Time-synchronized 2-deoxy-2-[18F]fluoro-D-glucose PET/MRI with MR-active trigger and Bayesian penalized likelihood reconstruction: Diagnostic utility for locoregional extension of endometrial cancer.

PURPOSE: Minimal misregistration of fused PET and MRI images can be achieved with simultaneous positron emission tomography/magnetic resonance imaging (PET/MRI). However, the acquisition of multiple MRI sequences during a single PET emission scan may impair fusion precision of each sequence. This study evaluated the diagnostic utility of time-synchronized PET/MRI using an MR active trigger and a Bayesian penalized likelihood reconstruction algorithm (BPL) to assess the locoregional extension of endometrial cancer. METHODS: Fifty-five patients with endometrial cancer who underwent pelvic 2-deoxy-2-[18F]fluoro-D-glucose PET/MRI were retrospectively evaluated. The PET emission time for the BPL reconstruction was determined by the MR active trigger of each MR sequence. The concordance rates of image interpretation with pathological T-staging, diagnostic performance for deep myometrial invasion (MI), and diagnostic confidence levels were evaluated by two readers and compared between time-synchronized, overlapping (conventional and simultaneous, but not time-synchronized), and sequential (not simultaneous) PET/MRI and MRI with diffusion-weighted imaging. Misregistration of the PET/MRI-fused images was determined by evaluating the differences in bladder dimensions. RESULTS: The T classification by time-synchronized PET/MRI was the most concordant with the pathological T classification for the two readers. Time-synchronized PET/MRI had a significantly higher diagnostic performance for deep MI and higher confidence level scores than overlapping PET/MRI for the novice reader (p = 0.033 and p = 0.038, respectively). The differences in bladder dimension on sequential PET/MRI were significantly larger than those on overlapping and time-synchronized PET/MRI (p <0.001). CONCLUSION: Time-synchronized PET/MRI is superior to conventional PET/MRI for assessing the locoregional extension of endometrial cancer.

Rapid Whole-Body FDG PET/MRI in Oncology Patients: Utility of Combining Bayesian Penalised Likelihood PET Reconstruction and Abbreviated MRI.

This study evaluated the diagnostic value of a rapid whole-body fluorodeoxyglucose (FDG) positron emission tomography (PET)/magnetic resonance imaging (MRI) approach, combining Bayesian penalised likelihood (BPL) PET with an optimised ß value and abbreviated MRI (abb-MRI). The study compares the diagnostic performance of this approach with the standard PET/MRI that utilises ordered subsets expectation maximisation (OSEM) PET and standard MRI (std-MRI). The optimal ß value was determined by evaluating the noise-equivalent count (NEC) phantom, background variability, contrast recovery, recovery coefficient, and visual scores (VS) for OSEM and BPL with ß100-1000 at 2.5-, 1.5-, and 1.0-min scans, respectively. Clinical evaluations were conducted for NECpatient, NECdensity, liver signal-to-noise ratio (SNR), lesion maximum standardised uptake value, lesion signal-to-background ratio, lesion SNR, and VS in 49 patients. The diagnostic performance of BPL/abb-MRI was retrospectively assessed for lesion detection and differentiation in 156 patients using VS. The optimal ß values were ß600 for a 1.5-min scan and ß700 for a 1.0-min scan. BPL/abb-MRI at these ß values was equivalent to OSEM/std-MRI for a 2.5-min scan. By combining BPL with optimal ß and abb-MRI, rapid whole-body PET/MRI could be achieved in ≤1.5 min per bed position, while maintaining comparable diagnostic performance to standard PET/MRI.

Diagnostic performance of zero-TE lung MR imaging in FDG PET/MRI for pulmonary malignancies.

