Determination of brain tumor recurrence using 11 C-methionine positron emission tomography after radiotherapy.

We conducted a prospective multicenter trial to compare the usefulness of 11 C-methionine (MET) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for identifying tumor recurrence. Patients with clinically suspected tumor recurrence after radiotherapy underwent both 11 C-MET and 18 F-FDG PET. When a lesion showed a visually detected uptake of either tracer, it was surgically resected for histopathological analysis. Patients with a lesion negative to both tracers were revaluated by magnetic resonance imaging (MRI) at 3 months after the PET studies. The primary outcome measure was the sensitivity of each tracer in cases with histopathologically confirmed recurrence, as determined by the McNemar test. Sixty-one cases were enrolled, and 56 cases could be evaluated. The 38 cases where the lesions showed uptake of either 11 C-MET or 18 F-FDG underwent surgery; 32 of these cases were confirmed to be subject to recurrence. Eighteen cases where the lesions showed uptake of neither tracer received follow-up MRI; the lesion size increased in one of these cases. Among the cases with histologically confirmed recurrence, the sensitivities of 11 C-MET PET and 18 F-FDG PET were 0.97 (32/33, 95% confidence interval [CI]: 0.85-0.99) and 0.48 (16/33, 95% CI: 0.33-0.65), respectively, and the difference was statistically significant (P < .0001). The diagnostic accuracy of 11 C-MET PET was significantly better than that of 18 F-FDG PET (87.5% vs. 69.6%, P = .033). No examination-related adverse events were observed. The results of the study demonstrated that 11 C-MET PET was superior to 18 F-FDG PET for discriminating between tumor recurrence and radiation-induced necrosis.

Met-PET uptake index for total tumor resection: identification of 11C-methionine uptake index as a goal for total tumor resection including infiltrating tumor cells in glioblastoma.

Glioblastoma multiforme (GBM) is largely due to glioma stem cells (GSCs) that escape from total resection of gadolinium (Gd)-enhanced tumor on MRI. The aim of this study is to identify the imaging requirements for maximum resection of GBM with infiltrating GSCs. We investigated the relationship of tumor imaging volume between MRI and 11C-methionine (Met)-PET and also the relationship between Met uptake index and tumor activity. In ten patients, tumor-to-contralateral normal brain tissue ratio (TNR) was calculated to evaluate metabolic activity of Met uptake areas which were divided into five subareas by the degrees of TNR. In each GBM, tumor tissue was obtained from subareas showing the positive Met uptake. Immunohistochemistry was performed to examine the tumor proliferative activity and existence of GSCs. In all patients, the volume of Met uptake area at TNR ≦ 1.4 was larger than that of the Gd-enhanced area. The Met uptake area at TNR 1.4 beyond the Gd-enhanced tumor was much wider in high invasiveness-type GBMs than in those of low invasiveness type, and survival was much shorter in the former than the latter types. Immunohistochemistry revealed the existence of GSCs in the area showing Met uptake at TNR 1.4 and no Gd enhancement. Areas at TNR > 1.4 included active tumor cells with relatively high Ki-67 labeling index. In addition, it was demonstrated that GSCs could exist beyond the border of Gd-enhanced tumor. Therefore, to obtain maximum resection of GBMs, including infiltrating GSCs, aggressive surgical excision that includes the Met-positive area at TNR 1.4 should be considered.

Critical transporters of methionine and methionine hydroxyl analogue supplements across the intestine: What we know so far and what can be learned to advance animal nutrition.

DL-methionine (DL-Met) and its analogue DL-2-hydroxy-4-(methylthio) butanoic acid (DL-methionine hydroxyl analogue or DL-MHA) have been used as nutritional supplements in the diets of farmed raised animals. Knowledge of the intestinal transport mechanisms involved in these products is important for developing dietary strategies. This review provides updated information of the expression, function, and transport kinetics in the intestine of known Met-linked transporters along with putative MHA-linked transporters. As a neutral amino acid (AA), the transport of DL-Met is facilitated by multiple apical sodium-dependent/-independent high-/low-affinity transporters such as ASCT2, B0AT1 and rBAT/b0,+AT. The basolateral transport largely relies on the rate-limiting uniporter LAT4, while the presence of the basolateral antiporter y+LAT1 is probably necessary for exchanging intracellular cationic AAs and Met in the blood. In contrast, the intestinal transport kinetics of DL-MHA have been scarcely studied. DL-MHA transport is generally accepted to be mediated simply by the proton-dependent monocarboxylate transporter MCT1. However, in-depth mechanistic studies have indicated that DL-MHA transport is also achieved through apical sodium monocarboxylate transporters (SMCTs). In any case, reliance on either a proton or sodium gradient would thus require energy input for both Met and MHA transport. This expanding knowledge of the specific transporters involved now allows us to assess the effect of dietary ingredients on the expression and function of these transporters. Potentially, the resulting information could be furthered with selective breeding to reduce overall feed costs.

