled methionine (Met) promises to be useful in the positron emission tomography (PET) imaging of hepatocellular carcinoma (HCC). However, its metabolic routes in HCC have not yet been fully understood. In this study, the metabolic pathway(s) of radiolabeled Met in HCC were investigated. Procedures: To simulate the rapid blood clearance of radiolabeled Met, pulse-chase experiments were conducted. l-[methyl-H]-Met or l-[1-C]-Met was pulsed over control or cycloheximide-treated WCH17 cells and rat hepatocytes for 5 min and chased with cold media. The water-soluble, lipid-soluble, DNA, RNA, and protein phases were subsequently extracted and measured from the acid-precipitable and acid-soluble fractions of whole cells. The radioactive metabolites Met, S-adenosylmethionine (SAM), S-adenosylhomocysteine, Met sulfoxide, and Met sulfone were further separated by radio thin layer chromatography. Results: (1) The uptake of l-[methyl-H]-Met in both cell types was higher than that of l-[1-C]-Met. In rat hepatocytes, the uptake of l-[methyl-H]-Met was significantly higher than that of l-[1-C]-Met, which may contribute to its physiologic accumulation in surrounding hepatic tissues seen in PET imaging of HCC using l-[methyl-C]-Met. Compared to rat hepatocytes, WCH17 cells had significantly higher uptake of both radiotracers. (2) For l-[methyl-H]-Met, the major intracellular uptake was found mostly in the protein phase and, to a lesser degree, in the phosphatidylethanolamine (PE) methylation pathway, which is fairly stabilized within the 55-min chase period (the main metabolites were SAM, Met, Met sulfoxide, and Met sulfone). In contrast, the uptake of Met in rat hepatocytes mainly points to phosphatidylcholine (PC) synthesis through the PE methylation pathway (the main metabolite was PC). (3) Both cell types incorporated l-[1-C]-Met predominantly into protein synthesis. (4) Finally, when the protein synthesis pathway was inhibited, the incorporation of SAM derived from l-[methyl-H]-Met to lipid class (PC was the main metabolite) occurred at a reduced rate in WCH17 cells, suggesting that the route may be impaired in HCC. Conclusions: This study demonstrated that different metabolic pathways of radiolabeled Met exist between HCC and surrounding hepatic tissue and contribute to the patterns of increased uptake of radiolabeled Met in HCC. [ABSTRACT FROM AUTHOR]

Purpose: Studies have established the value of [(methyl)1-(11)C]-acetate ([(11)C]Act) combined with 2-deoxy-2[(18)F]fluoro-D-glucose (FDG) for detecting hepatocellular carcinoma (HCC) using positron emission tomography (PET). In this study, the metabolic fate of [(11)C]Act in HCC was characterized.Methods: Experiments with acetic acid [1-(14)C] sodium salt ([(14)C]Act) were carried out on WCH-17 cells and freshly derived rat hepatocytes. PET scans with [(11)C]Act were also carried out on woodchucks with HCC before injection of [(14)C]Act. The radioactivity levels in different metabolites were quantified with thin-layer chromatography.Results: In WCH-17 cells, the predominant metabolite was phosphatidylcholine (PC). Regions of HCCs with the highest [(11)C]Act uptake had higher radioactivity accumulation in lipid-soluble compounds than surrounding hepatic tissues. In those regions, PC and triacylglycerol (TG) accumulated more radioactivity than in surrounding hepatic tissues.Conclusions: High [(11)C]Act uptake in HCC is associated with increased de novo lipogenesis. PC and TG are the main metabolites into which the radioactive label from [(11)C]Act is incorporated in HCC. [ABSTRACT FROM AUTHOR]

Abstract: A new spectrophotometric method for quantitation of acetyl-CoA synthetase (ACAS) activity is developed. It has been applied for ACAS assay in the liver tissues of a woodchuck model of hepatitis virus-induced hepatocellular carcinoma (HCC). The assay is based on the established pyrophosphate (PPi) detection system. ACAS activity is indexed by the amount of PPi, the product of ACAS reaction system of activated form of acetate (acetyl-CoA) with ACAS catalysis. PPi is determined quantitatively as the amount of chromophore formed with molybdate reagent, 1-amino-2-naphthol-4-sulfonic acid in bisulfite and 2-mercaptoethanol. PPi reacts with molybdate reagent to produce phosphomolybdate and PPi-molybdate complexes. 2-mercaptoethanol is responsible for color formation which has the peak absorbance at 580 nm. This method was sensitive from 1 to 20 nmol of PPi in a 380-μl sample (1-cm cuvette). A ten-fold excess of Pi did not interfere with the determination of PPi. To study the major metabolic pathways of imaging tracer [1-11C]-acetate in tumors for detection of HCC by Positron Emission Tomography (PET), the activity of one of the key enzymes involved in acetate or [1-11C]-acetate metabolism, ACAS was assayed by this newly developed assay in the tissue samples of woodchuck HCCs. A significant increase of ACAS activity was observed in the liver tissues of woodchuck HCCs as compared with neighboring regions surrounding the tumors (P <0.05). The respective ACAS activities in the subcellular locations were also significantly higher in HCCs than in the surrounding tissues (P <0.05) (total soluble fraction: 876.61±34.64 vs. 361.62±49.97 mU/g tissue; cytoplasmic fraction: 1122.02±112.39 vs. 732.32±84.44 mU/g tissue; organelle content: 815.79±100.77 vs. 547.91±97.05 mU/ g tissue; sedimentable fragment: 251.92±51.56 vs. 90.94±18.98 mU/ g tissue). The finding suggests an increase in ACAS activity in the liver cancer of woodchuck models of HCC as compared to that in the normal woodchuck liver. The developed assay is rapid, simple and accurate and is suitable for the investigation of ACAS activity under physiologic and pathophysiologic conditions. [Copyright &y& Elsevier]

Purpose: The Eastern woodchuck (Marmota monax) is considered as a naturally occurring animal model of hepatocellular carcinoma (HCC). The performance of 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) for imaging HCC on the woodchuck using Positron emission tomography (PET) was investigated in this study.Procedures: Dynamic FDG-PET scans were performed on five woodchucks with HCC and one healthy woodchuck before removal and processing of the liver tissues for histology. The parameters of a two-tissue compartment model with dual input were estimated using weighted least squares (WLS).Results: Ten HCCs were confirmed histologically. Six HCCs had a tumor-to-liver standardized uptake value (SUV) ratio < or =1.15, a k (4) / k (3) ratio similar to that in hepatic tissues and were well-differentiated. Four HCCs had a tumor-to-liver SUV ratio >1.15, a lower k (4) / k (3) ratio than the hepatic tissues and were moderately differentiated.Conclusions: Increased FDG uptake was observed in HCCs that were the least differentiated and correlated with a lower k (4) / k (3) ratio. [ABSTRACT FROM AUTHOR]