OBJECTIVES: This study aimed to evaluate the diagnostic performance of the lung zero-echo time (ZTE) sequence in FDG PET/MRI for detection and differentiation of lung lesions in oncologic patients in comparison with conventional two-point Dixon-based MR imaging. METHODS: In this single-institution retrospective study approved by the institutional review board, 209 patients with malignancies (97 men and 112 women; age range, 17-89 years; mean age, 66.5 ± 12.9 years) underwent 18F-FDG PET/MRI between August 2017 and August 2018, with diagnostic Dixon and ZTE under respiratory gating acquired simultaneously with PET. Image analysis was performed for PET/Dixon and PET/ZTE fused images by two readers to assess the detectability and differentiation of lung lesions. The reference standard was pathological findings and/or the data from a chest CT. The detection and differentiation abilities were evaluated for all lesions and subgroups divided by lesion size and maximum standardized uptake value (SUVmax). RESULTS: Based on the reference standard, 227 lung lesions were identified in 113 patients. The detectability of PET/ZTE was significantly better than that of PET/Dixon for overall lesions, lesions with a SUVmax less than 3.0 and lesions smaller than 4 mm (p < 0.01). The diagnostic performance of PET/ZTE was significantly better than that of PET/Dixon for overall lesions and lesions smaller than 4 mm (p < 0.01). CONCLUSIONS: ZTE can improve diagnostic performance in the detection and differentiation of both FDG-avid and non-FDG-avid lung lesions smaller than 4 mm in size, yielding a promising tool to enhance the utility of FDG PET/MRI in oncology patients with lung lesions. KEY POINTS: • The detection rate of PET/ZTE for lesions with a SUVmax of less than 1.0 was significantly better than that of PET/Dixon. • The performance for differentiation of PET/ZTE for lesions that were even smaller than 4 mm in size were significantly better than that of PET/Dixon. • Inter-rater agreement of PET/ZTE for the differentiation of lesions less than 4 mm in size was substantial and better than that of PET/Dixon.

Preoperative risk stratification using metabolic parameters of (18)F-FDG PET/CT in patients with endometrial cancer.

PURPOSE: To evaluate the usefulness of metabolic parameters obtained by (18)F-FDG PET/CT for preoperative stratification of high-risk and low-risk endometrial carcinomas. METHODS: Preoperative (18)F-FDG PET/CT was performed in 56 women with endometrial cancer. Maximum standardized uptake values (SUVmax), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) of primary tumours were compared with clinicopathological features of surgical specimens. Diagnostic performance in terms of differentiation of low-risk disease (endometrioid histology, histological grade 1 or 2, invasion of less than half of the myometrium, and FIGO stage I) from high-risk disease was assessed. RESULTS: MTV and TLG were significantly higher in patients with higher histological grade (p = 0.0026 and p = 0.034), larger tumour size (p = 0.002 and p = 0.0017), lymphovascular space involvement (LVSI; p = 0.012 and p = 0.0051), myometrial invasion (p = 0.027 and p = 0.031), cervical stromal invasion (p = 0.023 and p = 0.014), ovarian metastasis (p = 0.00022 and p = 0.00034), lymph node metastasis (p < 0.0001 and p < 0.0001), and higher FIGO stage (p = 0.0011 and p = 0.00048). SUVmax was significantly higher in patients with larger tumour size (p = 0.0025), LVSI (p = 0.00023) and myometrial invasion (p < 0.0001). The areas under the ROC curves (AUCs) for distinguishing high-risk from low-risk carcinoma were 0.625, 0.829 and 0.797 for SUVmax, MTV and TLG, respectively. AUCs for both MTV and TLG were significantly larger than that for SUVmax (p = 0.0049 and p = 0.021). The optimal TLG cut-off value of 70.2, determined by ROC analysis, was found to have 72.0% sensitivity and 74.2% specificity for risk stratification. CONCLUSION: MTV and TLG of primary endometrial cancer show better correlations with clinicopathological features and are more useful for differentiating high-risk from low-risk carcinoma than SUVmax.

Neutral biodegradable lipid-envelope-type nanoparticle using vitamin A-Scaffold for nuclear targeting of plasmid DNA.