Relative availability of metabolizable methionine from 2 ruminally protected sources of methionine fed to lactating dairy cattle.

Our objective was to evaluate the lactational responses of dairy cows to methionine provided from 2 ruminally protected sources of methionine activity. Twenty-one Holstein dairy cows [11 primiparous (634 kg of body weight, 140 d in milk) and 10 second-parity (670 kg of body weight, 142 d in milk)] were assigned to a treatment sequence in 4 replicated 5 × 5 Latin squares plus 1 cow, with 14-d periods. Treatments were as follows: control; 7.5 or 15 g/d of a ruminally protected product of 2-hydoxy-4-methylthio-butyric acid (NTP-1401; Novus International Inc., St. Charles, MO); or 7.5 or 15 g/d of a ruminally protected dl-methionine product (Smartamine M; Adisseo, Alpharetta, GA). The diet was predicted to meet metabolizable protein and energy requirements. Diets contained 16.1% crude protein, and the control diet was predicted to be deficient in metabolizable methionine (1.85% of metabolizable protein) but sufficient in lysine (6.8% of metabolizable protein). Feed intake and milk yield were measured on d 11 to 14. Blood was collected on d 14. Dry matter intake, milk yield, energy-corrected milk, milk fat yield and percentage, and efficiencies of milk and energy-corrected milk yield were not affected by treatment. Milk protein percentage and milk protein yield increased linearly with supplementation, without differences between methionine sources or interactions between source and level. Linear regressions of milk protein percentage and milk protein yield against supplement amount within source led to slope ratios (NTP-1401:Smartamine M) of 95% for protein percentage and 84% for protein yield, with no differences between sources for increasing milk protein. Plasma methionine concentrations were increased linearly by methionine supplementation; the increase was greater for Smartamine M than for NTP-1401. Plasma d-methionine was increased only by Smartamine M. Plasma 2-hydoxy-4-methylthio-butyric acid was increased only by NTP-1401. Our data demonstrated that supplementation with these methionine sources can improve milk protein percentage and yield, and the 2 methionine sources did not differ in their effect on lactation performance or milk composition.

Bioavailable Methionine Assessed Using the Indicator Amino Acid Oxidation Method Is Greater When Cooked Chickpeas and Steamed Rice Are Combined in Healthy Young Men.

BACKGROUND: In general, pulse protein is limiting in the indispensable amino acid methionine, and antinutritional factors in pulses can affect methionine bioavailability. Complementation with grains such as rice can improve pulse protein quality, but knowledge of methionine bioavailability in pulses and grains is necessary to correct for available methionine when planning and assessing dietary protein intake. OBJECTIVES: The study objectives were to determine the bioavailability of methionine in rice and chickpeas separately and to assess the effect of complementation of chickpeas and rice. METHODS: Eleven healthy young men (<30 y, BMI <25 kg/m2) were studied in a repeated-measures design using the indicator amino acid oxidation (IAAO) method, with l-[1-13C]phenylalanine as the indicator. Each received 7 or 10 methionine intakes in random order: 4 intakes of l-methionine-0.5, 1, 2, and 3 mg⋅kg-1⋅d-1 (reference diet); 3 intakes of methionine from rice and from chickpeas; and 3 intakes from the mixed meal of chickpeas plus rice (test diets). The bioavailability of methionine and the effect of complementation were assessed by comparing the IAAO response to varying intakes of methionine in rice, in cooked Canadian chickpeas, and in rice plus chickpeas combined compared with the IAAO response to l-methionine intakes in the reference protein (crystalline amino acid mixture patterned after egg protein) using the slope ratio method. RESULTS: The bioavailability of methionine from rice and from chickpeas was 100% and 63%, respectively. Complementation of cooked chickpeas with rice decreased the oxidation of l-[1-13C]phenylalanine by up to 14% (P < 0.05), suggesting an improved protein quality of the combined chickpeas plus rice protein. CONCLUSIONS: When chickpeas are the main protein source in the diet of young adult men, the combination of rice and chickpeas in a 3:1 ratio is recommended to improve dietary protein quality. This trial was registered at clinicaltrials.gov as NCT03339154 and NCT03674736.

The association between 11C-methionine uptake, IDH gene mutation, and MGMT promoter methylation in patients with grade II and III gliomas.

AIM: To evaluate the association between 11C-methionine positron-emission tomography (11C-methionine PET) findings, isocitrate dehydrogenase (IDH) gene mutation, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in patients with grade II and III gliomas. MATERIALS AND METHODS: Data were collected from 40 patients with grade II and III gliomas who underwent both magnetic resonance imaging (MRI) and 11C-methionine PET as part of their pre-surgical examination. IDH mutation was examined via DNA sequencing, and MGMT promoter methylation via quantitative methylation-specific polymerase chain reaction (PCR). RESULTS: A threshold of MGMT promoter methylation of 1% was significantly associated with tumour/normal tissue (T/N) ratio. The T/N ratio in samples with MGMT promoter methylation ≥1% was higher than that in samples with MGMT promoter methylation <1%, and the difference was statistically significant (p=0.011). Reliable prediction of MGMT promoter methylation (<1% versus ≥1%) was possible using the T/N ratio under the receiver operator characteristic (ROC) curve with a sensitivity and specificity of 75% each (cut-off value=1.6: p=0.0226, area under the ROC curve [AUC]=0.76172). Conversely, the T/N ratio had no association with IDH mutation (p=0.6). The ROC curve revealed no reliable prediction of IDH mutation using the T/N ratio (p=0.606, AUC=0.60577). CONCLUSION: 11C-methionine PET parameters can predict MGMT promoter methylation but not IDH mutation status. 11C-methionine uptake may have limited potential to reflect DNA methylation processes in grade II and III gliomas.

Dipicolylamine/Metal Complexes that Promote Direct Cell-Membrane Penetration of Octaarginine.

Marked promotion of membrane permeation of a cell-penetrating peptide, octaarginine (R8), was attained by attachment to a single 2,2'-dipicolylamine moiety (DPA-R8) that forms 1:1 complexes with metal ions. Studies using giant unilamellar vesicles demonstrated that DPA targets phospholipids and enhances R8 binding to the membranes in the presence of metal ions. While DPA/Zn(II) complex has been most frequently employed for chelate formation with phosphates, Ni(II) had the most prominent effect on the membrane binding and penetration of DPA-R8. Facile cytosolic distribution of DPA-R8 was also attained in a few minutes in the presence of Ni(II). Analysis of the cellular uptake methods of DPA-R8/Ni(II) suggested the involvement of direct permeation through cell membrane without the use of endocytosis. The applicability of this system to the intracellular delivery of bioactive compounds was exemplified using a peptidomimetic farnesyltransferase inhibitor, FTI277.

Preclinical evaluation of an 18F-trifluoroborate methionine derivative for glioma imaging.

PURPOSE: 11C-methionine (MET) is one of the most commonly used amino acid tracers for PET imaging of brain tumors. In this study, we report an 18F-labeled boron-derived methionine analogue, denoted as 18F-B-MET, as a potential substitute of 11C-MET for glioma PET imaging. METHODS: 19F-B-MET was synthesized from readily available chemicals according to our previous publication. For kit development, 19F-B-MET was aliquoted in quantities of 10 nmol for on-demand one-step labeling. The 18F-labeling was performed by 18F-19F isotope exchange, and quality control was performed by both HPLC and radio-TLC. Uptake of the tracer was determined in GL26, C6 and U87 tumor cells. PET imaging and the biodistribution assay were performed on mice bearing subcutaneous or orthotopic C6 and U87 tumor xenografts. RESULTS: Starting with 740-1110 MBq 18F-fluoride, >370 MBq of 18F-B-MET was obtained in 25 min (n = 5) with >99% purity and high specific activity (>37 GBq/µmol). 18F-B-MET demonstrated excellent in vitro stability with <1% decomposition after incubation with plasma for 2 h. In vitro cell uptake assay showed that 18F-B-MET accumulated in tumor cells in a time dependent manner and could be competitively inhibited by natural methionine and other L-type transporter transported amino acids. In vivo biodistribution and imaging studies showed high tumor accumulation (2.99 ± 0.23 %ID/g, n = 6) compared with low uptake of brain (0.262 ± 0.05 %ID/g, n = 6) at 60 min after injection in a subcutaneous C6 tumor model. Orthotropic C6 and U87 tumors were clearly visualized with high tumor to brain ratios at 60 min post-injection, corroborating with tumor L-type amino acid transporter 1 (LAT-1) expression levels. CONCLUSION: 18F-B-MET was radiolabeled with high yield in a one-step labeling process, showed excellent pharmacokinetic properties in vivo, with high tumor-to-brain contrast.