Biomembranes and cytoplasm, a diffusion-limited region for nanoparticles are critical barriers to be overcome for the successful gene delivery. We herein report on a neutral, and intracellularly degradable lipid nanoparticle (LNP), containing encapsulated plasmid DNA (pDNA) that can be effectively delivered to the nucleus. A key material component in this particle is a vitamin A-scaffold SS-cleavable Proton-Activated Lipid-like Material ((SS)PalmA), which contains tertiary amine groups as proton sponge units that can respond to the acidic pH in endosomes, disulfide bonding for programmed collapse in the cytoplasm, and retinoic acid (RA) as a hydrophobic unit for assembly into LNP. LNP prepared using (SS)PalmA (LNP(PalmA)) exhibited a 15-fold higher gene expression activity compared to particles prepared with a simple acyl chain (myristoyl group)-scaffold one (LNPPalmM). Intracellular imaging studies revealed that LNP(PalmA) unexpectedly showed excessive endosome-disruptive characteristics. Furthermore, the decapsulation of pDNA slowly, but successively occurred in parallel with peri-nuclear accumulation. Nuclear targeting was blocked in the presence of native RA. Collectively, LNP(PalmA) is an intelligent particle that passes through the cytoplasm in particle form with the aid of the intrinsic nuclear transport system of RA, and thereafter releases its encapsulated pDNA for effective gene expression.

The application of pH-sensitive polymer-lipids to antigen delivery for cancer immunotherapy.

For production of pH-sensitive liposomes, we developed pH-sensitive polymer-lipids that consists of pH-sensitive fusogenic polymer moieties such as 3-methyl glutarylated poly(glycidol) and 2-carboxycyclohexane-1-carboxylated poly(glycidol), connected to a phosphatidylethanolamine head group. Incorporation of these pH-sensitive polymer-lipids into egg yolk phosphatidylcholine liposomes produced highly pH-sensitive liposomes that were stable at neutral pH but which destabilized markedly in response to very small pH change in weakly acidic pH region. These liposomes delivered their contents (pyranine) into cytosol of dendritic cell-derived DC2.4 cells. When these polymer-lipid-incorporated liposomes loaded with antigenic protein ovalbumin (OVA) were administered subcutaneously to mice, the antigen-specific cellular immunity was induced efficiently in the mice. Furthermore, immunization of mice with these OVA-loaded pH-sensitive polymer-lipid-incorporated liposomes induced strong OVA-specific immunity, which achieved complete rejection of OVA-expressing E.G7-OVA cells and marked regression of E.G7-OVA tumors.

A neutral envelope-type nanoparticle containing pH-responsive and SS-cleavable lipid-like material as a carrier for plasmid DNA.

SS-cleavable proton-activated lipid-like material (ssPalm) functions as a key element in a lipid nanoparticle in which pDNA is encapsulated. The ssPalm contains dual sensing motifs that can respond to the intracellular environment; a proton-sponge unit (tertiary amines) that functions in response to an acidic environment (endosome/lysosome), and disulfide bonding that can be cleaved in a reducing environment (cytosol).

Compensatory expression of MRP3 in the livers of MRP2-deficient EHBRs is promoted by DHA intake.