2-Hydroxy-4-methylthio butanoic acid and DL-methionine for Japanese quails in production.

An experiment was performed using 1,000 laying Japanese quails to assess the availability of two alternative dietary methionine sources. Treatment 01 = Basal Feed that is deficient in digestible methionine + cystine (Met + Cys). The other treatments were constituted by Met + Cys levels of 0.8, 1.60 and 2.40 g/kg, supplemented with DL-Methionine-99%, HMTBA-88% and HMTBA-84%, being 10 treatments in total. The following characteristics were studied: feed intake (g/bird/day), egg production (egg/day × 100), egg weight (g/egg), egg mass (g/egg), feed conversion per egg dozen (kg feed/dozen eggs), feed conversion per egg mass (kg feed/kg eggs), relative yolk weight (g/100 g of egg), relative albumen weight (g/100 g of egg), relative shell weight (g/100 g of egg), shell thickness (mm) and specific gravity (g/cm3 ). In general result comment, supplemental methionine sources must be included in the poultry diet. The different methionine sources affect the performance of quails, and the increase in the levels within each source improves the performance variables. Significant effect was observable on performance variables and egg quality variables, being that DLM-99% is superior to the other sources. The HMTBA-88% source is superior to the HMTBA-84% source for the same aforementioned variables. In conclusion, the bioefficacy values of the HMTBA-88% and HMTBA-84% sources compared to the DLM-99% source on an equimolar basis were 81 and 79%, respectively, for the performance variables, and 83 and 74 while the methionine sources were equivalent for the variables related to egg quality.

18F-FBPA as a tumor-specific probe of L-type amino acid transporter 1 (LAT1): a comparison study with 18F-FDG and 11C-Methionine PET.

PURPOSE: The purpose of this study was to evaluate the usefulness of L-4-borono-2-18F-fluoro-phenylalanine (18F-FBPA) as a tumor-specific probe, in comparison to 18F-FDG and 11C-methionine (Met), focusing on its transport selectivity by L-type amino acid transporter 1 (LAT1), which is highly upregulated in cancers. METHODS: Cellular analyses of FBPA were performed to evaluate the transportablity and Km value. PET studies were performed in rat xenograft models of C6 glioma (n = 12) and in rat models of turpentine oil-induced subcutaneous inflammation (n = 9). The kinetic parameters and uptake values on static PET images were compared using the one-tissue compartment model (K1, k2) and maximum standardized uptake value (SUVmax). RESULTS: The cellular analyses showed that FBPA had a lower affinity to a normal cell-type transporter LAT2 and induced less efflux through LAT2 among FBPA, Met, and BPA, while the efflux through LAT1 induced by FBPA was similar among the three compounds. The Km value of 18F-FBPA for LAT1 (196.8 ± 11.4 µM) was dramatically lower than that for LAT2 (2813.8 ± 574.5 µM), suggesting the higher selectivity of 18F-FBPA for LAT1. K1 and k2 values were significantly smaller in 18F-FBPA PET (K1 = 0.04 ± 0.01 ml/ccm/min and k2 = 0.07 ± 0.01 /min) as compared to 11C-Met PET (0.22 ± 0.09 and 0.52 ± 0.10, respectively) in inflammatory lesions. Static PET analysis based on the SUVmax showed significantly higher accumulation of 18F-FDG in the tumor and inflammatory lesions (7.2 ± 2.1 and 4.6 ± 0.63, respectively) as compared to both 18F-FBPA (3.2 ± 0.40 and 1.9 ± 0.19) and 11C-Met (3.4 ± 0.43 and 1.6 ± 0.11). No significant difference was observed between 18F-FBPA and 11C-Met in the static PET images. CONCLUSION: This study shows the utility of 18F-FBPA as a tumor-specific probe of LAT1 with low accumulation in the inflammatory lesions.

Accumulation of 11C-methionine in the normal pituitary gland on 11C-methionine PET.

Background For pituitary tumors, positron emission tomography (PET) with 11C-methonine (MET) has been reported as feasible to facilitate diagnosis. MET is well-known to accumulate in the normal pituitary glands, but almost no studies have examined the degree of MET accumulation in the normal pituitary gland. Purpose To investigate accumulation of MET in normal pituitary gland on PET/CT. Material and Methods Among patients who underwent PET/CT using MET over the past 7 years, 77 patients who fulfilled our criteria for normal pituitary glands were retrospectively selected. Maximum standardized uptake value (SUVmax) for the pituitary gland was measured. Results SUVmax of MET in the pituitary gland was in the range of 0.9-6.6 (mean ± standard deviation = 2.60 ± 1.04). A negative correlation between SUVmax and patient age (y = -0.032 × + 4.29, n = 77, r = 0.55) was found by linear regression analysis. SUVmax of the pituitary gland did not differ significantly between women and men. Conclusion MET shows strong accumulation in normal pituitary gland. PET/CT would thus be feasible to differentiate between normal and abnormal pituitary glands.

Homocysteinemia control by cysteine in cerebral vascular patients after methionine loading test: evidences in physiological and pathological conditions in cerebro-vascular and multiple sclerosis patients.

The toxicity risk of hyperhomocysteinemia is prevented through thiol drug administration which reduces plasma total homocysteine (tHcy) concentrations by activating thiol exchange reactions. Assuming that cysteine (Cys) is a homocysteinemia regulator, the hypothesis was verified in healthy and pathological individuals after the methionine loading test (MLT). The plasma variations of redox species of Cys, Hcy, cysteinylglycine, glutathione and albumin (reduced, HS-ALB, and at mixed disulfide, XSS-ALB) were compared in patients with cerebral small vessels disease (CSVD) (n = 11), multiple sclerosis (MS) (n = 12) and healthy controls (n = 11) at 2-4-6 h after MLT. In MLT-treated subjects, the activation of thiol exchange reactions provoked significant changes over time in redox species concentrations of Cys, Hcy, and albumin. Significant differences between controls and pathological groups were also observed. In non-methionine-treated subjects, total Cys concentrations, tHcy and thiol-protein mixed disulfides (CSS-ALB, HSS-ALB) of CSVD patients were higher than controls. After MLT, all groups displayed significant cystine (CSSC) increases and CSS-ALB decreases, that in pathological groups were significantly higher than controls. These data would confirm the Cys regulatory role on the homocysteinemia; they also explain that the Cys-Hcy mixed disulfide excretion is an important point of hyperhomocysteinemia control. Moreover, in all groups after MLT, significant increases in albumin concentrations, named total albumin (tALB) and measured as sum of HS-ALB (spectrophometric), and XSS-ALB (assayed at HPLC) were observed. tALB increases, more pronounced in healthy than in the pathological subjects, could indicate alterations of albumin equilibria between plasma and other extracellular spaces, whose toxicological consequences deserve further studies.

Prognostic value of volume-based measurements on (11)C-methionine PET in glioma patients.

PURPOSE: (11)C-methionine (MET) PET is an established diagnostic tool for glioma. Studies have suggested that MET uptake intensity in the tumor is a useful index for predicting patient outcome. Because MET uptake is known to reflect tumor expansion more accurately than MRI, we aimed to elucidate the association between volume-based tumor measurements and patient prognosis. METHODS: The study population comprised 52 patients with newly diagnosed glioma who underwent PET scanning 20 min after injection of 370 MBq MET. The tumor was contoured using a threshold of 1.3 times the activity of the contralateral normal cortex. Metabolic tumor volume (MTV) was defined as the total volume within the boundary. Total lesion methionine uptake (TLMU) was defined as MTV times the mean standardized uptake value (SUVmean) within the boundary. The tumor-to-normal ratio (TNR), calculated as the maximum standardized uptake value (SUVmax) divided by the contralateral reference value, was also recorded. All patients underwent surgery (biopsy or tumor resection) targeting the tissue with high MET uptake. The Kaplan-Meier method was used to estimate the predictive value of each measurement. RESULTS: Grade II tumor was diagnosed in 12 patients (3 diffuse astrocytoma, 2 oligodendroglioma, and 7 oligoastrocytoma), grade III in 18 patients (8 anaplastic astrocytoma, 6 anaplastic oligodendroglioma, and 4 anaplastic oligoastrocytoma), and grade IV in 22 patients (all glioblastoma). TNR, MTV and TLMU were 3.1 ± 1.2, 51.6 ± 49.9 ml and 147.7 ± 153.3 ml, respectively. None of the three measurements was able to categorize the glioma patients in terms of survival when all patients were analyzed. However, when only patients with astrocytic tumor (N = 33) were analyzed (i.e., when those with oligodendroglial components were excluded), MTV and TLMU successfully predicted patient outcome with higher values associated with a poorer prognosis (P < 0.05 and P < 0.01, respectively), while the predictive ability of TNR did not reach statistical significance (P = NS). CONCLUSION: MTV and TLMU may be useful for predicting outcome in patients with astrocytic tumor.