We have hypothesized a suppressive mechanism against dietary docosahexaenoic acid (22:6n-3; DHA)-induced tissue lipid peroxidation, in which the degradation products, including their conjugates, are excreted into the urine by xenobiotic or organic anion transporters. In this study, we employed parent-strain Sprague-Dawley rats (SDRs), together with their mutant strain, Eisai hyperbilirubinuria rats (EHBRs). EHBRs are deficient in multidrug resistance-associated protein (MRP) 2, and show defective urinary excretion of numerous xenobiotics and organic anions. Both strains of rats were fed a diet containing DHA at 8.4% of total energy for 31 d. In the livers of the DHA-fed rats, the level of free malondialdehyde (MDA) + 4-hydroxy-2-alkenals (HAE) fell, and conversely glutathione S-transferase (GST) activity increased in MRP2-deficient EHBRs as compared to the SDRs, suggesting that the glutathione (GSH)-conjugation reaction for the aldehydes generated on DHA intake was accelerated in the MRP2-deficient EHBRs. Since the gene expression of liver MRP3 in the MRP2-deficient EHBRs was amplified to compensate for DHA intake, it is thought that the transport of MRP3 substrates into the bloodstream, rather than MRP2-mediated excretion of its substrates into the bile, was promoted. Indeed, excretion of mercapturic acid (acetylcysteine conjugates derived metabolically from the conjugate of each aldehyde with GSH) into the urine increased significantly in MRP2-deficient EHBRs fed DHA.

The effects of the extent of spinal block on the BIS score and regional cerebral oxygen saturation in elderly patients: A prospective, randomized, and double-blinded study.

BACKGROUND: Patients may become sedated with spinal anesthesia; however, the effect of the extent of spinal block on the Bispectral index (BIS), a processed electroencephalographic variable, has not been fully investigated. We evaluated the influence of the extent of spinal block on BIS values and on regional cerebral oxygen saturation (rSO(2)) in elderly patients. METHODS: A prospective, randomized, double-blinded study was performed in 55 ASA II patients undergoing urological surgery. The patients were randomly allocated into one of two groups to receive 2.7 ml of 0.5% hyperbaric bupivacaine or 1.5 ml, and then divided into two groups according to level of spinal blockade: high spinal group (Th6 and above) or low spinal group (Th12 and below). Systolic blood pressure (SBP), heart rate (HR), cardiac output (CO), stroke volume (SV), BIS values, and rSO(2) were measured for 30 min. CO and SV were evaluated using impedance cardiograph methods. RESULTS: The level of spinal blockade was Th4.7 +/- 1.0 in high spinal group (n = 20) and L2.5 +/- 2.2 in low spinal group (n = 20). High spinal anesthesia produced a significant decrease in SBP (p < 0.01) and SV (p < 0.01), but had no effect on CO. High spinal anesthesia significantly decreased BIS values (p < 0.01) without affecting rSO(2). There was relationship between level of spinal blockade and BIS values (r = 0.566). In contrast, no changes in above parameters were found in low spinal group. CONCLUSIONS: This study provides evidence that the extent of spinal block may have significant influence on BIS values without affecting rSO(2) in elderly patients.

The effects of volatile anesthetics on intraoperative monitoring of myogenic motor-evoked potentials to transcranial electrical stimulation and on partial neuromuscular blockade during propofol/fentanyl/nitrous oxide anesthesia in humans.

The aim of the present study was to compare the influence of volatile anesthetics on transcranial motor-evoked potentials (tcMEP) in humans anesthetized with propofol/fentanyl/nitrous oxide and on partial neuromuscular blockade (NMB). The authors studied 35 ASA I and II patients who were undergoing elective craniotomy and brain tumor resection. The patients were randomized to one of three groups to receive halothane (HAL), isoflurane (ISO), or sevoflurane (SEV). Anesthetic depth was initially adjusted using the bispectral index to 40+/-5, and NMB was adjusted to 40%-50% of one twitch of train of four (T1) after recovery from intubation. MEPs with train of five square-wave pulses were elicited using screw electrodes placed in the skull over C3-C4. After craniotomy, the inhalational agent was introduced at 0.5 MAC and then 1.0 MAC (20 minutes each), and the effects on MEPs, NMB, and hemodynamic variables were studied. A decrease in BIS and systolic blood pressure was observed with all agents. Both SEV and ISO at 1.0 MAC significantly decreased train-of-four ratio from 38.4+/-18.1 at control to 19.0+/-9.7 and from 35.3+/-12.4 to 26.1+/-13.7, respectively (P<0.001), but not HAL at 1.0 MAC. The amplitudes of tcMEPs were significantly reduced by all agents at 1.0 MAC, with the effect being less in HAL at 0.5 MAC. We have shown that HAL had a lesser suppressive effect on MEPs than either ISO or SEV at 0.5 MAC, which was partially due to a lesser degree of NMB.