Metal based imaging probes of DO3A-Act-Met for LAT1 mediated methionine specific tumors: synthesis and preclinical evaluation.

PURPOSE: Tumor cells are known to have an elevated requirement for methionine due to increased protein synthesis and trans-methylation reactions. A methionine based macrocyclic tumor imaging system, DO3A-Act-Met, has been designed to provide a novel platform for tumor imaging via modalities, PET/MRI using metal ions, (68)Ga and (157)Gd. METHODS: Synthesis of DO3A-Act-Met was confirmed through NMR and mass spectrometric techniques. Cytotoxicity of complexes was evaluated using MTT assay whereas receptor binding and trans-stimulation studies were performed on EAT and U-87 MG cell lines. Tumor targeting was assessed through imaging and biodistribution experiments on U-87 MG xenograft model. RESULTS: DO3A-Act-Met was synthesized and radiolabeled with (68)Ga in high radiochemical purity (85-92%). The receptor binding assay on EAT cells predicted high binding affinity with Kd of 0.78 nM. Efflux of (35)S-L-methionine trans-stimulated by extracellular DO3A-Act-Met on U-87MG cells suggested an L-system transport. MR studies revealed a longitudinal relaxivity of 4.35 mM(-1) s(-1) for Gd-DO3A-Act-Met and a 25% signal enhancement at tumor site. The biodistribution studies in U-87MG xenografts validated tumor specificity. CONCLUSION: DO3A-Act-Met, a methionine conjugated probe is a promising agent for targeted molecular imaging, exhibiting high specificity towards tumor owing to its essential role in proliferation of cancer cells mediated through LAT1.

A comparison study of dynamic [18F]Alfatide II imaging and [11C]MET in orthotopic rat models of glioblastoma.

PURPOSE: To investigate and compare the dynamic positron emission tomography (PET) imaging with [18F]Alfatide II Imaging and [11C]Methionine ([11C]MET) in orthotopic rat models of glioblastoma multiforme (GBM), and to assess the utility of [18F]Alfatide II in detecting and evaluating neoangiogenesis in GBM. METHODS: [18F]Alfatide II and [11C]MET were injected into the orthotopic GBM rat models (n = 20, C6 glioma cells), followed by dynamic PET/MR scans 21 days after surgery of tumor implantation. On the PET image with both radiotracers, the MRI-based volume-of-interest (VOI) was manually delineated encompassing glioblastoma. Time-activity curves were expressed as tumor-to-normal brain ratio (TNR) parameters and PET pharmacokinetic modeling (PKM) performed using 2-tissue-compartment models (2TCM). Immunofluorescent staining (IFS), western blotting and blocking experiment of tumor tissue were performed for the validation. RESULTS: Compared to 11C-MET, [18F]Alfatide II presented a persistent accumulation in the tumor, albeit with a slightly lower SUVmean of 0.79 ± 0.25, and a reduced uptake in the contralateral normal brain tissue, respectively. This resulted in a markedly higher tumor-to-normal brain ratio (TNR) of 18.22 ± 1.91. The time-activity curve (TACs) showed a significant increase in radioactive uptake in tumor tissue, followed by a plateau phase up to 60 min for [18F]Alfatide II (time to peak:255 s) and 40 min for [11C]MET (time to peak:135 s) post injection. PKM confirmed significantly higher K1 (0.23/0.07) and K3 (0.26/0.09) in the tumor region compared to the normal brain with [18F]Alfatide II. Compared to [11C]MET imaging, PKM confirmed both significantly higher K1/K2 (1.24 ± 0.79/1.05 ± 0.39) and K3/K4 (11.93 ± 4.28/3.89 ± 1.29) in the tumor region with [18F]Alfatide II. IFS confirmed significant expression of integrin and tumor vascularization in tumor region. CONCLUSION: [18F]Alfatide II demonstrates potential in imaging tumor-associated neovascularization in the context of glioblastoma multiforme (GBM), suggesting its utility as a tool for further exploration in neovascular characterization.

Relationship between multi-pool model-based chemical exchange saturation transfer imaging, intravoxel incoherent motion MRI, and 11C-methionine uptake on PET/CT in patients with gliomas.

PURPOSE: Magnetization transfer ratio asymmetry (MTRasym) analysis is used for chemical exchange saturation transfer (CEST) in patients with gliomas; however, this approach has limitations. CEST imaging using a multi-pool model (MPM) may allow a more detailed assessment of gliomas; however, its mechanism remains unknown. This study aimed to assess the relationship between CEST imaging by MPM, intravoxel incoherent motion (IVIM), and 11C-methionine (11C-MET) uptake on positron emission tomography/computed tomography (PET/CT) to clarify the clinical significance of CEST imaging using MPM in gliomas. METHODS: This retrospective study included 17 patients with gliomas who underwent 11C-MET PET/CT at our institution between January 2020 and January 2022. Two-dimensional axial CEST imaging was conducted using single-shot fast-spin echo acquisition at 3 T. The apparent diffusion coefficient (ADC), true diffusion coefficient (D), pseudo-diffusion coefficient (D*), f, MTRasym (3.5 ppm), parameters of MPM-based CEST imaging, and tumor-to-contralateral normal brain tissue (T/N) ratio were calculated using a region-of-interest analysis. Shapiro-Wilk test, weighted kappa coefficient, and Spearman's rank correlation coefficients were used for statistical analysis. RESULTS: Significant correlations were found between APT_T1 and T/N ratio (ρ = 0.87, p < 0.001), APT_T2 and T/N ratio (ρ = 0.47, p < 0.05), MTRasym and T/N ratio (ρ = 0.55, p < 0.01), and T2/T1 and T/N ratio (ρ = -0.36, p < 0.05). Furthermore, significant correlations were observed between APT_T1 and ADC (ρ = -0.67, p < 0.001), APT_T1 and D (ρ = -0.70, p < 0.001), APT_T2 and D* (ρ = -0.45, p < 0.05), and T2/T1 and D (ρ = 0.39, p < 0.05). CONCLUSION: These preliminary findings indicate that MPM-based CEST imaging parameters correlate with IVIM and 11C-MET uptake on PET/CT in patients with gliomas. In particular, the new parameter APT_T1 correlated more strongly with 11C-MET uptake compared to the traditional CEST parameter MTRasym.

Availability to lactating dairy cows of methionine added to soy lecithins and mixed with a mechanically extracted soybean meal.

We evaluated a product containing methionine mixed with soy lecithins and added to a mechanically extracted soybean meal (meSBM-Met). Lactational responses of cows, plasma methionine concentrations, and in vitro degradation of methionine were measured. Twenty-five Holstein cows were used in a replicated 5 × 5 Latin square design and fed a diet designed to be deficient in methionine or the same diet supplemented either with 4.2 or 8.3g/d of supplemental methionine from a ruminally protected source or with 2.7 or 5.3g/d of supplemental methionine from meSBM-Met. All diets were formulated to provide adequate amounts of metabolizable lysine. Concentration of milk true protein was greater when methionine was provided by the ruminally protected methionine than by meSBM-Met, but milk protein yield was not affected by treatment. Milk yields and concentrations and yields of fat, lactose, solids-not-fat, and milk urea nitrogen were not affected by supplemental methionine. Body condition scores increased linearly when methionine from meSBM-Met was supplemented, but responses were quadratic when methionine was provided from a ruminally protected source. Nitrogen retention was not affected by supplemental methionine. Plasma methionine increased linearly when methionine was supplemented from a ruminally protected source, but plasma methionine concentrations did not differ from the control when supplemental methionine from meSBM-Met was provided. In vitro degradation of supplemental methionine from meSBM-Met was complete within 3h. Data suggest that meSBM-Met provides negligible amounts of metabolizable methionine to dairy cows, and this is likely related to extensive ruminal destruction of methionine; however, cow body condition may be improved by ruminally available methionine provided by meSBM-Met.

Usefulness of FDG, MET and FLT-PET studies for the management of human gliomas.

The use of positron imaging agents such as FDG, MET, and FLT is expected to lead the way for novel applications toward efficient malignancy grading and treatment of gliomas. In this study, the usefulness of FDG, MET and FLT-PET images was retrospectively reviewed by comparing their histopathological findings. FDG, MET, and FLT-PET were performed in 27 patients with WHO grade IV, 15 patients with WHO grade III, and 12 patients with WHO grade II during 5.5 years. The resulting PET images were compared by measuring SUVs and T/N ratios (tumor to normal tissue ratios). Although there were no significant differences in FDG-PET, there were significant differences in the T/N ratios in the MET-PET between WHO grades II and IV and in the FLT-PET between the WHO grades III and IV. In glioblastoma patients, the SUVs of the areas depicted by MRI in the MET-PET were different from those SUVs in the FLT-PET. Importantly, the areas with high SUVs in both MET-PET and FLT-PET were also high in Ki-67 index and were histologically highly malignant. PET imaging is a noninvasive modality that is useful in determining a tumor area for removal as well as improving preoperative diagnosis for gliomas.