Dietary docosahexaenoic acid-induced generation of liver lipid peroxides is not suppressed further by elevated levels of glutathione in ODS rats.

OBJECTIVES: We examined the effects of ascorbic acid (AsA) and glutathione (GSH; experiment 1) and of GSH in acetaminophen-fed rats (experiment 2) on dietary docosahexaenoic acid (DHA)-induced tissue lipid peroxidation. METHODS: In experiment 1, AsA-requiring Osteogenic Disorder Shionogi/Shi-od/od (ODS) rats were fed soybean protein diets containing DHA (10.0% total energy) and AsA at 50 (low) or 300 (normal) mg/kg without (low) or with (normal) methionine at 2 g/kg for 32 d. In experiment 2, ODS rats were fed diets containing DHA (7.8% total energy) and acetaminophen (4 g/kg) with different levels of dietary methionine (low, moderate, high, and excessive at 0, 3, 6, and 9 g/kg, respectively) for 30 d. Tissue lipid peroxides and antioxidant levels were determined. RESULTS: In experiment 1, liver lipid peroxide levels in the low-AsA group were lower than those in the normal-AsA group, but kidney and testis lipid peroxide levels in the low-AsA group were higher than those in the normal-AsA group. Dietary methionine tended to decrease tissue lipid peroxide levels but did not decrease vitamin E (VE) consumption. In experiment 2, a high level of methionine (6 g/kg) decreased liver lipid peroxide levels and VE consumption. However, generation of tissue lipid peroxides and VE consumption were not decreased further by a higher dose of methionine (9 g/kg). CONCLUSIONS: Higher than normal levels of dietary methionine are not necessarily associated with decreased dietary DHA-induced generation of tissue lipid peroxides and VE consumption except that the GSH requirement is increased in a condition such as acetaminophen feeding.

Dietary docosahexaenoic acid-induced production of tissue lipid peroxides is not suppressed by higher intake of ascorbic acid in genetically scorbutic Osteogenic Disorder Shionogi/Shi-od/od rats.

In previous studies, we showed that docosahexaenoic acid (DHA) ingestion enhanced the susceptibility of rat liver and kidney to lipid peroxidation, but did not increase lipid peroxide formation to the level expected from the relative peroxidizability index (P-index) of the total tissue lipids. The results suggested the existence of some suppressive mechanisms against DHA-induced tissue lipid peroxide formation, as increased tissue ascorbic acid (AsA) and glutathione levels were observed. Therefore, we focused initially on the role of AsA for the suppressive mechanisms. For this purpose, we examined the influence of different levels of dietary AsA (low, moderate, high and excessive levels were 100, 300 (control), 600 and 3000 mg/kg diet respectively) on the tissue lipid peroxide and antioxidant levels in AsA-requiring Osteogenic Disorder Shionogi/Shi-od/od (ODS) rats fed DHA (6.4 % total energy) for 32 or 33 d. Diets were pair-fed to the DHA- and 100 mg AsA/kg diet-fed group. We found that the lipid peroxide concentrations of liver and kidney in the DHA-fed group receiving 100 mg AsA/kg diet were significantly higher or tended to be higher than those of the DHA-fed groups with AsA at more than the usual control level of 300 mg/kg diet. Contrary to this, the liver alpha-tocopherol concentration was significantly lower or tended to be lower in the DHA and 100 mg AsA/kg diet-fed group than those of the other DHA-fed groups. However, tissue lipid peroxide formation and alpha-tocopherol consumption were not suppressed further, even after animals received higher doses of AsA. The present results suggest that higher than normal concentrations of tissue AsA are not necessarily associated with the suppressive mechanisms against dietary DHA-induced tissue lipid peroxide formation.