Is D-methionine bioavailable to the dairy cow?

Rumen-protected forms of Met contain an equimolar mixture of the D- and L-isomers. Only L-Met can be directly used for protein synthesis, but it is unclear how much of the D-isomer can be transformed into L-Met in ruminants. Four lactating dairy cows, with an average milk yield of 32.4 kg/d, received a basal diet (12.5% crude protein, supplying 1,718 g/d of metabolizable protein) in 12 equal meals per day plus an abomasal infusion of amino acids (590 g/d, casein profile without Met). They were used in 3 consecutive studies to determine utilization of D-Met. First, the cows each received portal vein infusions for d of 5, 10, or 15 g/d of DL-Met in a Youden square. On the last day of each period, 6 arterial samples were collected at 45-min intervals. Concentrations of L- and D-Met were determined on a chiral column by gas chromatography-mass spectrometry. Portal infusion of 5, 10, and 15 g/d of DL-Met increased plasma total Met concentrations (19.7, 25.0, and 34.4±0.6 µM) and the proportion of Met as D (19.4, 30.5, and 37.3±0.7%). The fractional removal of D-Met was 6 to 7 times lower than the fractional removal of L-Met, with mean half-lives of 52 versus 8 min, respectively. Second, the same cows were infused for 8 h with L[methyl-(2)H(3)]Met at 1.3 mmol/h; at 2 h, cows received a bolus injection i.v. of D-[1-(13)C]Met (6.8 mmol), and arterial samples were collected after 10, 20, 30, 40, 60, 90, 120, 150, 180, 240, 300, 360, 420, and 480 min. Expressed relative to L-[(12)C]Met; that is, as tracer:tracee ratios, enrichments of plasma D-[1-(13)C]Met and L-[1-(13)C]Met averaged 1.77±0.14 and 0.144±0.026, respectively, 10 min after the bolus injection and declined exponentially thereafter. A minimum of 75±3% of the D-[1-(13)C]Met was transformed into L-[1-(13)C]Met. Third, the cows received, in a crossover design, an abomasal infusion for D of either DL-Met or L-Met (1g/d) and, on the last day of each experimental period, blood samples were collected simultaneously from arterial, portal, hepatic, and mammary vessels. Arterial total Met concentrations were higher with DL- versus L-Met infusions (37.4 vs. 25.4±0.5 µM), with 37.1±5.0% as D-Met. The mammary gland did not extract any D-Met. Hepatic removal of D-Met was observed, but was numerically lower than the fractional extraction of L-Met. In conclusion, much of the D-Met is transformed into L-Met by the dairy cow but at a slow rate. No uptake of D-Met occurs across the mammary gland but L-Met synthesized from the D-isomer elsewhere in the body can be utilized for milk protein synthesis.

Prognostic value of 11C-methionine volume-based PET parameters in IDH wild type glioblastoma.

PURPOSE: 11C-Methionine (11C-MET) PET prognostication of isocitrate dehydrogenase (IDH) wild type glioblastomas is inadequate as conventional parameters such as standardized uptake value (SUV) do not adequately reflect tumor heterogeneity. We retrospectively evaluated whether volume-based parameters such as metabolic tumor volume (MTV) and total lesion methionine metabolism (TLMM) outperformed SUV for survival correlation in patients with IDH wild type glioblastomas. METHODS: Thirteen IDH wild type glioblastoma patients underwent preoperative 11C-MET PET. Both SUV-based parameters and volume-based parameters were calculated for each lesion. Kaplan-Meier curves with log-rank testing and Cox regression analysis were used for correlation between PET parameters and overall survival. RESULTS: Median overall survival for the entire cohort was 393 days. MTV (HR 1.136, p = 0.007) and TLMM (HR 1.022, p = 0.030) were inversely correlated with overall survival. SUV-based 11C-MET PET parameters did not show a correlation with survival. In a paired analysis with other clinical parameters including age and radiotherapy dose, MTV and TLMM were found to be independent factors. CONCLUSIONS: MTV and TLMM, and not SUV, significantly correlate with overall survival in patients with IDH wild type glioblastomas. The incorporation of volume-based 11C-MET PET parameters may lead to a better outcome prediction for this heterogeneous patient population.